National Geographic : 1999 Nov
Prilosec*(omeprazole) Delayed-Release Capsules BRIEFSUMMARY. Beforeprescribing,please consult fullPrescribingInformation. CLINICALPHARMACOLOGY,Pharmacokinetics and Metabolism: Omeprazole In pharmacoki neticstudies ofsingle20 mg omeprazoledoses, an increaseinAUCofapproximatelyfour-foldwasnotedinAsian subjects compared to Caucasians. Dose adjustment, particularlywhere maintenance of healing of erosive esophagitisis indicated,forthe hepaticallyimpairedand Asiansubjects should beconsidered. INDICATIONSAND USAGE, Duodenal Ulcer: PRILOSECis indicatedforshort-termtreatmentofactive duodenalulcer.Most patientsheal within4 weeks. Some patientsmay requirean additional4 weeks of therapy. PRILOSEC,in combinationwith clarithromycinand amoxicillin,is indicatedfor treatment of patients with H.pyloriinfectionand duodenalulcerdisease (active or upto 1-year history)to eradicateH.pylori PRILOSEC, in combinationwith clarithromycin,is also indicatedfor treatmentof patients with H.pylori infection and duodenalulcer disease to eradicate H.pylori. Eradicationof H. pylorihas been shownto reduce the risk of duodenalulcerrecurrence.Amongpatients who failtherapy,PRILOSECwithclarithromycinis more likelyto be associatedwith the developmentof clarithromycinresistance as compared withtriple therapy.In patients who fail therapy,susceptibilitytestingshould bedone.If resistanceto clarithromycinis demonstratedor susceptibility testing is not possible, alternativeantimicrobialtherapyshould be instituted.(Seethe clarithromycinpackage insert,MICROBIOLOGY section.)Gastric Ulcer: PRILOSECis indicatedforshort-termtreatment(4-8 weeks) ofactivebenign gastriculcer.Treatment of Gastroesophageal Reflux Disease (GERD):Symptomatic GERD- PRILOSECis indicatedfor the treatment of heartburn and other symptoms associated with GERD. ErosiveEsophagitis- PRILOSECis indicatedforthe short-termtreatment(4-8 weeks) of erosive esophagitis whichhas been diagnosed by endoscopy.The efficacyof PRILOSECused for longer than 8 weeks in these patientshas not been established.Inthe rare instance ofa patientnot respondingto 8 weeksof treatment,it may behelpfulto giveup to an additional4 weeks oftreatment.If there is recurrenceoferosive esophagitisor GERD symptoms(e.g., heartburn),additional4-8 week coursesof omeprazolemay beconsidered.Maintenance of Healing of Erosive Esophagitis: PRILOSECis indicatedto maintain healing of erosive esophagitis. Controlledstudies do not extend beyond 12 months. Pathological Hypersecretory Conditions: PRILOSECis indicatedforthe long-term treatmentof pathologicalhypersecretoryconditions(e.g., Zollinger Ellisonsyndrome,multipleendocrineadenomasand systemic mastocytosis). CONTRAINDICATIONS,Omeprazole: PRILOSECDelayed-ReleaseCapsulesare contraindicatedin patientswithknown hypersensitivitytoany componentof theformulation.Clarithromycin: Clarithromycinis contraindicatedin patientswitha knownhypersensitivitytoany macrolideantibiotic.Concomitantadministration of clarithromycinwithcisapride, pimozide,or terfenadine is contraindicated.There have been post-marketing reports of drug interactionswhen clarithromycinand/or erythromycinare co-administeredwith cisapride, pimozide,or terfenadineresulting in cardiacarrhythmias(QTprolongation,ventriculartachycardia,ventricular fibrillation,and torsades de pointes) most likelydue to inhibitionof hepatic metabolismof these drugs by erythromycinand clarithromycin.Fatalitieshave been reported.(Please refer tofull prescribinginformationfor clarithromycinbefore prescribing.)Amoxicillin: Amoxicillinis contraindicatedin patients with a historyof allergicreactionto any of the penicillins.(Please refer to full prescribinginformationfor amoxicillinbefore prescribing.) WARNINGS, Clarithromycin: CLARITHROMYCIN SHOULDNOTBEUSEDINPREGNANT WOMENEXCEPT IN CLINICALCIRCUMSTANCES WHERENO ALTERNATIVE THERAPYIS APPROPRIATE. IF PREGNANCY OCCURSWHILETAKINGCLARITHROMYCIN, THEPATIENTSHOULDBE APPRISEDOFTHEPOTENTIAL HAZARDTOTHEFETUS.(See WARNINGSin prescribinginformationfor clarithromycin.)Amoxicillin: SERIOUSANDOCCASIONALLY FATALHYPERSENSITIVITY (anaphylactic)REACTIONSHAVEBEENREPORTED INPATIENTSON PENICILLINTHERAPY.THESEREACTIONSAREMORELIKELYTOOCCURININDIVIDUALS WITHA HISTORYOF PENICILLINHYPERSENSITIVITY AND/ORA HISTORYOF SENSITIVITYTOMULTIPLE ALLERGENS.BEFOREINITIATING THERAPYWITHAMOXICILLIN,CAREFULINQUIRYSHOULDBE MADE CONCERNING PREVIOUSHYPERSENSITIVITY REACTIONSTOPENICILLINS,CEPHALOSPORINS OROTHER ALLERGENS.IF ANALLERGICREACTIONOCCURS,AMOXICILLINSHOULDBEDISCONTINUED ANDAPPRO PRIATETHERAPYINSTITUTED.SERIOUSANAPHYLACTIC REACTIONS REQUIREIMMEDIATE EMERGENCY TREATMENTWITHEPINEPHRINE.OXYGEN,INTRAVENOUS STEROIDSANDAIRWAYMANAGEMENT, INCLUDING INTUBATION, SHOULDALSOBEADMINISTERED AS INDICATED. (SeeWARNINGSin prescribing informationfor amoxicillin.)Antimicrobials: Pseudomembranouscolitis has been reportedwithnearlyall antibacterialagents and may rangein severity frommildto life-threatening.Therefore,it is importantto considerthisdiagnosisin patientswhopresentwith diarrheasubsequenttothe administrationofantibacte rial agents.(See WARNINGSinprescribinginformationfor clarithromycinand amoxicillin.) PRECAUTIONS,General: Symptomaticresponse to therapywith omeprazoledoes not precludethe pres ence of gastric malignancy.Atrophicgastritis has been noted occasionallyin gastric corpus biopsies from patients treated long-termwithomeprazole.Information for Patients: PRILOSECDelayed-ReleaseCapsules should be takenbeforeeating. Patientsshouldbe cautionedthat the PRILOSECDelayed-ReleaseCapsuleshould not be opened, chewedor crushed,and shouldbe swallowedwhole.Drug Interactions: Other- Omeprazole can prolongthe eliminationof diazepam,warfarinand phenytoin,drugs that are metabolizedbyoxidationinthe liver Althoughinnormalsubjectsno interactionwiththeophyllineor propranololwasfound,therehave beenclin ical reports of interactionwithother drugs metabolizedvia the cytochrome P-450system (e.g ., cyclosporine, disulfiram,benzodiazepines).Patientsshouldbe montord to determineifitis necessarytoadjust thedosage of these drugs when taken concomitantlywithPRILOSEC.Becauseof its profound and long lastinginhibitionof gastric acid secretion,it is theoreticallypossiblethat omeprazolemay interferewithabsorptionof drugs where gastric pH is an importantdeterminantof their bioavailability(e.g ., ketoconazole,ampicillinesters, and iron salts). Inthe clinicaltrials,antacidswere used concomitantlywiththe administrationof PRILOSEC.Combination TherapywithClarithromycin-Co-administrationofomeprazoleandclarithromycinhaveresultedin increasesin plasma levelsof omeprazole,clarithromycin,and 14-hydroxy-clarithromycin. (SeeCLINICALPHARMACOLOGY, Pharmacokinetics:CombinationTherapy with Antimicrobials in full PrescribingInformation.)Concomitant administrationof clarithromycinwithcisapride, pimozide,or terfenadineis contraindicated.There have been reports of an interactionbetween erythromycinand astemizole resultingin QTprolongationand torsades de pointes. Concomitantadministrationof erythromycinand astemizoleis contraindicated.Because clarithromycin is also metabolizedby cytochromeP-450, concomitantadministrationof clarithromycinwithastemizoleis not recommended.(Seealso CONTRAINDICATIONS, Clarithromycin,above.Please refer to fullprescribinginforma tion for clarithromycinbeforeprescribing.)Carcinogenesis, Mutagenesis, Impairment of Fertility: In two 24-month carcinogenicitystudies in rats, omeprazoleat dailydoses of 1.7, 3.4, 13.8, 44.0 and 140.8 mg/kg/day(approximately4 to352 timesthe human dose, based on a patient weightof 50kg anda humandose of 20 mg) producedgastric ECLcell carcinoidsin a dose-relatedmannerin both maleand female rats; the inci dence ofthis effectwas markedlyhigher infemale rats, whichhad higher blood levelsof omeprazole.Gastric carcinoidsseldom occur inthe untreated rat. Inaddition, ECLcell hyperplasiawaspresent in alltreated groups of bothsexes. In one ofthese studies,female ratswere treated with 13.8 mg/kg/dayomeprazole(approximately 35 timesthe humandose) for 1 year,then followedfor an additionalyear withoutthe drug. Nocarcinoidswere seen inthese rats. Anincreasedincidenceoftreatment-relatedECLcell hyperplasiawas observedat the end of 1 year (94%treated vs 10% controls). By the second year the differencebetweentreated and control rats was much smaller(46% vs 26%) but stillshowed more hyperplasiainthe treated group.An unusualprimary malig nant tumor inthe stomach was seen in one rat (2%). Nosimilartumorwas seen in male or femalerats treated for 2 years. Forthis strain of rat no similartumor has been noted historically,but a findinginvolvingonly one tumor is difficultto interpret.A 78-weekmouse carcinogenicitystudy of omeprazoledid not show increased tumor occurrence, but the study was not conclusive. Omeprazolewas not mutagenicin an in vitro Ames Salmonellatyphimuriumassay, an in vitromouse lymphomacell assay and an in vivo rat liverDNAdamage assay.A mousemicronucleustest at 625 and 6250times the human dose gave a borderlineresult,as did an in vivobone marrow chromosomeaberrationtest. A second mouse micronucleusstudyat 2000timesthe human dose, but withdifferent(suboptimal)samplingtimes, was negative.Pregnancy: Omeprazole: Pregnancy CategoryC- In rabbits,omeprazolein a dose range of6.9 to 69.1 mg/kg/day(approximately17 to 172 times the human dose) produced dose-relatedincreases in embryo-lethality,fetalresorptionsand pregnancydisrup tions. Inrats, dose-relatedembryo/fetaltoxicityand postnataldevelopmentaltoxicitywere observedin offspring resulting from parents treated withomeprazole13.8 to 138.0 mg/kg/day(approximately35 to 345 timesthe human dose). Thereare no adequate or well-controlledstudies inpregnant women.Sporadicreports have been receivedof congenitalabnormalitiesoccurringin infants bornto women who have receivedomeprazoleduring pregnancy.Omeprazoleshouldbe used during pregnancyonlyif the potentialbenefitjustifiesthe potentialrisk to the fetus.Clarithromycin: PregnancyCategoryC- SeeWARNINGS(above) and fullprescribinginforma tion for clarithromycinbefore using in pregnant women. Nursing Mothers: It is not known whether omeprazoleis excretedin human milk.In rats, omeprazoleadministrationduringlate gestationand lactationat *Registeredtrademark of AstraAB. ©Astra Pharmaceuticals,L.P.,1998. Allrights reserved. doses of 13.8 to 138 mg/kg/day(35 to 345 times the human dose) resultedin decreased weight gain in pups. Because many drugs are excretedin human milk, becauseof the potentialfor serious adverse reactions in nursinginfants from omeprazole,and becauseof the potentialfor tumorigenicityshownfor omeprazolein rat carcinogenicitystudies, a decision should be made whether to discontinuenursing or discontinuethe drug, takinginto account the importanceofthe drug to the mother.Pediatric Use: Safety and effectivenessin pedi atricpatients havenot beenestablished. ADVERSEREACTIONS:In the U.S .clinical trial population of 465 patients (including duodenal ulcer, Zollinger-Ellisonsyndrome and resistant ulcerpatients), the followingadverse experiences were reported to occur in 1% or more of patients on therapy withPRILOSEC e (omeprazole).Numbers in parentheses indicate percentagesof the adverseexperiencesconsideredby investigatorsas possibly,probably,or definitelyrelatedto the drug. Omeorazole(n=465) Placebo(n=64) Ranitidine(n=195) Headache 6.9 (2.4) 6.3 7.7 (2.6) Diarrhea 3.0(1.9) 3.1 (1.6) 2.1 (0.5) AbdominalPain 2.4 (0.4) 3.1 2.1 Nausea 2.2 (0.9) 3.1 4.1 (0.5) URI 1.9 1.6 2.6 Dizziness 1.5 (0.6) 0.0 2.6 (1.0) Vomiting 1.5 (0.4) 4.7 1.5 (0.5) Rash 1.5 (1.1) 0.0 0.0 Constipation 1.1 (0.9) 0.0 0.0 Cough 1.1 0.0 1.5 Asthenia 1.1 (0.2) 1.6 1.6) 1.5(1.0) BackPain 1.1 0.0 0.5 Thefollowingadverse reactions which occurred in 1% or more of omeprazole-treatedpatients have been reportedin internationaldouble-blind,and open-label,clinicaltrialsinwhich2,631 patientsand subjectsreceived omeprazole. Incidenceof AdverseExperiences> 1% Causal RelationshipnotAssessed Omeprazole(n=2.631) Placebo(n=120) Bodyas a Whole,site unspecified Abdominalpain 5.2 3.3 Asthenia 1.3 0.8 DigestiveSystem Constipation 1.5 0.8 Diarrhea 3.7 2.5 Flatulence 2.7 5.8 Nausea 4.0 6.7 Vomiting 3.2 10.0 Acidregurgitation 1.9 3.3 NervousSystem/Psychiatric Headache 2.9 2.5 Additionaladverse experiencesoccurringin <1% of patientsor subjects in domesticand/or internationaltrials, or occurringsince the drug was marketed,are shownbelowwithin each bodysystem. In many instances, the relationshipto PRILOSECwas unclear.BodyAs a Whole:Allergicreactions including,rarely,anaphylaxis(see also Skin below),fever, pain,fatigue,malaise,abdominalswelling.Cardiovascular:Chestpain or angina,tachy cardia,bradycardia,palpitation,elevatedbloodpressure, peripheraledema. Gastrointestinal:Pancreatitis(some fatal),anorexia,irritablecolon,flatulence,fecaldiscoloration,esophageal candidiasis,mucosal atrophy of the tongue,dry mouth.Duringtreatmentwithomeprazole,gastricfundicglandpolyps havebeen noted rarely.These polypsare benignand appear to be reversiblewhen treatmentis discontinued.Gastro-duodenalcarcinoidshave been reported inpatients withZEsyndrome on long-termtreatmentwithPRILOSEC.Thisfindingis believedto bea manifestationof the underlyingcondition,whichis knownto be associated withsuch tumors. Hepatic:Mild 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,cholestatic,or mixedhepaitis, livernecrosis (somefatal),hepaticfailure(some fatal),andhepatic 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; hemifacialdysesthesia. Respiratory:Epistaxis, pharyngealpain.Skin: Rash and, rarely,cases of severe generalizedskin reactions includingtoxicepidermal necrolysis(TEN;some fatal), Stevens-Johnsonsyndrome, and erythema multiforme(some severe); purpura and/or petechiae(some withrechallenge);skin inflammation,urticaria,angioedema,pruritus,alopecia,dry skin, hyperhidrosis.SpecialSenses: Tinnitus,taste perversion. Urogenital:Interstitialnephritis (some withpositive rechallenge),urinarytract infection,microscopicpyuria,urinaryfrequency,elevatedserum creatinine,protein uria, hematuria, glycosuria, testicular pain, gynecomastia.Hematologic:Rare instances of pancytopenia, agranulocytosis(somefatal),thrombocytopenia,neutropenia,anemia,leucocytosis,and hemolyticanemia have been reported.Combination Therapyfor H. pylori Eradication: dual therapywithPRILOSECand clar ithromycinor triple therapy withPRILOSEC,clarithromycin,and amoxicillin.Adverse experiences that have occurred have been limitedto those that have been previouslyreported with omeprazole,clarithromycin,or amoxicillin.TripleTherapy(PRILOSEC/clarithromycin/amoxicillin)-The most frequent adverse experiences observedinclinicaltrials usingcombinationtherapywith PRILOSEC,clarithromycin,and amoxicillin(n = 274) were diarrhea (14%),taste perversion(10%), and headache(7%). Noneof these occurred at a higher frequency than that reported by patientstakingthe antimicrobialdrugs alone. DualTherapy(PRILOSEC/clarithromycin) Adverse experiencesobservedin controlledclinicaltrials usingcombinationtherapywith PRILOSECand clar ithromycin(n =346) whichdifferedfrom those previouslydescribedforomeprazolealonewere:Tasteperversion (15%),tongue discoloration(2%), rhinitis(2%), pharyngitis(1%) andflu syndrome (1%).Formore information onclarithromycinor amoxicillin,referto the respectivepackageinserts, ADVERSEREACTIONSsections. OVERDOSAGE:Rarereportshe been ret ceivedof overdosagewithomeprazole.Doses rangedfrom 320 mg to 900 mg (16-45timesthe usual recommendedclinicaldose). Manifestationswere variable,but includedconfu sion, drowsiness, blurred vision, tachycardia, nausea, diaphoresis, flushing, headache, and dry mouth. Symptomswere transient,and no seriousclinical outcomehas been reported.Nospecificantidotefor omepra zole overdosageis known.Omeprazoleis extensivelyproteinbound and is, therefore,not readilydialyzable.In the eventof overdosage,treatmentshould besymptomaticand supportive. DOSAGE AND ADMINISTRATION,Short-Term Treatment of Active Duodenal Ulcer: The recommendedadult oral dose of PRILOSECis 20 mg once daily.Most patients heal within4 weeks. Some patients may require an additional 4 weeks of therapy. (See INDICATIONS ANDUSAGE.)H. pylori Eradication for the Reduction of the Risk of Duodenal Ulcer Recurrence: TripleTherapy (PRILOSEC/clarithromycin/amoxicillin)- The recommendedadult oral regimen is PRILOSEC20 mg plus clar ithromycin500 mg plus amoxicillin1000mg each giventwicedailyfor10 days. Inpatients withan ulcer present at thetimeof initiationoftherapy,an additional18 daysof PRILOSEC20 mg once dailyis recommendedforulcer healingand symptom relief.DualTherapy(PRILOSEC/clarithromycin)-Therecommendedadultoral regimenis PRILOSEC40 mgonce dailyplus clarithromycin500 mg t.i .d .for 14days. In patientswithan ulcer presentat the time of initiationof therapy,an additional14 days of PRILOSEC20 mg once daily is recommendedfor ulcer healing andsymptom relief.Pleasereferto clarithromycinfullprescribinginformationforCONTRAINDICATIONS and WARNING,and for informationregardingdosing in elderlyand renallyimpairedpatients (PRECAUTIONS: General,PRECAUTIONS:GeriatricUse and PRECAUTIONS:DrugInteractions).Please refer to amoxicillinfull prescribing informationfor CONTRAINDICATIONS and WARNINGS.Gastric Ulcer: The recommendedadult oral dose is 40 mg once a day for 4 to 8 weeks. (See INDICATIONSANDUSAGE,Gastric Ulcer.) Gastroesophageal Reflux Disease (GERD):The recommendedadult oral dose for the treatment of patients withsymptomaticGERDand no esophageallesionsis 20 mg dailyfor upto 4 weeks. Therecommended adultoral doseforthe treatmentof patientswitherosive esophagitisand accompanyingsymptoms dueto GERD is 20 mg dailyfor 4 to 8 weeks.(See INDICATIONS ANDUSAGE.)Maintenance of Healing of Erosive Esophagitis: The recommended adult oral dose is 20 mg daily. Pathological Hypersecretory Conditions: Thedosage of PRILOSECinpatients withpathologicalhypersecretoryconditionsvarieswiththe individualpatient.The recommendedadult oral starting dose is 60 mg once a day. Dosesshould be adjustedto individualpatient needs and should continuefor as longas clinicallyindicated.Doses upto 120 mg t.i.d . have been administered.Dailydosagesof greater than 80 mg should be administeredin divideddoses. No dosage adjustmentis necessary forpatients withrenalimpairment,hepaticdysfunctionorfor the elderly. Manufacturedby: Merck&Co., Inc. West Point,PA19486,USA IssuedDecember1998 PRI31 Distributedby: AtS T ItA Astra Pharmaceuticals, L.P, Wayne, PA 19087 NOTE:Thissummaryprovidesimportantinformationabout PRILOSEC.If you wouldlikemore information, ask yourdoctoror pharmacistto let youreadthe professionallabelingandthen discussit withthem. Please read this summary carefully, and then ask your doctor about PRILOSEC.Noadvertisement can provide all the information needed to prescribe a drug. This advertise 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.