National Geographic : 2004 Jun
- P lese- rea t i sum ar carely an -he as you doto abu-EXU Noavr im nca poideal th ifr aion - ede to pecib a drug Thi aderiem n doe no tak th laeo N ex i Umf®(esomeprazole magnesium) 20-MG, 40-MG Delayed-Release Capsules BRIEF SUMMARY Beforeprescribing NEXIUM, please see fullPrescribing Information. INDICATIONS AND USAGE NEXIUMisindicatedfor the short-term treatment (4to 8 weeks) in the healing and symptomatic resolution ofdiagnostically confirmed erosive esophagitis. CONTRAINDICATIONS NEXIUM iscontraindicated inpatients withknown hypersensitivity to any component of the formulation or to substituted benzimidazoles. PRECAUTIONS Symptomatic response to therapy withNEXIUM does not preclude the presence ofgastric malignancy. Atrophicgastritis has been noted occasionally ingastric corpus biopsies from patients treated long-term withomeprazole, ofwhichNEXIUM isan enantiomer. Information for Patients: NEXIUM Delayed-Release Capsules should betaken at least one hour before meals. Forpatients who havedifficultyswallowing capsules, one tablespoon of applesauce canbe added to an empty bowland the NEXIUM Delayed-Release Capsuleopened, andthe pellets carefullyemptied onto the applesauce. Thepellets should be mixedwiththe applesauce and then swallowed immediately. Theapplesauce used should notbehot andshould be soft enough to beswallowed without chewing.Thepellets should not bechewed or crushed. Thepellet/applesauce mixtureshould not bestored forfuture use. Antacids maybeused while taking NEXIUM. Drug Interactions: Esomeprazole isextensively metabolized inthe liver byCYP2C19 and CYP3A4.Invitro and invivostudies haveshown that esomeprazole isnot likely to inhibitCYPs1A2,2A6,2C9,2D6,2E1and 3A4.Noclinically relevant interactions withdrugs metabolized bythese CYPenzymes wouldbeexpected. Druginteraction studies haveshown that esomeprazole does not haveanyclinically significant interactions withphenytoin, warfarin, quinidine, clarithromycin or amoxicillin. Post-marketing reports ofchanges in prothrombin measures have been receivedamong patients on concomitant warfarinand esomeprazole therapy. Increases inINRand prothrombin time may leadto abnormal bleedingandevendeath. Patients treated withproton pump inhibitors and warfarinconcomitantly may need to bemoni tored forincreases inINRandprothrombin time.Esomeprazole maypotentiallyinterfere with CYP2C19,the major esomeprazole metabolizing enzyme.Coadministration of esomeprazole 30 mgand diazepam, a CYP2C19substrate, resulted in a 45%decrease in clearance of diazepam. Increased plasma levelsof diazepamwereobserved 12 hours after dosing and onwards. However, at that time,the plasma levelsofdiazepam werebelowthe therapeutic interval,and thus this interaction is unlikelyto be ofclinicalrelevance. Esomeprazole inhibits gastric acidsecretion. Therefore,esomeprazole mayinterfere withthe absorption of drugs where gastric pHisan important determinant ofbioavailability (eg,ketoconazole, ironsalts and digoxin).Coadministration of oralcontraceptives, diazepam,phenytoin, or quinidine didnot seem to change the pharmacokinetic profileof esomeprazole. Carcinogenesis, Mutagenesis, Impairment of Fertility: Thecarcinogenic potential ofesomepra zolewas assessed using omeprazole studies. Intwo 24-month oralcarcinogenicity studies in rats, omeprazole at dailydoses of 1.7,3.4, 13.8,44.0 and 140.8 mg/kg/day (about 0.7 to 57 times the human dose of20 mg/day expressed ona body surface area basis) produced gastric ECLcellcarcinoids ina dose-related manner in both maleand femalerats;the incidence ofthis effectwas markedly higher infemalerats, whichhadhigher bloodlevelsofomeprazole. Gastriccarcinoids seldom occur in the untreated rat.Inaddition, ECLcellhyperplasia was present inalltreated groups ofbothsexes. Inone ofthese studies, female rats weretreated with 13.8 mgomeprazole/kg/day (about 5.6 times the human dose ona body surface area basis) for 1year, then followedforan additional year without the drug. Nocarcinoids wereseen in these rats. Anincreased incidenceoftreatment-related ECLcellhyperplasia was observed at the end of1year (94%treated vs 10%controls). Bythe second year the difference between treated and control rats was much smaller (46% vs 26%)but stillshowed more hyperplasia inthe treated group. Gastric adenocarcinoma was seen inone rat(2%).Nosimilar tumor was seen inmaleor female rats treated for2 years. Forthis strain ofratnosimilar tumor has been notedhistorically, but a findinginvolving onlyone tumor isdifficultto interpret. A78-weekmouse carcinogenicity study ofomeprazole didnotshow increased tumor occurrence, but the study was notconclu sive.Esomeprazole was negative in the Amesmutation test, inthe invivoratbone marrow cell chromosome aberration test, and the invivomouse micronucleus test. Esomeprazole, however, was positive in the in vitro human lymphocyte chromosome aberration test. Omeprazole was positive inthe in vitrohuman lymphocyte chromosome aberration test, the invivomouse bone marrow cellchromosome aberration test, and the in vivomouse micronucleus test. Thepoten tialeffects ofesomeprazole on fertilityand reproductive performance wereassessed using omeprazole studies. Omeprazole at oraldoses upto 138 mg/kg/day in rats (about 56 times the human dose ona body surface area basis) was found to havenoeffectonreproductive perfor mance of parental animals. Pregnancy: Teratogenic Effects. Pregnancy Category 8 Teratology studies havebeen performed in rats at oraldoses upto 280 mg/kg/day (about 57 times the human dose ona body surface area basis) and in rabbits at oraldoses upto 86 mg/kg/day (about 35 times the human dose ona body surface area basis) andhaverevealed no evidence ofimpaired fertilityor harm to the fetus dueto esomeprazole. Thereare, however, noadequate and well-controlled studies in pregnant women. Because animalreproduction studies are notalways predictiveofhuman response, this drug should be used during pregnancy onlyifclearlyneeded. Teratology studies conducted withomeprazole in rats at oraldoses upto 138 mg/kg/day (about56 times the human dose ona body surface area basis) andinrabbits at doses upto 69 mg/kg/day (about 56 times the human dose onabody surface area basis) didnot disclose anyevidence fora teratogenic potential ofomeprazole. Inrabbits, omeprazole inadose rangeof6.9 to 69.1mg/kg/day (about 5.5to 56 times the human dose ona bodysurface area basis) produced dose-related increases in embryo-lethality, fetalresorptions, and pregnancy disruptions. Inrats, dose-related embryo/fetal toxicityand postnatal developmental toxicitywere observed inoffspring resulting fromparents treated withomeprazole at13.8 to 138.0 mg/kg/day (about 5.6 to 56 times the human doses ona bodysurface area basis). Thereare noadequate and well-controlled studies in pregnant women. Sporadic reports havebeen receivedof congenital abnormalities occurring in infants born to women who havereceived omeprazole during pregnancy. Nursing Mothers: Theexcretion ofesomeprazole inmilkhas notbeen studied. However, omeprazole concentrations havebeen measured inbreast milkofa woman following oraladministration of20 mg.Because esomeprazole islikelyto be excreted inhuman milk,because ofthe potentialfor serious adverse reactions in nursing infants from esomepra zole,andbecause ofthe potentialfortumorigenicity shown for omeprazole inratcarcinogenicity studies, a decision should be made whether to discontinue nursing or to discontinue the drug, takingintoaccount the importance ofthe drug to the mother. Pediatric Use: Safety and effectiveness in pediatricpatients havenotbeen established. Geriatric Use: Ofthe total number ofpatients who receivedNEXIUM inclinicaltrials, 778 were65 to 74years ofage and 124patients were>75 years ofage. Nooveralldifferences insafety andefficacywereobserved between the elderlyand younger individuals, and other reported clinicalexperience has not identifieddifferences in responses between the elderlyand younger patients, but greater sensitivityofsome older individuals cannot be ruledout. ADVERSE REACTIONS The safety ofNEXIUM was evaluated in over10,000 patients (aged 18-84 years) in clinicaltrials worldwideincluding over 7,400 patients inthe UnitedStates and over 2,600 patients inEurope and Canada.Over2,900 patients were treated in long-term studies forupto 6-12 months. In general, NEXIUM was welltolerated inboth short- and long-term clinicaltrials. Thesafety inthe treatment ofhealingoferosive esophagitis was assessed infour randomized comparative clin icaltrials, whichincluded1,240 patients onNEXIUM 20 mg,2,434 patients onNEXIUM 40 mg, and 3,008 patients onomeprazole 20 mgdaily.Themost frequently occurring adverse events (>1%) inallthree groups was headache (5.5, 5.0, and 3.8, respectively) and diarrhea (nodiffer ence among the three groups). Nausea, flatulence, abdominal pain,constipation, and dry mouth occurred at similarrates among patients takingNEXIUM or omeprazole. Additional adverse events that werereported as possibly or probably relatedto NEXIUM withan incidence <1%are listedbelowbybodysystem: Bodyas a Whole:abdomen enlarged, allergicreaction, asthenia, backpain,chest pain,chest painsubsternal, facialedema, peripheral edema, hotflushes, fatigue,fever, flu-likedisorder, generalized edema, leg edema, malaise, pain,rigors; Cardiovascular:flushing, hypertension, tachycardia; Endocrine:goiter; Gastrointestinal:bowel irregularity, constipation aggravated, dyspepsia, dysphagia, dysplasia GI,epigastric pain,eruc tation, esophageal disorder, frequent stools, gastroenteritis, GIhemorrhage, GIsymptoms not otherwise specified, hiccup, melena, mouth disorder, pharynx disorder, rectaldisorder, serum gastrin increased, tongue disorder, tongue edema, ulcerativestomatitis, vomiting;Hearing: earache, tinnitus; Hematologic: anemia, anemia hypochromic, cervicallymphoadenopathy, epistaxis, leukocytosis, leukopenia, thrombocytopenia; Hepatic: bilirubinemia, hepatic function abnormal, SGOTincreased, SGPTincreased; Metabolic/Nutritional: glycosuria, hyperuricemia, hyponatremia, increased alkalinephosphatase, thirst, vitaminB12deficiency, weight increase, weightdecrease; Musculoskeletal: arthralgia, arthritis aggravated, arthropathy, cramps, fibromyalgiasyndrome, hernia,polymyalgiarheumatica; Nervous System/Psychialric: anorexia,apathy, appetite increased, confusion, depression aggravated, dizziness, hypertonia, nervousness, hypoesthesia, impotence, insomnia, migraine, migraine aggravated, paresthesia, sleep disorder, somnolence, tremor, vertigo, visualfielddefect; Reproductive: dysmenorrhea, menstrual disorder, vaginitis;Respiratory: asthma aggravated, coughing, dyspnea, larynx edema, pharyngitis, rhinitis,sinusitis; Skin and Appendages: acne, angioedema, dermatitis, pruritus, pruritus ani, rash, rash erythematous, rash maculo-papular, skininflammation, sweating increased, urticaria;Special Senses: otitis media, parosmia, taste loss, taste perversion; Urogenital: abnormal urine,albuminuria, cystitis, dysuria, fungal infection, 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,benignpolyps or nodules, Barrett's esophagus, and mucosal discoloration. Postmarketing Reports - Therehavebeen spontaneous reports of adverse events with postmarketing use ofesomeprazole. These reports haveincluded rarecases ofanaphylactic reaction. Otheradverse events not observed withNEXIUM, butoccurring withomeprazole can befoundin the omeprazole package insert,ADVERSE REACTIONS section. OVER DOSAGE Asingle oraldose ofesomeprazole at 510 mg/kg(about 103times the human dose ona bodysurface area basis), was lethalto rats. Themajor signs ofacute toxicitywerereduced motor activity,changes in respiratory frequency, tremor, ataxia,and intermittent clonic convulsions. Therehavebeen some reports ofoverdosage withesomeprazole. Reports have beenreceivedofoverdosage withomeprazole in humans. Doses ranged upto 2,400 mg (120 times the usual recommended clinicaldose). Manifestations werevariable,butincluded confusion, drowsiness, blurredvision, tachycardia, nausea, diaphoresis, flushing, headache, dry mouth, andother adverse reactions similar to those seen in normal clinicalexperience (see omeprazole package insert-ADVERSE REACTIONS). Nospecific antidote foresomeprazole is known.Sinceesomeprazole is extensivelyproteinbound, itis not expected to be removed by dialysis. Inthe event ofoverdosage, treatment should besymptomatic and supportive. Aswith the management ofanyoverdose, the possibility ofmultipledrug ingestion should be consid ered. Forcurrent information ontreatment ofanydrug overdose, a certifiedRegionalPoison ControlCenter should becontacted. Telephone numbers are listedin the Physicians' Desk Reference (PDR)or localtelephone book. NEXIUM isa registered trademark ofthe AstraZeneca group ofcompanies. ©AstraZeneca 2003. Allrights reserved. 213166 Rev.03/03 AstraZeneca '