National Geographic : 2007 Feb
Ambient © (zolpidem tartrate) INDICATIONS ANDUSAGE Ambien(zolpidem tartrate) is indicated forthe short-term treatment ofinsomnia.Ambienhasbeen shownto decrease sleeplatencyand increasethe duration ofsleepfor upto 35daysin controlled clinicalstudies (seeClinicalPharmacology:Controlledtrials supportingsafety and efficacy). Theclinicaltrials performed in support ofefficacywere4-5weeksinduration withthe finalformal assessments ofsleep latencyperformed at the end oftreatment. CONTRAINDICATIONS Ambieniscontraindicated inpatients withknownhypersensitivityto zolpidemtartrate orto anyof the inactiveingredients inthe formulation. WARNINGS Becausesleep disturbances maybe the presenting manifestationof a physicaland/or psychiatric disorder, symptomatic treatment of insomniashouldbe initiatedonlyafter a carefulevaluationof the patient. Thefailure of insomnia to remit after 7 to 10 daysof treatment mayindicate the presence of a primary psychiatricand/or medicalillnessthat shouldbe evaluated. Worsening of insomnia or the emergence ofnewthinking or behaviorabnormalities may betheconsequence of an unrecognizedpsychiatricor physicaldisorder.Suchfindingshaveemergedduring the course of treatment withsedative/hypnotic drugs, includingAmbien.Becausesome of the important adverseeffectsofAmbienappear to bedoserelated(seePrecautionsand DosageandAdminstraion), it isimportant to usethe smallest possibleeffectivedose, especiallyinthe elderly. Avarietyofabnormal thinking and behaviorchangeshavebeen reported to occurin associationwith the use ofsedative/hypnotics. Someofthese changesmaybe characterizedbydecreasedinhibition leg, aggressivenessand extroversionthat seemedout of character),similarto effectsproduced by alcoholand other CNSdepressants. Other reportedbehavioralchangeshaveincludedbizarre behavior, agitation, hallucinations, and depersonalization.Amnesiaand other neuropsychiatric symptoms may occur unpredictably.In primarilydepressedpatients, worseningof depression, includingsuicidalthinking, has been reportedin associationwiththe useof sedative/hypnotics. It canrarelybe determined withcertainty whether a particular instance ofthe abnormal behaviors listedabove is drug induced, spontaneous in origin,or a result of an underlyingpsychiatricor physicaldisorder. Nonetheless,the emergence ofany newbehavioralsignor symptomof concern requirescarefuland immediate evaluation. Followingthe rapid dose decrease or abrupt discontinuation of sedative/hypnotics, there have beenreports ofsignsand symptoms similarto those associatedwithwithdrawalfrom other CNS depressant drugs (seeDrugAbuse and Dependence). Ambien,likeother sedative/hypnotic drugs,has CNS-depressant effects.Dueto the rapid onset of action,Ambienshouldonlybe ingestedimmediatelyprior to goingto bed. Patientsshouldbe cautioned against engaginginhazardous occupationsrequiringcomplete mentalalertness or motor coordination suchasoperating machineryordrivinga motor vehicleafter ingestingthe drug,includ ing potential impairment of the performance of suchactivitiesthat mayoccurthe dayfollowing ingestionofAmbien.Ambienshowedadditive effectswhencombined withalcoholand shouldnot be taken withalcohol.Patientsshould alsobe cautioned about possiblecombined effectswith other CNS-depressant drugs. Dosageadjustments may be necessarywhen Ambienisadministered withsuchagents becauseofthe potentiallyadditiveeffects. PRECAUTIONS General Usein the elderlyand/or debilitated patients: Impairedmotor and/or cognitiveperformance after repeated exposure or unusual sensitivityto sedative/hypnotic drugsis a concerninthe treat ment ofelderly and/or debilitated patients. Therefore,the recommended Ambiendosageis 5 mg in such patients (seeDosageand Administration)to decrease the possibilityofside effects.These patients should becloselymonitored. Usein patients with concomitant illness:ClinicalexperiencewithAmbien(zolpidem tartrate) in patients with concomitant systemicillnessis limited.Cautionis advisablein usingAmbienin patients withdiseases or conditions that couldaffect metabolism or hemodynamic responses. Althoughstudies did not revealrespiratorydepressant effectsat hypnoticdoses of Ambienin normals or in patients with mildto moderate chronicobstructive pulmonary disease(COPD),a reductionin the TotalArousalIndextogether witha reduction in lowestoxygensaturation and increasein the times of oxygendesaturation below80%and 90%was observedin patients with mild-to-moderate sleep apnea when treated withAmbien(10 mg)when compared to placebo. However,precautions should be observedifAmbienis prescribedto patients withcompromised respiratoryfunction, sincesedative/hypnotics have the capacityto depress respiratorydrive.Post marketing reports of respiratoryinsufficiency, most of whichinvolvedpatients with pre-existing respiratoryimpairment, have been received.Data in end-stage renal failurepatients repeatedly treated withAmbiendid not demonstrate drug accumulation or alterations inpharmacokinetic parameters. Nodosage adjustment inrenallyimpaired patients isrequired; however,these patients should be closelymonitored (see Pharmacokinetics).A studyin subjectswithhepatic impairment did revealprolongedelimination inthis group;therefore, treatment shouldbe initiatedwith5 mg inpatients withhepatic compromise, and they should becloselymonitored. Use in depression: As withother sedative/hypnotic drugs, Ambienshould be administered with caution to patients exhibiting signsor symptoms ofdepression. Suicidaltendencies may bepresent in such patients and protective measures may be required. Intentional overdosageis more common inthis group of patients; therefore, the leastamount of drug that is feasibleshould be prescribedforthe patient at any one time. Information for patients: Patient information is printedat the end of this insert.To assure safe and effectiveuseof Ambien,this information and instructions providedinthe patient information sectionshould be discussedwithpatients. Laboratory tests: There are nospecificlaboratory tests recommended. Druginteractions CNSactivedrugs:Ambienwasevaluatedin healthyvolunteersin single-doseinteractionstudiesfor severalCNSdrugs.Astudyinvolvinghaloperidoland zolpidemrevealedno effectof haloperidolon the pharmacokineticsor pharmacodynamics ofzolpidem.Imipraminein combinationwithzolpidem producedno pharmacokinetic interactionother than a 20%decreasein peaklevelsof imipramine, but there wasan additiveeffectofdecreasedalertness.Similarly, chlorpromazine in combinationwith zolpidemproducedno pharmacokineticinteraction,butthere was an additiveeffectof decreased alertnessand psychomotorperformance.The lackofadrug interactionfollowingsingle-doseadmin istrationdoes not predicta lackfollowingchronicadministration. Anadditiveeffecton psychomotor performance between alcoholand zolpidem wasdemonstrated. A single-doseinteractionstudywithzolpidem10 mg and fluoxetine20 mg at steady-statelevels in male volunteersdid not demonstrate any clinicallysignificantpharmacokineticor pharmaco dynamicinteractions.Whenmultipledosesofzolpidemandfluoxetineat steady-stateconcentrations were evaluatedin healthyfemales,the onlysignificantchangewasa 17%increaseinthe zolpidem half-life.Therewasno evidenceofan additive effectin psychomotor performance. Followingfiveconsecutivenightlydoses ofzolpidem 10 mginthe presence of sertraline 50 mg(17 consecutivedailydoses, at 7:00am, inhealthy female volunteers),zolpidem Cmawassignificantly higher (43%)and Tmawas significantlydecreased (53%).Pharmacokineticsof sertraline and N-desmethylsertraline were unaffectedbyzolpidem. Sincethe systematicevaluations of Ambien(zolpidemtartrate) in combination withother CNS activedrugshavebeen limited,carefulconsideration should begivento the pharmacology ofany CNS-activedrug to be usedwithzolpidem. Anydrug withCNS-depressant effectscouldpotentially enhance the CNS-depressant effectsof zolpidem. Drugsthat affect drug metabolism via cytochromeP450: Arandomized, double-blind, crossover interaction studyinten healthy volunteers betweenitraconazole(200mg once dailyfor4 days)and a singledose ofzolpidem(10mg)given5 hours afterthe lastdose of itraconazoleresulted in a 34% increaseinAUCQ,ofzolpidem. Therewere nosignificantpharmacodynamic effectsofzolpidem on subjectivedrowsiness,posturalsway,or psychomotorperformance. A randomized,placebo-controlled, crossoverinteractionstudyin eight healthy female volunteers between5 consecutivedailydosesof rifampin(600mg)and a singledose ofzolpidem (20mg)given 17hoursafterthe lastdoseof rifampinshowedsignificantreductionsofthe AUC(-73%),Cm (-58%), andT 2 (-36%)ofzolpidemtogether withsignificantreductionsinthe pharmacodynamic effectsof zolpidem. Other drugs:A study involvingcimetidine/zolpidem and ranitidinel zolpidem combinations revealedno effectof either drug on the pharmacokinetics or pharmacodynamics of zolpidem. Zolpidemhad no effecton digoxinkineticsand did not affectprothrombin time when givenwith warfarinin normal subjects. Zolpidem'ssedative/hypnoticeffect was reversedby flumazenil; however,nosignificantalterations in zolpidempharmacokinetics werefound. Drug/Laboratorytest interactions: Zolpidemis not knownto interferewithcommonly employed clinicallaboratorytests.Inaddition, clinicaldata indicate that zolpidem does not cross-reactwith benzodiazepines, opiates, barbiturates, cocaine,cannabinoids, or amphetamines intwo standard urine drug screens. Cardinogenesis, mutagenesis, impairment of fertility Carcinogenesis: Zolpidemwasadministered to ratsand micefor2 yearsat dietarydosagesof4,18, and80 mg/kg/day.Inmice,these dosesare 26 to 520times or 2 to 35 times the maximum 10-mg human doseon a mg/kgormg/m2basis,respectively.Inrats these doses are 43 to 876times or 6 to 115times the maximum10-mghuman doseona mg/kgor mg/m 2 basis, respectively.Noevidence ofcarcinogenicpotentialwasobservedinmice.Renalliposarcomas wereseen in4/100rats(3males, 1 female) receiving80 mg/kg/dayand a renal lipoma was observedin one male rat at the 18mg/kg/daydose. Incidenceratesof lipomaand liposarcomafor zolpidemwerecomparable to those seeninhistoricalcontrolsandthe tumor findingsare thought to be a spontaneous occurrence. Mutagenesis:Zolpidemdidnot havemutagenicactivityin severaltestsincludingthe Amestest, geno toxicityinmouselymphomacellsinvitro,chromosomalaberrations in culturedhuman lymphocytes, unscheduledDNAsynthesisin rat hepatocytesin vitro,andthe micronucleustest inmice. Impairment of fertility: Ina rat reproductionstudy,the highdose (100mg base/kg)ofzolpidem resultedin irregularestruscyclesand prolongedprecoitalintervals,but there wasnoeffecton male orfemale fertilityafter dailyoraldosesof4 to 100mgbase/kgor 5to 130times the recommended human dose in mg/m 2 . Noeffectson any other fertilityparameters were noted. Pregnancy Teratogeniceffects:PregnancyCategoryC. Zolpidemtartrate was administered to pregnant Sprague-Dawley rats byoral gavageduring the periodof organogenesisat doses of4, 20,or 100mgbase/kg/day.Adversematernal and embryo/ fetal effectsoccurredat dosesof 20 mgbase/kgand higher,manifesting as dose-related lethargy and ataxiain pregnant rats whileexamination offetal skull bones revealeda dose-related trend towardincomplete ossification.Teratogenicitywas not observedat any dose level.The no-effect doseofzolpidemfor maternal and embryofetaltoxicitywas4 mgbase/kg/day (between 4 to 5times the MRHDofAmbienon a mg/m 2 basis). Administrationof zolpidemtartrate to pregnant HimalayanAlbinorabbitsat doses of 1, 4, or 16mgbase/kg/daybyoral gavage(over35 timesthe MRHDof Ambien,on a mg/m2basis)during the periodof organogenesisproduceddose-relatedmaternalseat aa daion and decreasedmaternal bodyweightgainat all doses.At the highdoseof 16 mgbase/kg,there wasan increasein post implantationfetal lossand under-ossification ofsternebrae in viablefetuses.Teratogenicitywasnot observedat any dose level The no-effectdose of zolpidemfor maternal toxicitywas below 1mgbase/kg/day< 2-timesthe MRHDofAmbienona mg/m 2 basis).Theno-effectdoseforembryo fetaltoxicitywas4mgbase/kg/day(between9and10timesthe MRHDofAmblenona mg/m 2 basis). Administrationof zolpidemtartrate at dosesof4, 20, or 100mg ase/kg/day to pregnant Sprague Dawleyrats starting on Day15of gestationand continuing through Day21 ofthe postnatal lacta tion periodproduceddose-dependent lethargyand ataxiaindams at doses of20 mgbase/kg and higher.Decreasedmaternal bodyweightgain as wellas evidenceon non-secreting mammary glandsand a singleincidenceof maternal death wasobservedat 100mgbase/kg. Effectsobserved on rat pups includeddecreasedbodyweightwithmaternal dosesof 20mgbase/kg and higher and decreasedpup survivalat maternal dosesof 100mgbase/kg.Theno-effectdose for maternal and offspringtoxicitywas 4 mgbase/kg(between 4 to 5 times the MRHDofAmbienon a mg/m 2 basis). Thereare no adequate and well-controlled studiesinpregnant women. Ambienshould be used during pregnancyonlyifthe potentialbenefitjustifiesthe potential riskto the fetus. Nonteratogenic effects:Studiesto assessthe effectson childrenwhose mothers took zolpidem during pregnancyhavenot been conducted. However,childrenbornof mothers taking sedative/ hypnoticdrugsmaybe at some riskforwithdrawalsymptoms from the drug during the postnatal period.Inaddition, neonatal flaccidityhas been reportedininfants bornof mothers who received sedative/hypnotic drugsduring pregnancy. Laborand delivery:Ambien(zolpidemtartrate) has noestablished usein labor and delivery. Nursingmothers: Studiesinlactatingmothersindicatethat the half-lifeof zolpidemissimilarto that inyoungnormal volunteers (2.6± 0.3 hr).Between0.004and 0.019%ofthe total administered dose isexcretedinto milk,but the effectofzolpidemon the infant isunknown. In addition, in a rat study,zolpidem inhibitedthe secretionof milk.The no-effectdose was 4 mgbase/kg or 6times the recommended human dose in mg/m 2 . The useof Ambienin nursing mothers is not recommended. Pediatric use: Safetyand effectivenessin pediatricpatients belowthe ageof 18havenot beenestablished. Geriatricuse: Atotal of154patients inU.S .controlledclinicaltrialsand 897patients in non-U.S .clinicaltrialswho receivedzolpidemwere>60yearsof age. Fora pool ofU.S .patients receivingzolpidemat dosesof <10 mg or placebo, there werethree adverseeventsoccurringat an incidenceof at least3%for zolpidemand for whichthe zolpidemincidencewasat leasttwicethe placeboincidence(ie,they couldbe considereddrug related). AdverseEvent Zolpidem Placebo Dizziness 3% 0% Drowsiness 5% 2% Diarrhea 3% 1% Atotalof30/1,959(1.5%non-U.S .patientsreceiving zolpidemreportedfalls,including28/30(93%)who were o70yearsofage.Ofthese 28patients,23 (82%)werereceivingzolpidemdoses>10 mgAtotal of 24/1,959(1.2%)non-U .S .patientsreceivingzolpidemreportedconfusion,including18/24(75%)who were>70yearsofage.Ofthese 18patients,14(78%)werereceivingzolpidemdoses>10 mg. ADVERSE REACTIONS Associatedwith discontinuation oftreatment: Approximatel oately 4%of1,71 patientswho received zolpidemat all doses (1.25to 90 mg)in U.S .premarketing clinicaltrials discontinued treatment becauseof an adverseclinicalevent. Eventsmost commonly associatedwithdiscontinuation from U.S .trialswere daytime drowsiness(0.5%),dizziness(0.4%),headache (0.5%),nausea (0.6%),and vomiting (0.5%). Approximately4%of 1,959patients who receivedzolpidemat all doses (1to 50 mg)in similar foreigntrialsdiscontinuedtreatment becauseofan adverseevent.Eventsmost commonlyassociated withdiscontinuation from these trials were daytime drowsiness(1.1%),dizziness/vertigo(0.8%), amnesia (0.5%),nausea (0.5%),headache (0.4%),and falls(0.4%). Datafroma clinicalstudyin whichselectiveserotoninreuptakeinhibitor-(SSRI)treatedpatientswere givenzolpidemrevealedthat fourof the sevendiscontinuations duringdouble-blindtreatment with zolpidem(n=95)wereassociatedwithimpairedconcentration,continuingoraggravateddepression,and manicreaction;one patienttreatedwithplacebo(n=97)wasdiscontinuedafteran attempted suicide.