National Geographic : 1997 Oct
. . . . . .. serea thi su mr caeuly anhnakyu otraotPIOE. Noavrieetcnpoiealteinomto eddtCrsrb rg PRILOSEC®*(OMEPRAZOLE) Delayed-Release Capsules BRIEF SUMMARY CLINICALPHARMACOLOGY Pharmacokinetics and Metabolism: Omeprazole- In pharmacokineticstudies of single 20 mg omeprazoledoses, an increasein AUCof approximatelyfour-foldwas noted inAsian subjectscompared to Caucasians. Dose adjustment, particularlywhere maintenance of healingof erosive esophagitisis indicated,forthe hepaticallyimpaired and Asiansubjects should be considered. INDICATIONSANDUSAGEDuodenal Ulcer PRILOSECis indicated for short-termtreatment of active duodenal ulcer.Most patients heal within4 weeks. Some patients may requirean additional4 weeks of therapy PRILOSEC,in combinationwithclarithromycin,is also indicated for treatmentof patients with H.pyloriinfectionand activeduodenal ulcerto eradicate H.pylori.Eradicationof H.pylorihas been shown to reduce the riskof duodenal ulcerrecurrence.In patients who failtherapy,susceptibilitytesting should be done.Ifresistance to clarithromycinis demonstratedorsuscep tibilitytesting is not possible, alternativeantimicrobialtherapyshould be instituted.(See the clarithromycinpackage insert,MICROBIOLOGYsection.)Gastric Ulcer: PRILOSECis indicatedforshort-termtreatment(4-8 weeks)of active benign gastriculcer. Treatment of Gastroesophageal RefluxDisease (GERD):Symptomatic GERD- PRILOSEC is indicated for the treatment of heartburn and other symptoms associated with GERD.Erosive Esophagitis PRILOSECis indicated forthe short-termtreatment (4-8 weeks) of erosiveesophagitis whichhas been diagnosed by endoscopy The efficacyof PRILOSECused forlonger than 8 weeks inthese patients has not been established. In the rare instance of a patient not respondingto 8 weeks of treatment,it may be helpfulto give up to an additional4 weeks of treatment. If there is recurrence of erosive esophagitis or GERDsymptoms (e.g. heartburn),additional4-8 week courses ofomeprazolemay be considered,Maintenance of Healing of Erosive Esophagitis: PRILOSECis indicated to maintain healing of erosive esophagitis. Controlledstudies do not extend beyond 12 months. Pathological Hypersecretory Conditions: PRILOSECis indicatedforthe long-termtreatmentof pathologicalhypersecretorycondi tions (e.g .,Zollinger-Ellison syndrome,multipleendocrineadenomas and systemic mastocytosis). CONTRAINDICATIONS Omeprazole: PRILOSECDelayed-ReleaseCapsules are contraindicatedin patients with known hypersensitivityto any component of the formulation.Clarithromycin:Clarithromycinis contraindicatedin patients with a known hypersensitivityto any macrolideantibiotic.Concomitantadministrationof clarithromycinwith cisapride,pimozide,or tertenadineis contraindicated.There havebeen post-marketingreportsof druginteractionswhen clarthromycinand/or erythromycinare co-administeredwithcisapride, pimozide,or terfenadine resultingin cardiac arrhythmias(QTprolongation,ventriculartachycardia,ventricularfibrillation,and torsades de pointes)most likelydue to inhibitionof hepatic metabolismof these drugs byerythromycinand claithromycin.Fatalitieshave been reported.(Please referto fullprescribinginformationfor clarithromycinbeforeprescribing.) WARNING:Clarithromycin:CLARITHROMYCINSHOULDNOT BEUSEDIN PREGNANTWOMENEXCEPTIN CLINICALCIRCUMSTANCESWHERE NO ALTERNATIVETHERAPYIS APPROPRIATE.IF PREGNANCY OCCURSWHILETAKINGCLARITHROMYCIN,THEPATIENTSHOULDBEAPPRISEDOF THEPOTENTIAL HAZARDTO THEFETUS.(SeeWARNINGSin prescribinginformationfor clarithromycin.) PRECAUTIONSGeneral: Symptomatic response to therapy withomeprazole does not preclude the presence of gastric malignancy.Atrophicgastritishas been noted occasionallyingastric corpus biopsiesfrom patients treated long termwithomeprazole.Informationfor Patients: PRILOSECDelayed-ReleaseCapsulesshould be taken before eating. Patientsshould be cautionedthat the PRILOSECDelayed-ReleaseCapsule shouldnot be opened, chewed orcrushed, and should be swallowedwhole. Drug Interactions: Other- Omeprazolecan prolong the eliminationof diazepam, warfarinand phenytoin,drugs that are metabolizedbyoxidationinthe liver.Althoughinnormalsubjects no interaction withtheophyllineor propranololwas found,there have been clinicalreportsof interactionwithother drugs metabolized via the cytochrome P-450 system (e.g ., cyclosporine,disulfiram,benzodiazepines).Patients should be monitoredto determinef itis necessary to adjustthe dosage of these drugs when taken concomitantlywithPRILOSEC.Because of its profoundand longlastinginhibitionof gastric acid secretion,it is theoreticallypossiblethat omeprazolemay interfere with absorption of drugs where gastric pH is an important determinantof their bioavailability(e.g ., ketoconazole, ampicillinesters, and iron salts). In the clinical trials, antacids were used concomitantly withthe administrationof PRILOSEC.CombinationTherapy with Clarithromycin- Co-administrationof omeprazoleand clarithromycinmay result in increases in plasma levels of omeprazole, clarithromycin,and 14-hydroxy-clarithromycin. (See CLINICAL PHARMACOLOGY,Pharmacokinetics:Combination Therapy with Clarithromycinin full Prescribing Information.) Concomitantadministrationof clarithromycinwith cisapide, pimozide,or terfenadineis contraindicated.There have been reports of an interactionbetween erythromycinand astemizole resultingin QT prolongationand torsades de pointes. Concomitantadministrationof erythromycinand astemizole is contraindicated.Because clarithromycinis also metabolizedby cytochrome P450, concomitant administrationof clarithromycinwithastemizole is not recommended. (See also CONTRAINDICATIONS, Clarithromycin,above. Pleaserefer to fullprescribing informationfor clarithromycin before prescribing.)Carcinogenesis, Mutagenesis, Impairment of Fertility:Intwo 24-month carcinogenicitystudies in rats, omeprazoleat dailydoses of 1.7, 3.4, 13.8, 44.0 and 140.8mg/kg/day(approximately4 to 352 timesthe human dose, based on a patient weight of 50 kgand a human dose of 20 mg)produced gastric ECLcellcarcinoidsina dose related manner inboth male and female rats; the incidenceofthis effect wasmarkedlyhigherin femalerats, whichhad higher blood levelsof omeprazole.Gastriccarcinoidsseldom occur inthe untreated rat. Inaddition, ECLcellhyperplasia was present inalltreated groups of both sexes. In one of these studies,female rats were treated with13.8 mg/kg/day omeprazole (approximately35 timesthe human dose) for 1 year,then followedforan additionalyear withoutthe drug. No carcinoidswere seen inthese rats. Anincreae idn o reased incidenceoftatmlated ECLcellhyperplasiawas observed at the end of 1 year (94%treated vs 10% controls).By the second year the differencebetween treated and controlrats was much smaller (46%vs 26%)but stillshowed more hyperplasiain the treated group.An unusual primarymalignant tumor inthe stomach was seen inone rat (2%).No similartumor wasseen in maleor female rats treated for2 years.For this strainof rat no similartumorhas been noted historically,but a findinginvolvingonlyone tumor isdifficultto interpret. A 78-week mousecarcinogenicitystudyof omeprazoledid not show increasedtumoroccurrence,but the studywas not conclusive. Omeprazole was not mutagenicin an in vitro Ames Salmonellatyphimuriumassay, an in vitro mouse lymphomacellassay and an in vivorat liverDNAdamage assay. A mouse micronucleustest at 625 and 6250 timesthe human dose gave a borderlineresult, as did an in vivo bone marrowchromosomeaberration test. A second mouse micronucleusstudy at 2000 times the human dose, but with different(suboptimal)samplingtimes, was negative. Pregnancy: Omeprazole:Pregnancy CategoryC - Inrabbits,omeprazoleina dose range of6.9 to 69.1 mg/kg/day (approximately17 to 172 timesthe human dose) produced dose-relatedincreases in embryo-lethality,fetalresorptions and pregnancy disruptions. In rats, dose-related embryo/fetal toxicityand postnatal developmental toxicitywere observed inoffspringresultingfrom parents treated withomeprazole13.8 to 138.0 mg/kg/day(approximately35 to 345 times the human dose). There are no adequate or well-controlledstudies in pregnant women.Sporadicreports have been received of congenitalabnormalitiesoccurringin infants born to women who have receivedomeprazoleduring pregnancy Omeprazole should be used duringpregnancy onlyi the potentialbenefitjustifiesthe potentialrisk to the fetus. Clarithromycin:Pregnancy Category C - See WARNING(above) and full prescribing informationfor clarithromycinbefore usinginpregnant women. NursingMothers: It is not known whetheromeprazoleis excretedin human milk.Inrats, omeprazoleadministrationduringlate gestationand lactationat doses of 13.8 to 138 mg/kg/day(35 to 345 timesthe human dose) resulted indecreased weight gain inpups. Because manydrugs are excreted inhuman milk, because of the potential forserious adverse reactions innursing infants from omeprazole,and because of the potentialfor tumorgenicityshown foromeprazolein rat carcinogenicitystudies, a decision should be made whetherto discontinuenursingor discontinuethe drug, taking into account the importance of the drug to the mother. Pediatric Use: Safety and effectivenessinchildrenhave not been established. ADVERSEREACTIONS:In the U.S . clinicaltrialpopulationof 465 patients (includingduodenal ulcer,Zollinger-Ellison syndrome and resistant ulcer patients),the followingadverse experiences were reported to occur in 1% or more of patients on therapy with PRILOSEC.Numbers in parentheses indicate percentages of the adverse experiences considered by investigatorsas possibly,probably,or definitelyrelated tothe drug. Headache Diarrhea AbdominalPain Nausea URI Dizziness Vomiting Rash Constipation Cough Asthenia BackPain Omeprazole (n=465) 6.9(2.4) 3.0(1.9) 2.4(0.4) 2.2(0.9) 1.9 1.5(0.6) 1.5(0.4) 1.5(1.1) 1.1(0.9) 1.1 1.1(0.2) 1.1 Placebo(n=64) 6.3 3.1(1,6) 3.1 3.1 1.6 0.0 4.7 0.0 0.0 0.0 1.6(1.6) 0.0 Ranitidine (n=195) 7.7(2.6) 2.1(0.5) 2.1 4.1(0.5) 2.6 2.6(1.0) 1.5(0.5) 0.0 0.0 1.5 1.5(1.0) 0.5 Thefollowingadverse reactionswhichoccurred in 1% or more of omeprazole-treatedpatients have been reportedin intemationaldouble-blind,and open-label,clinicaltrialsinwhich 2,631 patients and subjects receivedomeprazole. IncidenceofAdverse Experiences> 1%Causal Relationshipnot Assessed Omeprazole(n=2631) Placebo (n=120) Body asa 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 Nervous System/Psychiatric Headache 2.9 2.5 Additionaladverse experiences occurring in <1% of patients or subjects in domestic and/or internationaltrials, or occurringsince the drug was marketed,are shown below withineach body system. Inmany instances, the relationship to PRILOSEC ® (omeprazole)was unclear. Body As a Whole: Fever, pain, fatigue, malaise, abdominal swelling. Cardiovascular:Chest pain or angina, tachycardia,bradycardia,palpitation,elevated blood pressure, peripheraledema. Gastrointestinal:Pancreatitis(somefatal),anorexia,irritablecolon,flatulence,fecaldiscoloration,esophagealcandidiasis, mucosal atrophy of the tongue, dry mouth. Duringtreatmentwithomeprazole, gastric fundicgland polyps have been noted rarely.These polyps are benign and appear to be reversiblewhen treatmentis discontinued.Gastro-duodenal carcinoids have been reported in patients withZE syndrome on long-termtreatment with PRILOSEC.Thisfinding is believedto be a manifestationof the underlyingcondition,whichis knownto be associated withsuch tumors. Hepatic: Mildand, rarely,markedelevationsof liverfunctiontests [ALT(SGPT),AST (SGOT),y-glutamyltranspeptidase, alkaline phosphatase, and bilirubin(jaundice)].In rare instances, overt liverdisease has occurred, includinghepatocellular, cholestatic, or mixed hepatitis, livernecrosis (some fatal, hepatic failure(some fatal),and hepatic encephalopathy. Metabolic/Nutritional:Hyponatrema, 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, somnolence, anxiety,dream abnormalities;vertigo; paresthesia; hemifacialdysesthesia. Respiratory:Epistaxis,pharyngealpain.Skin: Rashand, veryrarely,cases ofsevere generalizedskin reactions includingtoxic epidermalnecrolysis (TEN;some fatal), Stevens-Johnson syndrome,and erythema multiforme(some severe);skininflammation,urticaria,angioedema, pruritus,alopecia,dry skin,hyperhidrosis. SpecialSenses: Tinnitus,taste perversion.Urogenital:Interstitalnephritis(some withpositiverechallenge),urinarytract infection,microscopicpyuria,urinaryfrequency,elevated serum creatinine,proteinuria,hematuria,glycosuria,testicular pain, gynecomastia. Hematologic:Rare instances of pancytopenia, agranulocytosis(some fatal), thrombocytopenia, neutropenia, anemia, leucocytosis, and hemolyticanemia have been reported. Combination Therapy with Clarithromycin:InclinicaltrialsusingcombinationtherapywithPRILOSECand clarithromycin,no adverse experiences peculiarto this drug combinationhave been observed. Adverse experiences that have occurred have been limitedto those that have been previouslyreportedwithomeprazoleor clarthromycin.Adverse experiencesobserved incontrolled clinicaltrialsusing combinationtherapywithPRILOSECand clarithromycin(n=346)which differedfromthose previously described foromeprazolealonewere: Tasteperversion(15%),tongue discoloration(2%),rhinitis(2%),pharyngitis(1%), and flu syndrome (1%).For more informationon clarithromycin,refer to the clarithromycinpackage insert, ADVERSE REACTIONSsection. OVERDOSAGE:Rare reports have been receivedof overdosagewithomeprazole. Doses ranged from 320 mg to 900 mg (16-45 times the usual recommended clinicaldose). Manfestations were variable, but included confusion, drowsiness, blurredvision, tachycardia, nausea, diaphoresis,flushing, headache, and dry mouth. Symptoms were transient, and no seriousclinicaloutcome has been reported. Nospecificantidotefor omeprazoleoverdosageis known. Omeprazoleis extensivelyproteinbound and is, therefore,not readilydialyzable.Inthe eventof overdosage, treatment should be symptomaticand supportive. DOSAGEANDADMINISTRATION Duodenal Ulcer Short-TermTreatmentof ActiveDuodenal Ulcer:The recom mended adultoraldose of PRILOSECis 20 mg once daily.Most patients healwithin4 weeks. Some patients may require an additional4 weeks of therapy.(SeeINDICATIONSANDUSAGE.) Reduction ofthe Riskof DuodenalUlcerRecurrence:CombinationTherapywithClarithromycin Days1-14: Days 15-28: PRILOSEC 4 0 mg q.d . (inthe morning)plus clarithromycin500 mg t.i.d . PRILOSEC20 mg q.d . Please referto clarithromycinfullprescribinginformationfor CONTRAINDICATIONS and WARNING,and for information regardingdosing in elderlyand renallyimpairedpatients (PRECAUTIONS:General,PRECAUTIONS:GenatricUse and PRECAUTIONS:Drug Interactions).Gastric Ulcer The recommended adultoral dose is 40 mg once a day for 4 to 8 weeks. (SeeINDICATIONSANDUSAGE,GastricUlcer.)Gastroesophageal Reflux Disease (GERD):The recom mended adultoraldose for the treatmentof patients withsymptomaticGERDand no esophageal lesionsis 20 mg daily for upto 4 weeks. The recommendedadultoraldose forthe treatmentof patients witherosive esophagitisand accom panyingsymptoms due to GERDis 20 mg dailyfor4 to 8 weeks. (SeeINDICATIONSANDUSAGE.)Maintenance of Healing of Erosive Esophagitis: The recommended adult oraldose is 20 mg daily.Pathological Hypersecretory Conditions: Thedosage of PRILOSECinpatients withpathologicalhypersecretoryconditionsvarieswiththe individual patient.The recommendedadult oral startingdose is 60 mg once a day.Doses should be adjusted to individualpatient needs and should continueforas longas clinicallyinicated. Doses up to 120 mg t.i .d . have been administered.Daily dosages ofgreaterthan 80 mg should beadministeredin divideddoses, Nodosage adjustmentis necessary for patients withrenalimpairment,hepaticdysfunctionor for the elderly Distributedby: AstraMerck Wayne,PA 19087,USA February1997 PRC-40/3/97 Manufacturedby: MERCK&C., INC. West Point,PA 19486,USA PR124 NOTE:This summary provides important information about PRILOSEC.If you would like more information, ask your doctor or pharmacist to let you read the professional labeling and then discuss it with them. 'Registeredtrademarkof AstraAB.