National Geographic : 2003 Mar
Plas read thi sumar careully an hnakyordco botNXU Noadetsmn ca proid al 0h ifrato neede to prescibe adrg Thi arismn doe no take th pace of N OX I U il (esomeprazole magnesium) 20-MG, 40-MG Delayed-Release Capsules BRIEF SUMMARY Beforeprescribing NEXIUM, please see fullPrescribing Information. INDICATIONS AND USAGE NEXIUM is indicatedfor the short-term treatment (4to 8 weeks) inthe healingandsymptomatic resolution ofdiagnostically confirmed erosive esophagitis. CONTRAINDICATIONS NEXIUM is contraindicated in patients with knownhypersensitivity to anycomponent ofthe formulation or to substituted benzimida zoles. PRECAUTIONS Symptomatic response to therapy withNEXIUMdoes not preclude the presence ofgastric malignancy. Atrophicgastritis has beennotedoccasionally in gastric corpus biopsies frompatients treated long-term withomeprazole, ofwhich NEXIUMis an enantiomer. Information for Patients: NEXIUM Delayed-Release Capsules should betakenat least one hour beforemeals. Forpatients whohavedifficulty swallowing capsules, onetablespoon ofapplesauce canbeadded to an empty bowlandthe NEXIUM Delayed-Release Capsuleopened, andthe pellets carefully emptied onto the apple sauce. Thepellets should be mixedwiththe applesauce andthen swallowedimmediately. Theapplesauce used should notbehot andshould besoft enough to be swallowed without chewing.Thepellets should notbechewedorcrushed. Thepellet/applesauce mixtureshould not be stored for future use. Antacidsmaybe used whiletakingNEXIUM.Drug Interactions: Esomeprazole is extensively metabolizedin the liverbyCYP2C19and CYP3A4.Invitro andin vivostudies haveshown that esomeprazole is notlikelyto inhibit CYPs1A2,2A6,2C9,206, 2E1and3A4.Noclinically relevantinteractions withdrugs metab olizedbythese CYPenzymes wouldbeexpected. Druginteraction studies haveshown that esomeprazole does nothaveanyclinically significant interactions withphenytoin, warfarin, quinidine,clarithromycin or amoxicillin. Esomeprazole maypotentiallyinterferewith CYP2C19, the major esomeprazole metabolizing enzyme.Coadministration ofesomeprazole 30 mganddiazepam, a CYP2C19substrate, resulted in a 45% decrease in clearance of diazepam.Increased plasma levelsofdiazepamwereobserved 12hours afterdosing and onwards. However, at that time, the plasma levelsofdiazepam werebelowthe therapeutic interval,andthus this interaction is unlikelytobe ofclinicalrelevance. Esomeprazole inhibits gastric acidsecretion. Therefore, esomeprazole mayinterferewiththe absorption ofdrugs where gastric pHisan important determinant ofbioavailability (eg,ketoconazole, ironsalts anddigoxin).Coadministration oforalcontraceptives, diazepam, phenytoin, orquinidine did not seem to change the pharmacokinetic profileofesomeprazole. Carcinogenesis, Mutagenesis, Impairment of Fertility: Thecarcinogenic potential ofesomepra zolewas assessed usingomeprazole studies. Intwo24-month oralcarcinogenicity studies inrats, omeprazole atdailydoses of1.7,3.4,13.8, 44.0 and140.8 mg/kg/day (about 0.7 to 57times the human dose of20mg/day expressed ona bodysurface area basis) produced gastric ECLcellcarcinoids ina dose-related manner in bothmaleandfemalerats;the inci dence ofthis effectwas markedlyhigher infemalerats, whichhadhigher bloodlevelsof omeprazole. Gastriccarcinoids seldom occur in the untreated rat.Inaddition,ECLcell hyperplasia was present inalltreated groups ofbothsexes. Inone ofthese studies, female rats weretreated with13.8 mgomeprazole/kg/day (about 5.6 times the human dose ona bodysurface area basis) for1 year, then followedforanadditional year without the drug. No carcinoids wereseen in these rats. Anincreased incidenceoftreatment-related ECLcell hyperplasia was observed at the endof1year(94%treated vs10%controls). Bythe second yearthe difference between treated andcontrolrats wasmuchsmaller (46%vs 26%)but stillshowed more hyperplasia inthe treated group. Gastricadenocarcinoma was seen inone rat(2%).Nosimilar tumor was seen inmaleor femalerats treated for2 years. Forthis strain ofratnosimilar tumor has beennotedhistorically, buta findinginvolving onlyonetumor is difficultto interpret. A78-weekmouse carcinogenicity study ofomeprazole didnotshow increased tumor occurrence, butthe study wasnotconclusive. Esomeprazole wasnegative inthe Amesmutation test, inthe in vivoratbonemarrow cellchromosome aberration test, andthe invivomouse micronucleus test. Esomeprazole, however, was positiveinthe invitro human lymphocyte chromosome aberration test. Omeprazole was positivein the in vitro human lymphocyte chromosome aberration test, the invivomouse bonemarrow cellchro mosome aberration test, andthe in vivomouse micronucleus test. Thepotentialeffects of esomeprazole onfertilityandreproductive performance wereassessed usingomeprazole studies. Omeprazole at oraldoses upto 138mg/kg/day in rats (about 56times the human dose onabody surface area basis) wasfound to havenoeffectonreproductive performance ofparental animals. Pregnancy: TeratogenicEffects. PregnancyCategory B-Teratology studies havebeenperformed inrats at oraldoses upto 280 mg/kg/day (about 57times the human dose ona bodysurface area basis) andinrabbits at oraldoses upto 86mg/kg/day (about 35times the human dose on a bodysurface area basis) andhaverevealedno evidence ofimpairedfertilityor harmto the fetus dueto esomeprazole. Thereare, however, noadequate andwell-controlled studies in pregnant women. Becauseanimalreproduction studies are notalways predictiveofhuman response, this drug should beused during preg nancy onlyifclearlyneeded. Teratology studies conducted withomeprazole inrats at oral doses upto 138mg/kg/day (about 56times the human dose ona bodysurface area basis) and in rabbits at doses upto 69 mg/kg/day (about 56times the human dose on a body surface area basis) didnot disclose anyevidencefora teratogenic potentialofomeprazole. Inrabbits, omeprazole in a dose rangeof6.9 to 69.1mg/kg/day (about 5.5to 56times the human dose ona body surface area basis) produced dose-related increases inembryo lethality,fetalresorptions, and pregnancy disruptions. Inrats, dose-related embryo/fetal toxicityand postnatal developmental toxicitywereobserved in offspringresultingfrom parents treated withomeprazole at 13.8to 138.0 mg/kg/day (about 5.6 to 56times the human doses on a bodysurface area basis). Thereare noadequate andwell-controlled studies inpregnant women. Sporadic reports havebeen receivedofcongenital abnormalities occurring in infantsbornto womenwhohavereceivedomeprazole during pregnancy. Nursing Mothers: Theexcretionof esomeprazole in milkhas not been studied. However, omeprazole concentrations havebeenmeasured in breast milkof a woman followingoraladministration of20 mg.Because esomeprazole is likelyto be excreted in human milk,because ofthe potentialforserious adverse reactions in nursing infants from esomeprazole, andbecause ofthe potentialfor tumorigenicity shown for omeprazole inrat carcinogenicity studies, a decision should be made whether to discontinue nursing orto discontinue the drug, takingintoaccount the importance of the drug to the mother. Pediatric Use: Safetyandeffectiveness inpediatricpatients havenot been established. Geriatric Use: Ofthe totalnumber ofpatients whoreceivedNEXIUM inclinicaltrials, 778 were65to 74years ofage and124patients were >75years ofage. Nooveralldiffer ences insafety andefficacy wereobserved between the elderlyandyounger individuals, and other reported clinicalexperience has notidentifieddifferences in responses between the elderlyandyounger patients, butgreater sensitivity ofsome older individuals cannot be ruledout. ADVERSE REACTIONS Thesafety ofNEXIUM wasevaluated inover 10,000 patients (aged 18-84years) in clinicaltrialsworldwideincluding over 7,400 patients inthe UnitedStates andover2,600 patients in EuropeandCanada.Over2,900 patients were treated inlong-term studies forupto6-12 months. Ingeneral, NEXIUM was welltolerated in bothshort- andlong-term clinicaltrials. Thesafety in the treatment ofhealingoferosive esophagitis was assessed in four randomized comparative clinicaltrials, whichincluded 1,240 patients onNEXIUM 20mg,2,434 patients onNEXIUM 40mg,and3,008 patients on omeprazole 20mgdaily.Themost frequently occurring adverse events (>1%)inallthree groups was headache (5.5,5.0,and3.8, respectively) anddiarrhea (nodifference among the three groups). Nausea, flatulence, abdominal pain,constipation, anddrymouth occurred at similar rates among patients takingNEXIUM or omeprazole. Additional adverse events that werereported as possibly or probablyrelatedto NEXIUM withan incidence < 1%are listed belowbybodysystem: Bodyas a Whole:abdomen enlarged, allergicreaction,asthenia, backpain,chest pain,chest painsubsternal, facialedema, peripheral edema, hot flushes, fatigue,fever,flu-likedisorder, generalized edema, leg edema, malaise, pain,rigors; Cardiovascular: flushing, hypertension, tachycardia; Endocrine: goiter;Gastrointestinal: bowelirregularity, constipation aggravated, dyspepsia, dysphagia, dysplasia GI,epigastric pain,eructation, esophageal disorder, frequent stools, gastroenteritis, GIhemorrhage, GI symptoms nototherwise specified,hiccup,melena,mouth disorder, pharynx disorder, rectal disorder, serum gastrin increased, tongue disorder, tongue edema, ulcerativestomatitis, vomiting;Hearing: earache, tinnitus; Hematologic: anemia, anemia hypochromic, cervical lymphoadenopathy, epistaxis, leukocytosis, leukopenia, thrombocytopenia; Hepatic: biliru binemia,hepaticfunction abnormal, SGOTincreased, SGPTincreased; Metabolic/ Nutritional: glycosuria, hyperuricemia, hyponatremia, increased alkalinephosphatase, thirst, vitaminB12deficiency,weightincrease, weightdecrease; Musculoskeletal: arthralgia, arthritis aggravated, arthropathy, cramps, fibromyalgia syndrome, hernia, polymyalgia rheumatica; Nervous System/Psychiatric: anorexia, apathy, appetite increased, confusion, depression aggravated, dizziness, hypertonia, nervousness, hypoesthesia, impo tence, insomnia, migraine,migraineaggravated, paresthesia, sleep disorder, somnolence, tremor, vertigo,visualfielddefect;Reproductive: dysmenorrhea, menstrual disorder, vaginitis;Respiratory: asthma aggravated, coughing, dyspnea, larynxedema, pharyngitis, rhinitis,sinusitis; Skinand Appendages: acne, angioedema, dermatitis, pruritus, pruritus ani,rash, rasherythematous, rash maculo-papular, skininflammation, sweating increased, urticaria;Special Senses: otitismedia,parosmia, taste loss, taste perversion; Urogenital: abnormal urine,albuminuria, cystitis, dysuria, fungalinfection,hematuria, micturition frequency, moniliasis, genitalmoniliasis, polyuria;Visual:conjunctivitis, visionabnormal. Endoscopic findings that werereported as adverse events include:duodenitis, esophagitis, esophageal stricture, esophageal ulceration,esophageal varices, gastric ulcer, gastritis, hernia,benignpolypsor nodules, Barrett's esophagus, and mucosal discoloration. Postmarketing Reports - Therehavebeenspontaneous reports ofadverse events withpost marketing use ofesomeprazole. These reports haveincludedrarecases ofanaphylactic reac tion.Otheradverse events notobserved withNEXIUM, but occurring withomeprazole canbe foundin the omeprazole packageinsert, ADVERSE REACTIONS section. OVER DOSAGE Asingleoraldose ofesomeprazole at 510 mg/kg(about 103times the human dose ona bodysurface area basis), was lethalto rats. Themajorsigns ofacute toxicitywere reducedmotor activity,changes in respiratory frequency, tremor, ataxia,andintermittent clonicconvulsions. Therehavebeenno reports ofoverdose withesomeprazole. Reports havebeenreceivedofoverdosage withomeprazole inhumans. Doses ranged upto 2,400 mg (120times the usual recommended clinicaldose). Manifestations werevariable,butincluded confusion, drowsiness, blurredvision,tachycardia, nausea, diaphoresis, flushing, headache, drymouth,andother adverse reactions similar to those seen innormalclinicalexperience (see omeprazole packageinsert-ADVERSE REACTIONS). Nospecificantidote for esomepra zoleisknown.Sinceesomeprazole is extensivelyproteinbound, itis notexpected to be removedbydialysis.Inthe event ofoverdosage, treatment should besymptomatic and supportive. Aswiththe management ofanyoverdose, the possibility ofmultipledrug inges tionshould beconsidered. Forcurrent information ontreatment ofanydrug overdose, a certifiedRegionalPoison ControlCentershould becontacted. Telephone numbers are listed inthe Physicians' DeskReference (PDR)or localtelephone book. NEXIUM isa registered trademark ofthe AstraZeneca group. ©AstraZeneca 2002. Allrights reserved. 210177 AstraZeneca Rev.09/02 J'