National Geographic : 2000 Apr
Prilosec®(omeprazole) Delayed-Release Capsules BRIEFSUMMARY. Beforeprescribing,please consult lull PrescribingInformation. CUNICALPHARMACOLOGY,Pharmacokinetics and Metabolism: Omeprazole In pharmacoki netic studies ofsingle20 mg omeprazoledoses, an increasein AUCofapproximatelyfour-foldwasnoted inAsian subjects compared to Caucasians Dose adjustment, particularlywhere maintenance of healing of erosive esophagitis is indicated, for the hepalicallyimpairedand Asian subjectsshould beconsidered. INDICATIONSAND USAGE, Duodenal Ulcer: PRILOSECis indicatedfor short-termtreatmentofactive duodenalulcer Most patients heal within4 weeks. Some patientsmay requirean additional4 weeks oftherapy. PRILOSEC,in combination with clarithromycinand amoxicillin,is indicated for treatment of patients with H.pyloriinfectionand duodenal ulcerdisease (active or up to 1-year history)to eradicateH pylori PRILOSEC, in combinationwith clarithromycin,is also indicated for treatment of patients with H pylori infectionand duodenal ulcerdisease to eradicateH pylori Eradicationof H pylorihas been shown to reduce the risk of duodenalulcer recurrence.Amongpatients who failtherapy. PRILOSECwithclarithromycinis more likelyto be associated withthe developmentof clarithromycinresistance as comparedwith tripletherapy Inpatients who failtherapy,susceptibilitytesting should bedone.IIresistance toclarithromycinis demonstratedor susceptibility testing is not possible, alternativeantimicrobialtherapyshould be instituted.(See the clarithromycinpackage insert, MICROBIOLOGY section) Gastric Uker: PRILOSECis indicatedfor short-termtreatment(4-8 weeks) of activebenigngastric ulcer Treatment of Gostroesophageal Reflux Disease (GERD):Symptomatic GERD-- PRILOSECis indicatedfor the treatment of heartburn and other symptoms associated withGERD. Erosive Esophagitis- PRILOSECis indicatedfor the short-termtreatment (4-8 weeks)of erosiveesophagitis which has been diagnosed by endoscopy. The efficacyof PRILOSECused for longer than 8 weeks in these patients has not been established.Inthe rare instanceofa patientnot respondingto 8 weeks oftreatment,it may be helpfulto give up to an additional4 weeks of treatment.Ifthere is recurrenceof erosiveesophagitisor GERD symptoms (e.g ., heartburn),additional4-8 week courses ofomeprazolemay beconsidered.Maintenance of Healing of Erosive Esophagitis: PRILOSECis indicated to maintain healing of erosive esophagitis. Controlled studies do not extend beyond 12 months. Pathological Hypersecretory Conditions: PRILOSECis indicated for the long-term treatmentof pathologicalhypersecretoryconditions(e.g ., Zollinger Ellisonsyndrome,multipleendocrineadenomasand systemicmastocytosis). CONTRAINDICATIONS,Omeprozole: PRILOSECDelayed-ReleaseCapsules are contraindicatedin patients withknown hypersensitivityto anycomponent ofthe formulation.Clarithromycin: Clarilhromycinis contraindicatedinpatients witha knownhypersensitivityto anymacrolideantibiotic.Concomitantadministration of clarithromycinwithcisapride, pimozide,or terfenadineis contraindicated.There have been post-marketing reports of drug interactions when clarithromycinand/or erythromycinare co-administered with cisapride, pimozide,or tertenadineresulting in cardiacarrhythmias(OT prolongation,ventriculartachycardia,ventricular fibrillation,and torsades de pointes) most likelydue to inhibitionof hepatic metabolismof these drugs by erythromycinand clarithromycin.Fatalitieshave been reported.(Please referto full prescribinginformationfor clarithromycinbeforeprescribing.) Amoxicilin: Amoxicillinis contraindicatedin patients witha history of allergic reactionto any of the penicillins(Please refer to fullprescribing informationfor amoxicillinbefore prescribing.) WARNINGS, Clarithromycin: CLARITHROMYCIN SHOULDNOTBEUSEDINPREGNANT WOMENEXCEPT IN CLINICALCIRCUMSTANCES WHERENO ALTERNATIVE THERAPYIS APPROPRIATE. IF PREGNANCY OCCURSWHILETAKINGCLARITHROMYCIN, THEPATIENTSHOULDBE APPRISEDOFTHEPOTENTIAL HAZARDTOTHEFETUS.(See WARNINGSin prescribinginformationIor clarithromycin.)Amoxicillin: SERIOUSANDOCCASIONALLY FATALHYPERSENSITIVITY (anaphylactic)REACTIONSHAVEBEENREPORTED IN PATIENTSONPENICILLINTHERAPY.THESEREACTIONSAREMORELIKELYTOOCCURININDIVIDUALS WITHA HISTORYOFPENICILLINHYPERSENSITIVITY AND/ORAHISTORYOF SENSITIVITYTOMULTIPLE ALLERGENS.BEFOREINITIATINGTHERAPYWITHAMOXICILLIN,CAREFULINQUIRYSHOULDBE MADE CONCERNINGPREVIOUSHYPERSENSITIVITY REACTIONSTOPENICILLINS,CEPHALOSPORINS OROTHER ALLERGENS.IF ANALLERGICREACTIONOCCURS,AMOXICILLINSHOULDBE DISCONTINUED ANDAPPRO PRIATETHERAPYINSTITUTED.SERIOUSANAPHYLACTIC REACTIONS REQUIREIMMEDIATE EMERGENCY TREATMENTWITHEPINEPHRINE.OXYGEN,INTRAVENOUS STEROIDSAND AIRWAYMANAGEMENT, INCLUDINGINTUBATION, SHOULDALSOBEADMINISTERED AS INDICATED. (See WARNINGSin prescribing informationfor amoxicillin.)Antimicrobials: Pseudomembranouscolitis has been reportedwith nearlyall antibacterialagents and mayrange in severity frommildto lile-threatening.Therefore,it is importantto considerthisdiagnosisin patientswhopresentwithdiarrheasubsequentto the administrationofantibacte rial agents. (SeeWARNINGSin prescribinginformationlor clarithromycinand amoxicillin.) PRECAUTIONS,General: Symptomaticresponse to therapywithomeprazoledoes not precludethe pres ence ol gastric malignancy Atrophicgastritis has been noted occasionallyin gastric corpus biopsies from patients treated long-termwithomeprazole.Information for Patients: PRILOSECDelayed-ReleaseCapsules should be taken before eating.Patientsshould becautionedthat the PRILOSECDelayed-ReleaseCapsuleshould notbe opened, chewedor crushed,and should beswallowedwhole Drug Interactions: Other- Omeprazole can prolong the eliminationof diazepam,wartarin and phenytoin,drugs that are metabolizedbyoxidationin the liver.Althoughinnormalsubjects nointeractionwiththeophyllineor propranololwasfound,therehave been clin icalreports of interaction withother drugs metabolizedvia the cytochrome P-450system (e.g .. cyclosporine, disulliram,benzodiazepines).Patientsshouldbe monitoredto determineifitis necessaryto adjustthe dosageof these drugs when takenconcomitantlywithPRILOSEC.Becauseof its profoundand long lastinginhibitionof gastric acid secretion, it is theoreticallypossiblethat omeprazolemay interferewithabsorption ofdrugs where gastric pH is an important determinantof their bioavailability(e.g., ketoconazole,ampicillinesters, and iron salts). In theclinicaltrials, antacidswere used concomitantlywiththe administrationof PRILOSEC.Combination Therapywith Clarithrmycm-Co-administration ofomeprazoleandclarithromycinhave resultedin increasesin plasma levels of omeprazole,clarithromycin,and 14-hydroxy-clarithromycin. (See CLINICALPHARMACOLOGY, Pharmacokinetics:CombinationTherapy with Antimi-crobials in lull PrescribingInformation.)Concomitant administrationof clarithromycinwithcisapride, pimozide,or terfenadineis contraindicated.There have been reportsof an interactionbetween erythromycinand astemizole resultingin OT prolongationand torsades de pointes. Concomitantadministrationot erythromycinand astemizoleis contraindicated.Becauseclarithromycin is also metabolizedbycytochrome P-450, concomitantadministrationof clarithromycinwithastemizoleis not recommended. (Seealso CONTRAINDICATIONS, Clarithromycin,above. Please referto fullprescribinginforma tion forclarithromycinbefore prescribing.)Carcinogenesis, Mutgenesis, Impairment of Fertility: In two 24-month carcinogenicitystudies in rats, omeprazole at dailydoses of 1.7, 3.4 . 13.8, 44.0 and 140.8 mg/kg/day(approximately4 to 352 times thehuman dose, based on a patient weightof 50 kgand a human dose of 20 mg) produced gastric ECLcell carcinoidsin a dose-relatedmannerin both male and femalerats: the inci dence of this effect was markedlyhigher infemale rats, which had higher blood levels of omeprazole.Gastric carcinoids seldom occurin the untreated rat. Inaddition, ECLcell hyperplasiawas present inall treated groups of both sexes. Inone of these studies, female rats were treated with138 mg/kg/dayomeprazole(approximately 35 limes the human dose) for 1 year,then followedfor an additionalyear withoutthe drug. No carcinoidswere seen inthese rats. Anincreasedincidenceof treatment-relatedECLcell hyperplasiawas observedat the end of 1 year (94%treated vs 10% controls). Bythe second year the differencebetween treated and control rats was much smaller (46%vs 26%)but still showed morehyperplasiainthe treated group. Anunusual primarymalig nant tumorin the stomach was seen in one rat (2%). Nosimilartumor was seen in male or female rats treated for 2 years.For this strain of rat no similartumor has been noted historically,but a finding involvingonlyone tumor is difficultto interpret.A 78-weekmouse carcinogenicitystudy of omeprazoledid not show increased tumor occurrence,but the study was not conclusive. Omeprazolewas not mutagenic in an in vitro Ames Salmonellatyphimoriumassay, an in vitromouse lymphomacell assay and an in vivo rat liverDNAdamage assay A mouse micronucleustest at 625 and 6250 timesthe human dose gave a borderlineresult, as did an in vivobone marrowchromosomeaberrationtest. A second mouse micronucleusstudyat 2000 timesthe human dose, but withdifferent(suboptimal)samplingtimes, was negative.Pregnancy: Omeprzole: Pregnancy CategoryC- In rabbits, omeprazolein a dose range of 6.9 to 69.1 mg/kg/day(approximately17to 172 times the human dose) produced dose-relatedincreases in embryo-lethality,fetalresorptions and pregnancydisrup tions.In rats, dose-relatedembryo/fetaltoxicityand postnataldevelopmentaltoxicitywereobserved inoffspring resultingfrom parents treated withomeprazole 138 to 138.0 mg/kg/day(approximately35 to 345 times the human dose).There are no adequate or well-controlledstudiesin pregnantwomen.Sporadicreportshave been receivedof congenitalabnormalitiesoccurringin infants born to womenwho have receivedomeprazoleduring pregnancy.Omeprazoleshould be used during pregnancyonlyit the potentialbenefitjustifiesthe potentialrisk to the letus. Clrithromycin: PregnancyCategoryC- SeeWARNINGS(above)and lull prescribinginforma tion for clarithromycinbefore using in pregnant women. Nursing Mothers: It is not known whether omeprazoleis excretedin human milk In rats, omeprazoleadministrationduringlate gestationand lactationat Registered trademark of Astra AB © Astra Pharmaceuticals.L.P .,1998. Allrights reserved. doses of 13.8 to138 mg/kg/day (35to 345 times the human dose) resultedin decreased weight gain inpups. Because many drugs are excreted in human milk, becauseof the potentialfor serious adverse reactionsin nursing infants from omeprazole,and because of the potentialfor tumorigenicityshown for omeprazolein rat carcinogenicitystudies, a decision should be made whether to discontinuenursing or discontinuethe drug, taking intoaccountthe importanceof the drug to the mother Pediatric Use: Safetyand effectivenessinpedi atric patientshave not been established. ADVERSEREACTIONS: In the U.S. clinical trial population of 465 patients (includingduodenal ulcer, Zollinger-Ellisonsyndrome and resistant ulcer patients), the followingadverse experiences were reported to occur in 1% or more of patients on therapy withPRILOSEC(omeprazole) Numbersin parentheses indicate percentagesof the adverseexperiencesconsidered byinvestigatorsas possibly,probably,or definitelyrelated to the drug. OmeprazoleIn=4651 PlaceboIn641 Ranitidie i(n=195) Headache 6.9 (2.4) 6.3 7.7 (2.6) Diarrhea 30(1.9) 3.1 (16) 2.1(05) AbdominalPain 24 (0.4) 3.1 2.1 Nausea 22(0.9) 31 41 (0.5) URI 1.9 1.6 2.6 Dizziness 15(0.6) 00 26(1.0) Vomiting 1.5 (0.4) 4.7 15 (0.5) Rash 15 (1.1) 00 0.0 Constipation 1.1(0.9) 0.0 0.0 Cough 1.1 0.0 15 Asthena 1.1 (02) 1.6(16) 15(1.0) BackPain 1.1 0.0 0.5 The followingadverse reactionswhich occurred in 1% or more of omeprazole-treatedpatients have been reported ininternationaldouble-blind,and open-label,clinicaltrialsin which2,631 patientsand subjects received omeprazole. Incidenceof AdverseExperiences .1% Causal Relationshipnot Assessed Omeprazole(n=2.631) Placebo(n=1201 Bodyasa Whole,siteunspecified Abdominalpain 5.2 3.3 Asthenia 13 0.8 DigestiveSystem Constipation 1.5 0.8 Diarrhea 3.7 25 Flatulence 2.7 5.8 Nausea 40 6.7 Vomiting 3.2 10.0 Acid regurgitation 1.9 3.3 NervousSystem/Psychiatric Headache 2.9 2.5 Additionaladverse experiencesoccurringin <1% of patients or subjects indomestic and/or internationaltrials, or occurringsince the drug was marketed,are shownbelow withineach bodysystem. In many instances, the relationshipto PRILOSECwasunclear. BodyAs a Whole:Allergicreactionsincluding,rarely,anaphylaxis(see also Skin below),fever, pain,fatigue,malaise,abdominalswelling CardiovascularChest pain or angina,tachy cardia, bradycardia,palpitation,elevated blood pressure,peripheraledema. GastrointestinalPancreatitis(some fatal), anorexia,irritablecolon, flatulence,lecal discoloration,esophagealcandidiasis, mucosal atrophy of the tongue,dry mouth.Duringtreatmentwithomeprazole,gastric fundicgland polypshave been noted rarely These polypsare benignand appear to be reversiblewhentreatmentis discontinued.Gastro-duodenalcarcinoidshave been reported inpatients withZEsyndrome on long-termtreatmentwith PRILOSEC.Thisfindingis believedto bea manifestationolthe underlyingcondition,whichis known tobe associated withsuch tumors. HepaticMild and, rarely,markedelevationsof liverfunctiontests (ALT(SGPT),AST(SGOT),y-glutamyltranspeptidase,alka line phosphatase, and bilirubin (jaundice)].In rare instances, overt liver disease has occurred, including hepatocellular,choleslatic,or mixedhepatitis,livernecrosis(some fatal),hepatic failure(some fatal),and hepatic encephalopathy Metabolic/Nutritional:Hyponatremia,hypoglycemia, weight gain Musculoskeletal:Muscle cramps, myalgia, muscle weakness, joint pain, leg pain. Nervous System/Psychiatric:Psychic disturbances includingdepression, aggression, hallucinations,confusion,insomnia, nervousness, tremors, apathy, somno lence, anxiety, dream abnormalities; vertigo: paresthesia; hemifacal dysesthesia. Respiratory Epistaxis, pharyngealpain.Skin: Rash and, rarely,cases olsevere generalizedskin reactionsincludingtoxic epidermal necrolysis(TEN;some fatal),Stevens-Johnson syndrome,and erythema multiforme(some severe);purpura and/or petechiae(some withrechallenge):skin inllammalion,urticaria,angioedema,pruritus,alopecia,dry skin, hyperhidrosis.SpecialSenses:Tinnitus,taste perversion UrogenitalInterstitialnephritis (some with positive rechallenge),urinarytract infection,microscopic pyuria,urinaryfrequency,elevated serum creatinine,protein uria, hematuria. glycosuria. testicular pain, gynecomastia. Hematologic:Rare instances of pancytopenia, agranulocytosis(some fatal),thrombocytopenia.neutropenia.anemia, leucocytosis,and hemolyticanemiahave been reported.Combination Therapy for H. pylori Erdication: dual therapywithPRILOSECand clar ithromycinor triple therapy with PRILOSEC.clarthromycin, and amoxicillin.Adverse experiences that have occurred have been limitedto those that have been previouslyreported with omeprazole,clarithromycin,or amoxicillin.TripleTherapy(PRILOSEC/clarithromycin/amoicillin--- The most frequent adverse experiences observedin clinicaltrialsusing combinationtherapywithPRILOSEC,clarithromycin,and amoxicillin n =274) werediarrhea (14%), taste perversion(10%),and headache (7%). Noneof these occurred ata higherfrequency than that reported by patientstaking the antimicrobialdrugs alone.Dual Therapy(PRILOSEC/clarithromycin) Adverseexperiencesobserved incontrolledclinical trialsusing combinationtherapy withPRILOSECand clar ithromycin(n= 346)whichdifferedfrom those previouslydescribedforomeprazolealonewere: Tasteperversion (15%),tonguediscoloration(2%), rhinitis(2%),pharyngitis(1%)and flu syndrome (1%). Formoreinformation onclarithromycinor amoxicillin.refer to the respectivepackageinserts, ADVERSEREACTIONSsections OVERDOSAGE:Rare reportshave beenreceivedofoverdosage withomeprazole.Dosesranged from 320 mg to900 mg (16-45 imes the usual recommendedclinicaldose).Manifestationswerevariable,but includedconfu sion, drowsiness, blurred vision, tachycardia, nausea, diaphoresis, flushing, headache, and dry mouth. Symptomswere transient,and noserious clinicaloutcome hasbeen reported Nospecificantidote foromepra zoleoverdosageis known.Omeprazoleis extensivelyproteinbound and is, therefore,not readilydialyzable.In the event ooverdosage,treatmentshould besymptomaticand supportive. DOSAGE AND ADMINISTRATION,Short-Term Treatment of Active Duodenal Uker: The recommendedadult oral dose of PRILOSECis 20 mg once daily,Most patients heal within4 weeks. Some patients may require an additional4 weeks ol therapy. (See INDICATIONSANDUSAGE.) H. pylori Eradication for the Reduction of the Risk of Duodenal Ulcer Recurrence: TripleTherapy (PRILOSEC/clarithromycin/amoxicillin)The recommendedadult oral regimenis PRILOSEC20 mg plus clar ithromycin500 mg plusamoxicillin1000mg eachgiventwicedailyfor10 days. In patientswithan ulcerpresent atthetimeof initiationof therapy,an additional18 dayso PRILOSEC20 mg once dailyis recommendedforulcer healingand symptomrelief.DualTherapy(PRILOSEC/clarithromycin)-The recommendedadultoral regimenis PRILOSEC40 mg once dailyplus clarilhromycin500 mg t.i .d .lor 14days. In patientswithan ulcerpresent at the timeof initiationof therapy, an additional14 days of PRILOSEC20 mg once dailyis recommendedforulcer healingand symptomrelief.Pleasereferto clarithromycinfullprescribinginformationforCONTRAINDICATIONS and WARNING,and for informationregardingdosing inelderlyand renallyimpairedpatients (PRECAUTIONS: General,PRECAUTIONS: GeriatricUse and PRECAUTIONS:Drug Interactions).Please refer to amoxicillinfull prescribinginformationfor CONTRAINDICATIONS and WARNINGS.Gastric Uker: The recommendedadult oral dose is 40 mg once a day for4 to 8 weeks. (See INDICATIONSAND USAGE,Gastric Ulcer) Gostroesophogeal Reflux Disease (GERD):The recommendedadult oral dose totthe treatmentof patientswithsymptomaticGERDand no esophageallesionsis 20 mg dailyfor upto 4 weeks.Therecommended adultoraldose forthe treatmentof patientswitherosiveesophagitis andaccompanyingsymptomsdue to GERD is 20 mg dailytor 4 to 8 weeks. (See INDICATIONS ANDUSAGE.)Maintenance of Healing of Erosive Esophogitis: The recommended adult oral dose is 20 mg daily. Pathological Hypersecretory Conditions: Thedosageof PRILOSECin patients withpathologicalhypersecretoryconditionsvarieswiththe individualpatient.The recommendedadult oral startingdose is 60 mg once a day. Doses should beadjusted to individualpatient needs and should continuefor as long as clinicallyindicated.Doses up to 120 mg t.i .d . have been administered.Dailydosages of greater than 80 mg should be administeredindivideddoses. No dosage adjustmentis necessaryfor patients withrenalimpairment,hepatic dysfunctionor forthe elderly. Manufacturedby:Merck&Co., Inc. WestPoint. PA19486,USA Issued December1998 Distributedby: PRI31 AST trA Astra Pharmaceuticals, LP., Wayne, PA 19087 NOTE:This summaryprovidesimportantinformationabout PRILOSEC.IIyouwouldlike moreinformation, askyourdoctoror pharmacisttoletyou readthe professionallabelingandthen discuss itwith them. Please read this summary carefully, and then ask your doctor about r ment does not take the place of careful discussions with your doctor. Only your doctor has the training to weigh the risks and benefits of a prescription drug for you.