National Geographic : 2002 Nov
UPITOR (AtorvastatinCalcium)Tablets Brief Summary of Prescribing Information CONTRAINDICATIONS: Activeliverdisease or unexplainedpersistentelevations ofserum transaminases. Hypersensitivityto anycomponentofthismedication.PregnancyandLactation-Atherosclerosis is a chronicprocess and discontinuationof lipid-loweringdrugs duringpregnancyshould have littleimpact on the outcome oflong-termtherapy of primaryhypercholesterolemia.Cholesteroland other products of cholesterolbiosynthesis are essential componentsforfetal development(includingsynthesis ofsteroids and cell membranes).Since HMG-CoAreductase inhibitorsdecrease cholesterolsynthesis and possibly the synthesis of other biologicallyactive substances derivedfrom cholesterol,they may cause fetalharm when administeredto pregnant women.Therefore,HMG-CoAreductase inhibitorsare contraindicated duringpregnancyand innursingmothers. ATORVASTATIN SHOULDBEADMINISTERED TOWOMENOF CHILDBEARING AGEONLYWHENSUCHPATIENTSAREHIGHLYUNLIKELY TOCONCEIVEANDHAVE BEENINFORMEDOFTHEPOTENTIALHAZARDS.Ifthe patient becomes pregnant whiletaking this drug, therapy shouldbe discontinued andthe patient apprisedof the potential hazardto the fetus. WARNINGS:LiverDysfunction- HMG-CoAreductase inhibitors,likesome other lipid-loweringtherapies, have been associated withbiochemicalabnormalitiesofliverfunction.Persistentelevations(>3timesthe upperlimitof normal[ULN]occurringon2 or moreoccasions) inserumtransaminasesoccurredin 0.7% of patientswho receivedatorvastatininclinical trials.Theincidenceof theseabnormalitieswas 02%, 02%,0.6%,and2.3%for10.20,40, and80mg,respectively.One patient in clinicaltrialsdeveloped jaun dice. Increases in liverfunctiontests (LFT)inother patients were not associated withjaundiceor other clinical signsor symptoms.Upondose reduction,druginterruption,or discontinuation,transaminase levels returned to or near pretreatmentlevels withoutsequelae. Eighteenof 30patients withpersistent LFTeleva tionscontinued treatment witha reduceddose ofatorvastatin.Itis recommendedthat liverfunctiontests be performedpriorto andat 12weeks followingboththe initiationof therapyandany elevationof dose, andperiodicallyleg, semiannually)thereafter.Uver enzymechanges generallyoccur inthe first 3 months of treatmentwith atorvastatin.Patients who developincreased transaminase levelsshould be monitored untilthe abnormalitiesresolve. Shouldan increase inALTor ASTof >3times ULNpersist, reductionof dose or withdrawalof atorvastatinis recommended. Atorvastatinshouldbe used with caution inpatients who consumesubstantial quantitiesof alcohol and/or have a historyof liverdisease. Activeliverdisease or unexplained persistenttransaminase elevationsare contraindicationsto the use of atorvastatin(see CONTRAINDICATIONS). SkeletalMuscle- Rarecases of rhabdomyolysiswith acute renalfailuresec ondaryto myoglobinuriahavebeen reportedwith trtatinandwith otherdrugsin thisclass. Uncomplicatedmyalgiahas been reported inatorvastatin-treated patients(see ADVERSEREACTIONS). Myopathy,defined as muscle aches or muscleweakness in conjunctionwith increases increatine phos phokinase (CPKIvalues>10timesULN,should beconsidered inany patient withdiffusemyalgias,muscle tenderness orweakness, and/or marked elevationof CPK.Patientsshould beadvised to reportpromptly unexplainedmuscle pain,tenderness or weakness, particularlyif accompaniedby malaise orfever. Atorvastatintherapy shouldbe discontinued ifmarkedlyelevated CPKlevels occur or myopathyis diag nosed or suspected. The risk of myopathyduringtreatmentwithdrugs inthis class is increasedwith con current administrationofcyclosporine,fibricacid derivatives,erythromycin,niacin, or azole antifungals. Physicians consideringcombined therapywithatorvastatin and fibricacid derivatives,erythromycin, immunosuppressivedrugs, azole antifungals,or lipid-loweringdoses of niacinshould carefullyweighthe potential benefitsand risks and should carefullymonitor patients forany signs or symptomsof muscle pain,tenderness, or weakness, particularlyduringthe initialmonths oftherapy and duringany periodsof upward dosage titrationof either drug. Periodiccreatinephosphokinase (CPK)determinationsmay be considered insuch situations, butthere is no assurance that such monitoringwillpreventthe occurrence of severe myopathy.Atorvastatintherapyshouldbetemporarilywithheld or discontinuedin anypatient with an acute,serious conditionsuggestive ofa myopathyor havinga risk factorpredisposingtothe developmentof renalfailuresecondaryto rhabdomyolysisleg,severe acute infection,hypotension, majorsurgery,trauma,severe metabolicendocrineandelectrolytedisorders,anduncontrolledseizures). PRECAUTIONS: General- Beforeinstitutingtherapywith atorvastatin,an attemptshouldbe madeto con trolhypercholsteroemia withappropriate diet exercise, and weight reductioninobese patients, and to treat other underlyingmedicalproblems (see INDICATIONSANDUSAGEinfullprescribinginformation). Informationfor Patients- Patients shouldbe advised to report promptlyunexplained musclepain,ten derness, or weakness, particularlyifaccompanied bymalaiseor fever. DrugInteractions- The risk of myopathyduringtreatmentwith drugsof this class is increasedwithconcurrent administrationof cyclosporine,fibricacid derivatives,niacin (nicotinicacid),erythromycin,azoleantifungals(see WARN INGS,SkeletalMuscle).Antacid:When atorvastatinand Maalox TC suspensionwere coadministered, plasma concentrationsof atrti er apxiatoratatin decreasedpprimately 35%.However,LDL-Creductionwas not altered.Antipyine: Because atorvastatindoes not affectthe pharmacokineticsof antipyrine,interactions withother drugs metabolizedvia the same cytochrome isozymesare not expected. ColestipolPlasma concentrationsof atorvastatindecreased approximately25%when colestipoland atorvastatinwere coad ministered.However,LDL-Creductionwas greater when atorvastatinand colestipolwere coadministered than when either drugwas givenalone.Ctimetdine:Atorvastatinplasma concentrationsand LDL-Creduc tion were not altered by coadministrationofcimetidine.DigoxinWhenmultipledoses ofatorvastatinand digoxinwere coadministered,steady-state plasmadigoxinconcentrationsincreasedby approximately 20%.Patientstaking digoxinshould be monitoredappropriately.Erythromycin:Inhealthyindividuals,plas ma concentrationsof atorvastatinincreased approximately40%withcoadministrationof atorvastatinand erythromycin,a known inhibitorof cytochromeP4503A4(see WARNINGS,SkeletalMuscle).Oral Contraceptives:Coadmnistrationof atorvastatinand an oral contraceptiveincreased AUCvaluesfor norethindroneand ethinylestradiolby approximately30%and 20%.These increases shouldbe considered when selecting an oral contraceptivefor a woman taking atorvastatin.Waarlan:Atorvastatinhad no clinicallysignificanteffect on prothrombintimewhen administeredto patients receivingchronicwarfarin treatmentEndocrineFunction- HMG-CoAreductase inhibitorsinterferewithcholesterolsynthesisand theoreticallymightblunttadrenal and/or gonadalsteroid production.Clinicalstudies have shownthat ator vastatin does not reduce basal plasmacortisolconcentrationor impairadrenal reserve. Theeffects of HMG-CoAreductase inhibitorsonmalefertilityhave not been studied inadequate numbersof patients. Theeffects, ifany, on the pituitary-gonadalaxisin premenopausalwomen are unknown.Cautionshould be exercised ifan HMG-CoAreductase inhibitoris administeredconcomitantlywithdrugsthat maydecrease the levels or activityof endogenoussteroidhormones,such as ketoconazole,spironolactone,and cimti dine.CNSToxicity- Brainhemorrhagewas seen ina female dog treated for3 months at 120mg/kg/day. Brainhemorrhageand optic nervevacuolationwere seen inanother female dog that was sacrificed in moribundconditionafter 11weeks ofescalating doses upto 280 mg/kg/day.The120mg/kgdose resultedin a systemic exposure approximately16timesthe humanplasma area-under-the-curve(AUC,0-24hours) based onthe maximumhuman dose of80 mg/day.A singletonic convulsionwas seen ineach of2 male dogs (onetreated at 10mgkg/day and one at 120mg/kg/day)ina 2-year study.No CNSlesionshave been observed inmice after chronictreatmentfor upto 2 years at doses up to 400mg/kg/dy or inrats at doses up to 100mg/kg/day.These doses were 6 to 11times(mouse)and 8 to 16times(rat) the humanAUC(0-24 based onthe maximumrecommendedhuman dose of 80mg/day.CNS vascular lesions,characterized by perivascular hemorrhages,edema,and mononuclearcell infiltrationof perivascularspaces, have been observed indogs treated withothereer membersof this class.A chemicallysimilardruginthis class pro duced optic nervedegenration (Walleriandegenerationof retinogeniculatefibers) inclinicallynormal dogs in a dose-dependent fashion at a dose that produced plasmadrug levels about 30times higher than the mean drug levelinhumans taking the highest recommended dose. Carcinogenesis, Mutagenesis,Impairmentof Fertility- Ina 2-year carcinogenicitystudyinrats at dose levels of 10,30, and 100 mg/kg/day,2 raretumorswere found in muscle inhigh-dosefemales:inone, there was a rhab domyosarcoma and, inanother,there was a fibrosarcoma.Thisdose represents a plasma AUC(0-24) valueof approximately16timesthe meanhuman plasma drug exposureafter an 80mg oraldose. A 2 year carcinogenicitystudyin micegiven100,200,or 400mg/kg/dayresultedin a significantincrease in liveradenomas inhigh-dose males and livercarcinomas inhigh-dosefemales.These findingsoccurred at plasma AUC10-24)values of approximately6 timesthe mean human plasma drug exposure after an 80 mg oraldose. In vitro,atorvastatinwas not mutagenicor clastogenic in the followingtests withand without metabolic activation:the Ames test withSalmonellatyphimurium and Escherichiacoli,the HGPRTforwardmutationassay in Chinesehamster lungcells, and the chromosomalaberration assay inChinese hamster lung cells.Atorvastatin was negativein the in vivomouse micronucleustest Studies inrats performed at doses up to 175mg/kg(15times the human exposure)produced no changes in fertility.There was aplasia and aspermia inthe epididymisof 2 of 10rats treated with 100mg/kg/dayof atorvastatin for3 months(16times the human AUCat the 80mg dose);testis weights were significantly lower at 30 and 100mg/kgand epididymalweight was lowerat 100mg/kg.Male rats given100mg/kg/dayfor 11weeks priorto matinghad decreased sperm motility,spermatidhead concentration,and increased abnormalsperm. Atorvastatincaused no adverse effects on semen parameters, or reproductiveorgan histopathologyindogs givendoses of 10,40,or 120mg/kgfor two years.Pregnancy- PregnancyCategoryX See CONTRAINDICATIONS. Safetyinpregnantwomenhas notbeenestablished.Atorvastatincrosses the ratplacentaandreachesa levelinfetal liverequivalenttothatof maternalplasma.Atorvastatinwas not teratogenicin ratsat doses upto 300 mg/kg/dayor inrabbitsat doses up to 100mg/kg/day.These doses resultedin multiplesof about30times(rat)or 20times(rabbit)thehumanexposurebasedon surfacearea (mg/m).Ina studyin rats given20,100,or 225mg/kg/day,fromgestationday7 throughto lactationday21 (weaning),therewas decreasedpupsurvivalat birth,neonate,weaning,andmaturityinpups ofmothers dosed with225mg/kg/day.Bodyweightwas decreasedondays4 and 21inpupsof mothersdosedat 100 mg/kg/day;pupbodyweightwas decreasedatbirthandatdays4,21, and91at 225mg/kg/day.Pupdevel opmentwas delayed(rotorodperformanceat 100mg/kg/dayandacousticstartleat225 mg/kg/day;pinnae detachmentandeye openingat225 mg/kg/day).These doses correspondto 6 times (100mg/kg)and22 times (225mg/kg)the humanAUCat 80mg/day.Rarereportsof congenitalanomalieshavebeenreceived followingintrauterineexposuretoHMG-CoAreductaseinhibitors.Therehas beenone reportof severe con genitalbonydeformity,tracheo-esophagealfistula,andanalatresia(VATERassociation)in a babybor to a womanwhotook lovastatinwithdextroamphetamine sulfateduringthefirsttrimesterof pregnancy.UPITOR shouldbe administeredto womenofchild-bearingpotentialonlywhen such patients arehighlyunlikelyto conceiveandhavebeeninformedofthe potentialhazards.Ifthe womanbecomes pregnantwhiletaking LIPITOR,itshouldbe discontinuedandthepatientadvisedagainas to thepotentialhazardsto thefetus. NursingMothers- Nursingrat pupshadplasmaandliverdruglevels of50%and40%,respectively,of that intheirmother'smilk.Becauseofthe potentialfor adversereactionsinnursinginfants,womentaking LIPITORshouldnotbreastfeed(see CONTRAINDICATIONS). PediatricUse - Treatmentexperienceina pediatricpopulationis limitedto doses of LIPITORupto 80mg/dayfor1year in8 patientswith homozygous FH.No clinicalor biochemicalabnormalitieswere reportedinthese patients.Noneof thesepatientswas below9 years of age. GeriatricUse - The safetyandefficacyof atorvastatin(10-80mg)inthegeriatric population(>65years of age)was evaluatedinthe ACCESSstudy.Inthis 54-weekopen-labeltrial1,958 patientsinitiatedtherapywithatorvastatin10mg.Ofthese,835were elderly(>65years)and1,123were non-elderly.Themeanchangein LDL-Cfrombaselineafter6 weeks oftreatmentwithatorvastatin 10mg was -38 .2%inthe elderlypatientsversus -34.6%inthe non-elderlygroup.The ratesof discontinuationdue to adverseeventswere similarbetweenthetwo agegroups.Therewere no differencesin clinicallyrele vantlaboratoryabnormalitiesbetweenthe age groups. ADVERSEREACTIONS: LIPITORis generallywell tolerated.Adversereactionshaveusuallybeenmildand transient Incontrolledclinicalstudiesof 2502patients,<2%of patientswere discontinueddueto adverse experiencesattributableto atorvastatin. The most frequent adverseevents thoughtto be relatedto ator vastatinwere constipation,flatulence,dyspepsia,andabdominalpain.ClinicalAdverseExperiences Adverseexperiencesreportedin>2% of patientsin placebo-controlledclinicalstudiesof atorvastatin, regardlessof causalityassessment,are shownin thefollowingtable. AdverseEventsin Placebo-ControlledStudies (%of Patients) BODYSYSTEM Placebo Atorvastatin Atorvastatin Atorvastatin Atorvastatin AdverseEvent 10mg 20mg 40mg 80mg N=270 N=863 N=36 N=79 N=94 BODYAS AWHOLE Infection 10.0 10.3 2.8 10.1 7.4 Headache 7.0 5.4 16.7 2.5 6.4 AccidentalInjury 3.7 4.2 0.0 1.3 3.2 FluSyndrome 1.9 2.2 0.0 2.5 32 AbdominalPain 0.7 2.8 0.0 3.8 2.1 BackPain 3.0 2.8 0.0 3.8 1.1 AllergicReaction 2.6 0.9 2.8 1.3 0.0 Asthenia 1.9 2.2 0.0 3.8 0.0 DIGESTIVE SYSTEM Constipation 1.8 21 0.0 2.5 1.1 Diarrhea 1.5 27 0.0 3.8 5.3 Dyspepsia 4.1 2.3 2.8 13 2.1 Flatulence 3.3 2.1 28 13 1.1 RESPIRATORY SYSTEM Sinusitis 2.6 2.8 0.0 2.5 6.4 Pharyngitis 1.5 2.5 0.0 13 2.1 SKINANDAPPENDAGES Rash 0.7 3.9 2.8 3.8 1.1 MUSCULOSKELETAL SYSTEM Arthralgia 1.5 2.0 0.0 5.1 0.0 Myalgia 1.1 3.2 5.6 1.3 0.0 The followingadverseeventswere reported,regardlessof causalityassessmentin patientstreatedwith atorvastatininclinicaltrials.Theevents initalicsoccurredin>2%of patientsandtheevents inplaintype occurredin<2%ofpatients. Bodyas a Whole:Chest pain,face edema,fever,neckrigidity,malaise,photosensitivityreaction,general izededema.DigestiveSystem Nausea, gastroenteritis,liverfunctiontests abnormal,colitis,vomiting, gastritis,dry mouth,rectalhemorrhage,esophagitis,eructation,glossitis,mouthulceration,anorexia, increasedappetite,stomatitis,biliarypain, cheilitis,duodenalulcer,dysphagia,enteritis,melena,gum hemorrhage,stomachulcer,tenesmus,ulcerativestomatitis,hepatitis,pancreatitis,cholestaticjaundice. RespiratorySystem: Bronchitis,rhinitis,pneumonia,dyspnea,asthma,epistaxis.Nervous System Insomnia,dizziness,paresthesia,somnolence,amnesia,abnormaldreams,libidodecreased, emotional lability,incoordination,peripheralneuropathy,torticollis,facial paralysis,hyperkinesia,depression, hypesthesia,hypertonia.MusculoskeletalSystne Arthritis,legcramps,bursitis,tenosynovitis,myasthe nia,tendinouscontracture,myositis.SkinandAppendages Pruritus,contactdermatitis,alopecia,dryskin, sweating,acne,urticaria,eczema,seborrhea,skinulcer. hUgenitelSystem: Urinarytract infection,urinary frequency,cystitis,hematuria,impotence,dysuria,kidneycalculus,nocturia,epididymitis,fibrocystic breast,vaginalhemorrhage,albuminuria,breastenlargementmetrorrhagia,nephritis,urinaryinconti nence, urinaryretention,urinaryurgency,abnormalejaculation,uterinehemorrhage.SpecialSenses Amblyopia,tinnitus,dryeyes, refractiondisorder,eye hemorrhage,deafness, glaucoma,parosmia,taste loss,taste perversion.CardiovascularSystem:Palpitation, vasodilatation,syncope,migraine,postural hypotension,phlebitis,arrhythmia,anginapectoris,hypertension.Metabolicand Nutitinal Disorders Peripheraledema,hyperglycemia,creatinephosphokinaseincreased,gout weightgain, hypoglycemia. HemicandLymphaticSystem Ecchymosis,anemia,lymphadenopathy,thrombocytopenia, petechia. PolsintroductionReports-Adverse events associatedwith LIPITORtherapyreportedsince market introduction, that arenotlistedabove, regardlessof causalityassessment, includethe following:anaphy laxis,angioneuroticedema,bullousrashes(includingerythemamultiforme,Stevens-Johnsonsyndrome, andtoxicepidermalnecrolysis),andrhabdomyolysis. OVERDOSAGE: Thereis no specifictreatmentforatorvastatin overdosage.Inthe event of anoverdose, the patientshouldbe treatedsymptomatically, andsupportivemeasuresinstitutedas required.Dueto extensivedrugbindingto plasmaproteins,hemodialysisis notexpectedto significantlyenhance atorvastatinclearance. Please see fullprescribinginformationformoreinformationaboutUPITOR. 1] only Pharmaceuticals Manufactured by: Pfizer IrelandPharmaceuticals Dublin,Ireland Distributedby: Parke-Davis DivisionofPfizerInc,NY,NY1017 MADEIN PUERTORICO 01998-'02Pfizer Ireland Rev. 1,April2002 -A LP106204F © 2002 Pfjzer InC. All rjghtS roSorved, U.S. PhartasaceraBiemle LP106204F © 2002 Pfizer Inc. M U.S. Pharmaceuticals Allrights reserved.