HIGHLIGHTSOFPRESCRIBINGINFORMATION

Thesehighlightsdonotinclude alltheinformationneededtouseCODEINEsulfate tablets,USPsafely andeffectively.See fullprescribinginformationforCODEINEsulfatetablets,USP.

CODEINEsulfatetablets,USPfororal use, CIIInitialU.S.Approval: 1950

------INDICATIONSAND USAGE ------

CodeineSulfateTablets,USParean opioidanalgesicindicatedfor the reliefof mildto moderatelyseverepainwhere theuseof anopioid analgesicisappropriate.

------DOSAGEAND ADMINISTRATION------

Usual adultdosage:15to 60mgup to every4hours asneeded.

Dosesabove60mg mayfail to givecommensuratepain relief,andmaybeassociatedwithan increased incidenceof undesirablesideeffects.

------DOSAGEFORMSAND STRENGTHS ------

CodeineSulfateTablets,USP: 15mg,30mg,and 60mg.

------CONTRAINDICATIONS------

  • Postoperativepainmanagementof childrenundergoingtonsillectomyand/or adenoidectomy(4)
  • Hypersensitivityto codeinesulfateoranycomponentof theproduct(4)
  • Respiratorydepressionintheabsenceof resuscitativeequipment (4)
  • Acuteor severebronchial asthmaorhypercarbia(4)
  • ParalyticIleus (4)

------WARNINGS AND PRECAUTIONS ------

  • Riskofdeath in ultra-rapidmetabolizers: Conversionof codeineinto itsactivemetabolite,morphine,mayoccur morerapidlyandcompletelyresultingin higher thanexpected morphinelevels andrespiratorydepressionor death.(5.1)
  • Respiratorydepression:Increasedrisk inelderly,debilitatedpatients,thosesuffering fromconditionsaccompanied byhypoxia,hypercapnia,or upper airwayobstruction.(5.2)
  • Controlledsubstance: CodeinesulfateisaScheduleIIcontrolledsubstance withan abuseliabilitysimilar toother opioids.(5.3)
  • CNSeffects: AdditiveCNSdepressiveeffects,includingrespiratorydepression,hypotension,profoundsedation,coma,or

deathwhen usedin conjunctionwithalcohol,other opioids,orillicit drugs.(5.4)

  • Elevationof intracranial pressure: Maybemarkedly exaggeratedinthepresenceof head injury,other intracranial lesions.(5.5)
  • Hypotensiveeffect:Increasedrisk withcompromised abilitytomaintain bloodpressure.(5.6)
  • Prolongedgastricobstruction:Inpatientswithgastrointestinalobstruction,especiallyparalyticileus.(5.7)
  • Pancreatic/biliarytract disease: Maycausespasmof the sphincterof Oddi and diminish biliaryand pancreaticsecretions.(5.8)
  • Impairedmental/physical abilities: Cautionmustbeusedwithpotentiallyhazardousactivities.(5.10)

------ADVERSEREACTIONS ------

Themostcommon adversereactionsinclude: drowsiness,lightheadedness,dizziness,sedation,shortnessof breath,nausea,vomiting,and sweating.(6)To report SUSPECTED ADVERSE REACTIONS,contactRoxaneLaboratories,Inc.at800-962-8364or FDA at1-800-FDA-1088 or

------DRUGINTERACTIONS ------

  • CNSdepressants: IncreasedriskofadditiveCNSdepression.Usewithcautioninreduced dosages.(7.1)
  • Anticholinergics: Additiverisk of urinaryretention and paralyticileus.(7.3)
  • Antidepressants:Maycauseexcessivesedation,acute hypotensionandexcessiveanticholinergiceffects.Usewith caution inreduceddosages to personsreceiving MAOinhibitorsor tricyclicantidepressants.(7.4)
  • Metabolicenzymes: Concomitant useof cytochromeP-4502D6and 3A4enzyme inducersor inhibitorsmayresultin analteredresponseto codeine.Monitor analgesicactivityand adversedrugreactions.(7.5)

------USEIN SPECIFICPOPULATIONS------

  • Pregnancy: Basedon animal data,maycausefetal harm.(8.1)
  • Nursing mothers: Therisk of infantexposure to codeineandmorphinethrough breastmilkshouldbe weighedagainst thebenefitsofbreastfeeding forboth themother and the baby.(8.3)
  • Pediatric use: Codeineiscontraindicatedfor postoperativepainmanagementof children undergoingtonsillectomyand/oradenoidectomy(8.4)
  • Geriatricpatients(8.5),Renalimpairment(8.6),Hepaticimpairment(8.7): Usecaution duringdoseselection,startingat thelowendof thedosing range while carefullymonitoring for sideeffects

See17forPATIENTCOUNSELINGINFORMATION

Revised:09/2015

FULL PRESCRIBINGINFORMATION: CONTENTS*

WARNING: DEATHRELATEDTOULTRA-RAPID METABOLISMOF CODEINETOMORPHINE

1INDICATIONSAND USAGE

2DOSAGEAND ADMINISTRATION

2.1Individualizationof Dosage

2.2Initiationof Therapy

2.3Cessationof Therapy

3DOSAGEFORMSAND STRENGTHS

4CONTRAINDICATIONS

5WARNINGS AND PRECAUTIONS

5.1Death Relatedto Ultra-Rapid MetabolismofCodeineto Morphine

5.2RespiratoryDepression

5.3Misuseand Abuseof Opioids

5.4Interaction withAlcohol andDrugsof Abuse

5.5HeadInjuryandIncreasedIntracranial Pressure

5.6HypotensiveEffect

5.7Gastrointestinal Effects

5.8UseinPancreatic/BiliaryTractDisease

5.9SpecialRiskPatients

5.10Driving and OperatingMachinery

6ADVERSE REACTIONS

7DRUGINTERACTIONS

7.1CNSDepressants

7.2MixedAgonist/AntagonistOpioid Analgesics

7.3Anticholinergics

7.4Antidepressants

7.5MetabolicEnzymes

7.6Drug-Laboratory TestInteraction

8USE IN SPECIFIC POPULATIONS

8.1Pregnancy

8.2Labor andDelivery

8.3Nursing Mothers

8.4PediatricUse

8.5GeriatricUse

8.6Renal Impairment

8.7HepaticImpairment

9DRUGABUSEAND DEPENDENCE

9.1ControlledSubstance

9.2Abuse

9.3Dependence

10OVERDOSAGE

10.1Symptoms

10.2Treatment

11DESCRIPTION

12CLINICAL PHARMACOLOGY

12.1Mechanismof Action

12.2Pharmacodynamics

12.3Pharmacokinetics

13NONCLINICAL TOXICOLOGY

13.1Carcinogenesis,Mutagenesis,Impairmentof Fertility

13.3 ReproductionandDevelopmentalToxicology16 HOWSUPPLIED/STORAGE AND HANDLING17 PATIENT COUNSELINGINFORMATION

*Sectionsor subsectionsomittedfromthe full prescribinginformationarenotlisted.

FULLPRESCRIBING INFORMATION

1INDICATIONSAND USAGE

CodeineSulfateTablets,USP arean opioidanalgesicindicatedfortherelief of mild tomoderatelysevere painwheretheuse of an opioidanalgesicisappropriate.

2DOSAGEAND ADMINISTRATION

Selectionofpatientsfortreatmentwithcodeinesulfateshould be governed bythesameprinciplesthatapplyto the useofsimilaropioidanalgesics.Physiciansshouldindividualizetreatmentin everycase,usingnon-opioidanalgesics,opioids onan as neededbasisand/orcombinationproducts,andchronicopioidtherapyin a progressive planof painmanagement.

2.1IndividualizationofDosage

As withanyopioiddrugproduct,adjustthedosingregimen for eachpatientindividually,takingintoaccountthe patient’sprioranalgesictreatmentexperience.In the selection oftheinitialdoseof codeinesulfate,attentionshould be given to thefollowing:

•thetotaldailydose, potencyand specificcharacteristics oftheopioidthepatienthas beentakingpreviously;

•thereliabilityof the relative potencyestimateusedtocalculatetheequivalentcodeinesulfatedoseneeded;

•the patient’sdegreeofopioidtolerance;

•the generalconditionandmedicalstatusofthepatient;

•concurrentmedications;

•thetype and severityof thepatient’spain;

•riskfactorsforabuse,addictionordiversion,includinga priorhistoryof abuse,addiction ordiversion.

Thefollowingdosingrecommendations,therefore,can onlybe consideredsuggestedapproachesto whatisactuallyaseriesof clinicaldecisionsovertime inthe managementofthepain ofeachindividualpatient.

Continualre-evaluationofthepatientreceivingcodeinesulfateisimportant,withspecial attentiontothemaintenanceofpaincontrolandtherelativeincidenceofsideeffectsassociatedwiththerapy.Duringchronictherapy,especiallyfornoncancer-relatedpain,thecontinuedneedfortheuseof opioidanalgesicsshouldbe re-assessed as appropriate.

Duringperiodsofchanginganalgesicrequirements,includinginitialtitration,frequentcontactisrecommendedbetweenphysician,other membersofthehealthcareteam, the patient,andthecaregiver/family.

2.2InitiationofTherapy

Theusualadultdosagefortabletsis 15mgto 60 mgrepeated upto everyfourhoursasneededfor pain.Themaximum24hour doseis 360mg.

Theinitialdoseshouldbe titratedbased upontheindividualpatient’sresponseto theirinitialdose ofcodeine.Thisdosecan thenbeadjustedto anacceptablelevelofanalgesiatakingintoaccounttheimprovementin painintensityand thetolerabilityof thecodeinebythe patient.

Itshould be keptin mind,however,thattoleranceto codeinesulfatecan developwithcontinueduse andthattheincidenceof untowardeffectsis dose-related.Adultdosesof codeinehigherthan60 mgfailto givecommensuraterelief of painandare associatedwith anappreciablyincreasedincidenceof undesirablesideeffects.

2.3Cessation ofTherapy

Whenthe patientnolongerrequirestherapywithcodeinesulfate,dosesshouldbe taperedgraduallyto preventsignsandsymptoms ofwithdrawalinthe physicallydependentpatient.

3DOSAGEFORMSAND STRENGTHS

Each 15 mgtabletfororaladministrationcontains 15mgof codeinesulfate,USP.Itis awhiteto off-whitebiconvextabletwith“15”debossedon thescoredsideand“54 613”debossed onthe otherside.

Each 30 mgtabletfororaladministrationcontains 30mgof codeinesulfate,USP.Itis awhiteto off-whitebiconvextabletwith“30”debossedon thescoredsideand“54 783”debossed onthe otherside.

Each 60 mgtabletfororaladministrationcontains 60mgof codeinesulfate,USP.Itis awhiteto off-whitebiconvextabletwith“60”debossedon thescoredsideand“54 412”debossed onthe otherside.

4CONTRAINDICATIONS

Codeinesulfateiscontraindicatedforpostoperativepainmanagementinchildrenwhohaveundergonetonsillectomyand/oradenoidectomy[seeWarnings and Precautions(5.1)].

Codeinesulfateiscontraindicatedin patientswithknownhypersensitivitytocodeineor anycomponents oftheproduct.Personsknown to behypersensitive to certainotheropioidsmay exhibitcross-sensitivityto codeine.

Codeinesulfateiscontraindicatedin patientswithrespiratorydepressionintheabsence ofresuscitativeequipment [see Warnings and Precautions(5.2)].

Codeinesulfateiscontraindicatedin patientswithacuteorseverebronchial asthma orhypercarbia.Codeinesulfateiscontraindicatedin anypatient whohas or issuspectedofhavingparalyticileus.

5WARNINGSAND PRECAUTIONS

5.1DeathRelated toUltra-RapidMetabolismof Codeine toMorphine

Respiratorydepressionanddeathhaveoccurredin children whoreceivedcodeinein thepost-operativeperiodfollowingtonsillectomyand/or adenoidectomyand had evidenceof beingultra-rapidmetabolizersofcodeine(i.e., multiplecopiesof thegeneforcytochrome P450 isoenzyme 2D6 [CYP2D6] orhighmorphineconcentrations).Deathshavealsooccurredin nursinginfantswhowereexposed tohighlevelsofmorphine inbreastmilkbecausetheirmotherswere ultra-rapidmetabolizers ofcodeine[seeUsein SpecificPopulations (8.4)].

Someindividualsmay be ultra-rapidmetabolizersbecauseof a specificCYP2D6genotype(geneduplicationsdenotedas

*1/*1xN or*1/*2xN).TheprevalenceofthisCYP2D6phenotypevarieswidelyand has beenestimatedat0.5 to 1%inChinese andJapanese, 0.5to 1%in Hispanics,1 to10% in Caucasians,3% in AfricanAmericans,and 16 to28%in NorthAfricans,Ethiopians, and Arabs.Dataare notavailablefor otherethnicgroups.Theseindividualsconvertcodeineintoitsactivemetabolite,morphine,morerapidlyandcompletelythanotherpeople.Thisrapidconversionresultsinhigherthanexpectedserummorphinelevels.Even atlabeleddosageregimens,individualswhoareultra-rapidmetabolizersmay havelife-threateningor fatalrespiratorydepressionorexperiencesigns ofoverdose(such asextremesleepiness,confusion,orshallowbreathing)[see Overdosage(10.1)].

Childrenwithobstructivesleepapneawhoaretreatedwithcodeinefor post-tonsillectomyand/or adenoidectomypainmaybe particularlysensitive totherespiratorydepressanteffectsofcodeinethathasbeenrapidlymetabolized tomorphine.Codeineiscontraindicatedforpost-operativepainmanagementin allpediatricpatientsundergoingtonsillectomyand/or adenoidectomy[see Contraindications(4)].

When prescribingcodeine,healthcareprovidersshouldchoosethelowesteffectivedosefortheshortestperiodof timeand informpatientsand caregiversabouttheserisksand thesignsofmorphineoverdose[seeUsein SpecificPopulations (8),Overdosage (10.1)].

5.2Respiratory Depression

Respiratorydepressionistheprimaryriskof codeinesulfate.Respiratorydepressionoccursmorefrequentlyinelderlyordebilitatedpatientsandinthosesufferingfromconditionsaccompanied byhypoxia,hypercapnia,orupperairwayobstruction, in whomevenmoderatetherapeuticdosesmaysignificantlydecreasepulmonaryventilation.Codeineproducesdose-relatedrespiratorydepression.

Cautionshouldbe exercisedwhencodeinesulfateisusedpostoperatively, in patientswithpulmonarydisease orshortnessof breath, orwheneverventilatoryfunctionis depressed.Opioidrelatedrespiratorydepressionoccursmorefrequentlyinelderlyor debilitatedpatientsand inthosesufferingfromconditionsaccompaniedbyhypoxia,hypercapnia, orupperairwayobstruction,in whomevenmoderatetherapeuticdosesmay significantlydecreasepulmonaryventilation.Opioids,includingcodeinesulfate,shouldbeusedwithextremecautionin patients with chronicobstructivepulmonarydiseaseorcorpulmonaleandinpatientshavinga substantiallydecreasedrespiratoryreserve(e.g.,severekyphoscoliosis),hypoxia,hypercapnia,orpre-existingrespiratorydepression.In such patients,evenusualtherapeuticdoses ofcodeinesulfatemayincreaseairwayresistanceanddecreaserespiratorydrive tothe pointofapnea.Alternative non-opioidanalgesicsshouldbeconsidered, andcodeinesulfateshouldbeemployed onlyunder carefulmedical supervisionatthelowest effective dose insuchpatients [seeOverdosage(10.1)].

5.3Misuseand AbuseofOpioids

Codeinesulfateisan opioidagonist ofthe morphine-type anda ScheduleIIcontrolledsubstance.Suchdrugs are soughtbydrugabusers and peoplewithaddictiondisorders.Diversion of ScheduleIIproductsisan actsubjecttocriminalpenalty.

Codeinecanbe abusedinamannersimilar tootheropioidagonists,legal orillicit.Thisshould beconsideredwhenprescribingordispensingcodeinesulfateinsituationswherethe physicianorpharmacistisconcernedaboutanincreasedriskof misuse,abuse,ordiversion.

Misuseand abuseofcodeinesulfateposesa significantrisktotheabuserthatcouldresultinoverdose and death. Codeinemaybe abused bycrushing,chewing,snortingorinjectingthe product[see DrugAbuse andDependence (9)].

Concernsaboutabuse andaddictionshouldnotprevent the propermanagementof pain. HealthcareprofessionalsshouldcontacttheirStateProfessionalLicensingBoard orStateControlledSubstancesAuthorityforinformationon howtopreventand detectabuseordiversionofthisproduct.

5.4Interaction with Alcohol and DrugsofAbuse

Codeinesulfatemay be expected tohaveadditiveeffects whenusedinconjunctionwithalcohol,otheropioids, orillicitdrugsthatcausecentralnervoussystemdepression,becauserespiratorydepression,hypotension,profoundsedation,comaor deathmay result.

5.5Head Injuryand IncreasedIntracranialPressure

Respiratorydepressant effectsofopioidsandtheircapacityto elevatecerebrospinalfluidpressureresultingfromvasodilation followingCO2retentionmay be markedlyexaggeratedinthe presence ofheadinjury,otherintracraniallesionsor apre-existingincreaseinintracranialpressure.Furthermore,opioidsincludingcodeinesulfate,produceadversereactionswhichmay obscuretheclinicalcourseofpatientswithheadinjuries.

5.6Hypotensive Effect

Codeinesulfatemay causeseverehypotensionin anindividualwhoseabilityto maintainbloodpressurehasalreadybeencompromised bya depletedblood volume orconcurrentadministrationofdrugssuch as phenothiazinesor generalanesthetics.Codeine sulfatemayproduce orthostatichypotension andsyncopein ambulatorypatients.

Codeinesulfateshould beadministeredwithcaution topatientsin circulatoryshock, as vasodilationproducedbythe drugmayfurtherreducecardiacoutputandbloodpressure.

5.7GastrointestinalEffects

Codeinesulfateshouldnotbe administeredto patientswithgastrointestinalobstruction,especiallyparalyticileusbecausecodeinesulfatediminishespropulsiveperistalticwavesin thegastrointestinaltractand mayprolongthe obstruction.

Chronicuse ofopioids,includingcodeinesulfate,mayresultin obstructiveboweldiseaseespeciallyin patients withunderlyingintestinalmotilitydisorder.Codeinesulfatemaycause oraggravateconstipation.

Administrationofcodeinesulfatemay obscurethediagnosis orclinicalcourseof patientswithacuteabdominalconditions.

5.8UseinPancreatic/BiliaryTractDisease

Codeinesulfateshould beusedincautioninpatients with biliarytractdisease,includingacutepancreatitis, ascodeinesulfatemay cause spasmof the sphincterofOddianddiminishbiliaryand pancreaticsecretions.

5.9Special Risk Patients

As with otheropioids,codeinesulfateshouldbe usedwithcautionin elderlyordebilitatedpatientsandthosewithsevereimpairmentof hepatic orrenalfunction,hypothyrodism,Addison’sdisease,prostatichypertrophyor urethral stricture[see Use in SpecificPopulations(8)].The usualprecautionsshould be observed andthe possibilityof respiratorydepressionshould be keptin mind.

Cautionshouldbe exercised inthe administration ofcodeinesulfateto patientswithCNSdepression,acutealcoholism,and deliriumtremens.

Allopioidsmay aggravateconvulsionsin patientswithconvulsivedisorders,andallopioidsmay induce oraggravateseizuresinsomeclinicalsettings.

5.10Driving and OperatingMachinery

Patientsshouldbe cautionedthatcodeinesulfatecouldimpairthemental and/orphysicalabilitiesneeded toperformpotentiallyhazardousactivitiessuch asdrivinga caroroperatingmachinery.

Patientsshouldalso becautionedaboutthepotentialcombinedeffectsofcodeinesulfatewithotherCNSdepressants,includingopioids,phenothiazines,sedative/hypnotics,and alcohol [see DrugInteractions(7.1)].

6ADVERSEREACTIONS

Seriousadversereactionsassociatedwithcodeinearerespiratorydepressionand,to a lesserdegree,circulatorydepression,respiratoryarrest,shock, and cardiacarrest.

Themostfrequentlyobservedadversereactionswithcodeineadministrationincludedrowsiness,lightheadedness,dizziness,sedation,shortnessofbreath,nausea,vomiting,sweating, andconstipation.

Otheradversereactionsincludeallergicreactions,euphoria,dysphoria,abdominalpain,andpruritis.

Otherlessfrequentlyobservedadversereactionsexpectedfromopioid analgesics,includingcodeinesulfate,include:

Cardiovascularsystem:faintness,flushing,hypotension,palpitations,syncope

DigestiveSystem:abdominalcramps,anorexia,diarrhea, drymouth,gastrointestinaldistress,pancreatitis

Nervoussystem:anxiety,drowsiness,fatigue,headache,insomnia,nervousness,shakiness,somnolence,vertigo,visualdisturbances,weakness

Skin andAppendages: rash,sweating,urticaria

7DRUGINTERACTIONS

7.1CNSDepressants

Concurrentuseof otheropioids,antihistamines,antipsychotics,antianxietyagents, or otherCNSdepressants(includingsedatives,hypnotics,generalanesthetics,antiemetics,phenothiazines,orothertranquilizersoralcohol) concomitantlywithcodeinesulfatetabletsmayresultinadditiveCNSdepression,respiratorydepression,hypotension,profoundsedation, orcoma. Use codeinesulfatewithcautionand in reduceddosagesinpatientstakingtheseagents.

7.2Mixed Agonist/Antagonist OpioidAnalgesics

Mixedagonist/antagonistanalgesics(i.e.,pentazocine,nalbuphine,andbutorphanol)shouldNOT be administeredtopatients who havereceivedor arereceivinga courseof therapywitha pureopioidagonist analgesicsuchas codeinesulfate.In these patients,mixedagonist/antagonist analgesicsmay reducetheanalgesiceffectand/ormay precipitatewithdrawalsymptoms.

7.3Anticholinergics

Anticholinergicsorother medicationswithanticholinergicactivitywhenusedconcurrentlywithopioidanalgesicsincludingcodeinesulfate,mayresultinincreasedriskof urinaryretentionand/orsevereconstipation,whichmaylead toparalyticileus.

7.4Antidepressants

Use ofMAOinhibitorsortricyclicantidepressantswithcodeinesulfate may increasethe effectofeithertheantidepressantorcodeine.MAOIsmarkedlypotentiate theactionof morphinesulfate,the majormetaboliteof codeine.Codeineshouldnotbeusedin patientstakingMAOIs orwithin14 daysofstoppingsuch treatment.

7.5MetabolicEnzymes

PatientstakingcytochromeP-450enzymeinducers orinhibitorsmay demonstratean alteredresponsetocodeine,thereforeanalgesicactivityshould be monitored.Codeinesulfateis metabolized bythe cytochrome P-450 3A4 and 2D6

isoenzymes[see ClinicalPharmacology(12.3)].Theconcurrentuse ofdrugsthatpreferentiallyinducecodeineN-demethylation(cytochromeP-4503A4)mayincreasetheplasmaconcentrations ofcodeine’sinactivemetabolitenorcodeine.Drugsthat arestronginhibitorsofcodeineO-demethylation(cytochromeP-4502D6)maydecreasetheplasmaconcentrationsofcodeine’sactivemetabolites,morphine andmorphine-6-glucuronide.Thecontribution oftheseactivemetabolites totheoverallanalgesiceffectofcodeineis notfullyunderstood, butshould beconsidered.

7.6Drug-Laboratory Test Interaction

Codeinesulfate tabletsmaycause an elevationofplasmaamylase andlipase dueto thepotentialofcodeinetoproducespasmof thesphincter of Oddi.Determination oftheseenzyme levels may be unreliableforsometimeafter anopiateagonisthasbeengiven.

8USE IN SPECIFIC POPULATIONS

8.1Pregnancy

TeratogenicEffects

PregnancyCategoryC

Thereareno adequateandwell-controlledstudiesin pregnantwomen.Codeineshouldbeused duringpregnancyonlyifthe potentialbenefitjustifies thepotentialrisktothefetus.

Codeinehasbeenshowntohaveembryolethal andfetotoxiceffects(reducedfetalbodyweights anddelayedorincompleteossification) inthe hamster,ratand mousemodels atapproximately2-4 timesthemaximumrecommendedhuman dose of360mg/day basedon a bodysurfaceareacomparison.Maternallytoxicdosesthatwereapproximately7times themaximumrecommendedhuman dose of360mg/day,wereassociatedwithevidence ofresorptionsandincompleteossification,including meningioencephaloceleand cranioschisis. In contrast,codeinedidnotdemonstrateevidenceof embrytoxicityor fetotoxicityin therabbitmodelatdosesup to2 times the maximumrecommendedhumandose of360 mg/day basedon a bodysurfaceareacomparison[seeNonclinicalToxicology(13.3)].

NonteratogenicEffects

Neonatalcodeinewithdrawalhasoccurredininfantsborntoaddictedand non-addictedmothers who hadbeentakingcodeine-containingmedicationsinthe dayspriorto delivery.Typicalsymptoms ofnarcoticwithdrawalincludeirritability,excessivecrying,tremors,hyperreflexia,seizures,fever,vomiting,diarrhea,andpoorfeeding.Thesesignsoccurshortlyafterbirthandmay requirespecifictreatment.

Codeine(30 mg/kg)administeredsubcutaneouslyto pregnantratsduringpregnancyand for 25daysafterdeliveryincreasedneonatal mortalityatbirth.Thisdoseis 0.8times the maximumrecommendedhumandose of 360mg/dayon abodysurfaceareacomparison.

8.2Laborand Delivery

Opioidanalgesicscrosstheplacentalbarrierandmay produce respiratorydepression and psycho-physiologiceffectsinneonates.Occasionally,opioidanalgesicsmay prolonglabor throughactionswhichtemporarilyreducethestrength,duration, andfrequencyofuterinecontractions.However,thiseffectis notconsistentand may be offsetbyan increasedrate ofcervicaldilatation,whichtends toshortenlabor.Thecloserto deliveryand thelargerthedoseused,thegreaterthepossibilityof respiratorydepressioninthenewborn.Opioidanalgesicsshouldbeavoidedduringlaborifdeliveryof aprematureinfantisanticipated.If the mother has receivednarcoticanalgesics duringlabor, newborninfantsshouldbeobservedcloselyforsignsofrespiratorydepression.Resuscitationmay be required[see Overdosage(10.2)].A specificopioidantagonist,suchasnaloxoneornalmefene,should beavailableforreversalof opioid-inducedrespiratorydepressionin theneonate.

8.3NursingMothers

Codeineissecretedintohumanmilk.Inwomen with normalcodeinemetabolism(normalCYP2D6activity), the amountof codeinesecretedintohumanmilkislowanddose-dependent.However,somewomen are ultra-rapidmetabolizersofcodeine.Thesewomenachievehigher-than-expectedserumlevelsofcodeine’sactivemetabolite,morphine,leadingtohigher-than-expectedlevelsof morphinein breastmilkand potentiallydangerouslyhigh serummorphinelevels intheirbreastfedinfants.Therefore,maternal useof codeinecanpotentiallylead toseriousadversereactions,includingdeath, innursinginfants.

Theriskof infantexposureto codeine andmorphinethroughbreastmilkshouldbeweighedagainst thebenefitsofbreastfeedingforboththemotherandthe baby.Cautionshould beexercisedwhencodeineisadministeredto a nursingwoman.If a codeinecontainingproductis selected,thelowestdoseshould be prescribedfortheshortestperiod oftime toachieve the desiredclinicaleffect.Mothersusingcodeineshouldbeinformedaboutwhento seekimmediatemedicalcareand how toidentifythesigns andsymptoms ofneonataltoxicity, such asdrowsinessor sedation,difficultybreastfeeding,breathingdifficulties,anddecreasedtone,intheirbaby.Nursingmothers who areultra-rapid metabolizersmay alsoexperienceoverdosesymptoms such as extremesleepiness,confusion,orshallowbreathing.Prescribersshould closelymonitormother-infantpairsand notifytreatingpediatriciansaboutthe useofcodeineduringbreastfeeding[seeWarnings and Precautions (5.1)].

8.4PediatricUse

Thesafetyand effectiveness andthepharmacokineticsof codeinesulfatein pediatricpatientsbelow theage of18 havenotbeenestablished.FDA has notrequiredpediatricstudiesinagesbirthto onemonthbecausethereisevidencestronglysuggestingthat codeinewould beineffective inthis pediatricgroupsincethemetabolicpathways to metabolizecodeineare notmature.

Respiratorydepressionanddeathhaveoccurredin childrenwithobstructivesleepapnea whoreceivedcodeine inthe post-operativeperiodfollowingtonsillectomyand/or adenoidectomyand had evidenceof beingultra-rapid metabolizersofcodeine(i.e.,multiplecopies ofthe geneforcytochrome P450isoenzyme 2D6 or high morphine concentrations).Thesechildrenmay be particularlysensitive totherespiratorydepressanteffectsofcodeinethat hasbeenrapidlymetabolized tomorphine.Codeineiscontraindicatedforpost-operativepainmanagementin allpediatricpatientsundergoingtonsillectomyand/or adenoidectomy[see Contraindications(4)].

8.5Geriatric Use

Codeinemaycauseconfusionandover-sedation inthe elderly.In general,doseselectionfor an elderlypatientshould becautious,usuallystarting atthelowendof the dosingrange,reflecting the greaterfrequency ofdecreasedhepatic,renal,or cardiacfunction, andofconcomitantdisease orotherdrugtherapy.

8.6RenalImpairment

Codeinepharmacokineticsmaybe alteredin patientswithrenalfailure.Clearancemay be decreasedandthemetabolitesmayaccumulatetomuchhigherplasma levels inpatientswithrenalfailure ascomparedto patientswithnormalrenalfunction.Startthesepatientscautiouslywithlowerdoses ofcodeinesulfateorwithlongerdosingintervalsandtitrateslowlywhilecarefullymonitoringforsideeffects.

8.7HepaticImpairment

Noformalstudieshavebeenconducted inpatientswithhepaticimpairmentsothepharmacokinetics ofcodeine inthispatientpopulationareunknown.Startthesepatientscautiouslywithlowerdoses of codeine sulfateorwithlongerdosingintervalsandtitrateslowlywhilecarefully monitoringforsideeffects.

9DRUGABUSE ANDDEPENDENCE

9.1ControlledSubstance

Codeinesulfate isan opioidagonist and is a ScheduleIIcontrolledsubstance.Codeinesulfate can beabused andissubjecttocriminaldiversion.

9.2Abuse

Drugaddictionischaracterized bycompulsive use, use fornon-medicalpurposes,and continueduse despite harmor riskof harm.Drugaddictionisa treatabledisease,utilizinga multi-disciplinaryapproach, but relapseis common.

“Drugseeking”behaviorisverycommon in addictsand drugabusers.Drug-seekingtacticsincludeemergencycalls orvisitsneartheend ofofficehours,refusalto undergoappropriateexamination,testingorreferral,repeated“loss”ofprescriptions,tamperingwithprescriptionsandreluctancetoprovidepriormedicalrecordsorcontactinformationforothertreatingphysician(s).“Doctorshopping”to obtainadditionalprescriptionsiscommon amongdrugabusers andpeoplesufferingfromuntreatedaddiction.

Abuse andaddictionareseparateanddistinctfromphysicaldependence andtolerance.Physiciansshould beawarethataddictionmay notbe accompanied byconcurrenttolerance andsymptoms ofphysicaldependence.The converseisalsotrue.Inaddition,abuseof opioidscanoccurinthe absenceoftrueaddictionandischaracterized bymisusefornon-medicalpurposes,oftenincombinationwithotherpsychoactivesubstances.Carefulrecord-keepingof prescribinginformation,includingquantity,frequency, andrenewalrequests isstronglyadvised.

Codeineisintendedfor oraluseonly.Abuseofcodeineposes ariskofoverdose and death.Theriskisincreasedwithconcurrentabuseof alcoholand othersubstances.Parenteraldrugabuse iscommonlyassociatedwithtransmissionofinfectiousdiseasessuch ashepatitisandHIV.

Properassessmentofthe patient,properprescribingpractices,periodicre-evaluation of therapy, and properdispensingand storage areappropriatemeasuresthathelptolimit abuseof opioiddrugs.

Infants borntomothersphysicallydependenton opioidswillalsobephysicallydependent andmay exhibitrespiratorydifficultiesandwithdrawalsymptoms[see Usein SpecificPopulations(8.2),Overdosage (10.1)].

9.3Dependence

Toleranceistheneedforincreasingdosesofopioidstomaintaina definedeffectsuch asanalgesia(intheabsenceofdiseaseprogression orotherexternalfactors).Physicaldependenceis manifestedbywithdrawalsymptoms afterabruptdiscontinuation ofa drugorupon administrationofanantagonist.Physicaldependenceandtolerancearenotunusualduringchronicopioidtherapy.

Theopioidabstinenceor withdrawalsyndrome is characterized bysome orallofthefollowing:restlessness,lacrimation,rhinorrhea,yawning,perspiration,chills,myalgia, and mydriasis.Othersymptomsalso may develop,includingirritability,anxiety,backache,jointpain,weakness,abdominalcramps,insomnia,nausea,anorexia,vomiting,diarrhea,orincreasedblood pressure,respiratoryrate, or heartrate.

Ingeneral,opioidsshouldnotbeabruptlydiscontinued [see Dosageand Administration (2.3)].

10OVERDOSAGE

10.1Symptoms

Acuteoverdoseof codeineis characterized byrespiratorydepression(adecreaseinrespiratoryrateand/ortidalvolume,Cheyne-Stokesrespiration,cyanosis),extremesomnolenceprogressingto stuporor coma,miosis(mydriasismay occurin

terminalnarcosisorseverehypoxia),skeletalmuscleflaccidity, coldand clammy skin, and sometimesbradycardiaandhypotension.Insevereoverdosage,apnea,circulatorycollapse,cardiacarrest,anddeathmay occur.

Codeinesulfatemay causemiosis,even intotaldarkness.Pinpointpupilsarea sign of opioidoverdosebutare notpathognomonic(e.g.,pontinelesionsofhemorrhagic orischemicoriginmay produce similarfindings).Markedmydriasisratherthanmiosismay be seen withhypoxia inoverdosesituations.

10.2Treatment

Primaryattentionshould be given to there-establishmentofadequaterespiratoryexchangethroughprovisionof a patentairwayandinstitution ofassistedorcontrolledventilationasnecessary.Supportivemeasures(includingoxygen andvasopressors)should beemployed inthe managementof circulatoryshockand pulmonaryedemaaccompanyingoverdoseas indicated.Cardiacarrest or arrhythmiasmay requirecardiacmassageordefibrillation.Induction ofemesisis notrecommendedbecause of thepotentialforCNSdepressionand seizures.Activatedcharcoalisrecommendedifthe patientis awakeandableto protect his/herairway.In personswho areatriskfor abruptonsetofseizuresormentalstatusdepression,activatedcharcoalshould beadministeredby medicalor paramedicalpersonnelcapable of airwaymanagementto preventaspiration intheeventofspontaneousemesis.Severeagitationorseizuresshould betreatedwithan intravenousbenzodiazepine.

Theopioidantagonistnaloxonehydrochlorideis a specificantidoteagainst respiratorydepressionresultingfromoverdosage orunusualsensitivityto opiateagonists,includingcodeine.Therefore,an appropriatedoseof naloxonehydrochloride(seeprescribinginformationfornaloxonehydrochloride)shouldbe administered,preferablyby theintravenousroute,simultaneouslywitheffortsatrespiratoryresuscitation.Sincethedurationofaction ofcodeinemayexceedthatof the antagonist,thepatientshould bekept undercontinuedsurveillance andrepeateddosesoftheantagonistshould be administered asneededto maintainadequaterespiration. A narcoticantagonistshouldnotbe administeredinthe absenceofclinicallysignificantrespiratoryor cardiovasculardepressionsecondaryto codeinesulfateoverdose.

In an individualphysicallydependenton opioids,administration oftheusualdoseof theantagonistwillprecipitateanacutewithdrawalsyndrome.Theseverityofthewithdrawalsymptomsexperiencedwilldepend onthedegreeof physicaldependenceandthe doseof the antagonist administered.Use ofan opioidantagonist shouldbereservedforcaseswheresuchtreatmentis clearlyneeded.If itis necessaryto treatserious respiratorydepressioninthephysicallydependentpatient,administrationoftheantagonistshouldbeinitiatedwithcareandtitratedwithsmallerthanusualdoses.

11DESCRIPTION

Chemically,codeinesulfateisMorphinan-6-ol,7,8-didehydro-4,5-epoxy-3-methoxy-17-methyl-(5α,6α)-,sulfate(2:1)(salt), trihydrate. Itsempiricalformulais(C18H21NO3)2·H2SO4·3H2O and itsmolecularweightis 750.85.

Itsstructureis asfollows:

Each tabletcontains 15,30,or60 mgof codeinesulfate,USP andthefollowinginactiveingredients: colloidalsilicondioxide,microcrystallinecellulose,pregelatinizedstarch, and stearicacid.

12CLINICALPHARMACOLOGY

12.1MechanismofAction

Codeinesulfateisan opioid analgesic,relatedtomorphine,butwithlesspotentanalgesicproperties.Codeineisselectiveforthe mureceptor,butwith a muchweakeraffinitythan morphine.The analgesicproperties ofcodeinehave beenspeculatedto comefromitsconversiontomorphine,although theexactmechanismof analgesicactionremainsunknown.

Effects ofthe CentralNervousSystem(CNS)

Theprincipaltherapeuticaction ofcodeinesulfateis analgesia.Althoughtheprecisemechanismof theanalgesicactionisunknown,specificCNSopiatereceptorsand endogenouscompoundswithmorphine-likeactivityhavebeenidentifiedthroughoutthebrainandspinalcord andarelikelyto playa rolein theexpressionand perceptionofanalgesiceffects.

Some otherCNSeffectsofcodeineincludeanxiolysis,euphoria,andfeelingsofrelaxation.Codeinesulfatecausesrespiratorydepression,in partbya directeffectonthebrainstemrespiratorycenters.Codeinesulfateand otherrelatedopioidsdepressthecoughreflex bydirecteffect onthecoughcenterinthe medulla.Codeinesulfatemay also causemiosis.

Effects onthe GastrointestinalTractand on OtherSmoothMuscle

Gastric,biliaryand pancreaticsecretionsmay be decreased bycodeine.Codeinealsocauses areductionin motilityand isassociatedwithanincreasein tonein theantrumof thestomach and duodenum.Digestionoffoodin thesmallintestineisdelayedandpropulsivecontractionsaredecreased.Propulsiveperistalticwavesinthe colonaredecreased,whiletoneisincreasedto thepointofspasm. The endresultmay be constipation.Codeine cancausea markedincreaseinbiliarytractpressure asa resultofthespasmof thesphincterof Oddi.Codeinemay also causespasms ofthesphincteroftheurinarybladder.

Effects onthe CardiovascularSystem

Codeineproducesperipheralvasodilationwhichmay resultinorthostatichypotensionand fainting.Releaseofhistaminecan occur,whichmay playa roleinopioid-inducedhypotension.Manifestationsofhistaminereleaseand/orperipheralvasodilationmay includepruritus,flushing, red eyes,andsweating.

EndocrineSystem

Opioidagonistssuchascodeinesulfatehave beenshown to have a varietyof effectsonthesecretionofhormones.Opioidsinhibitthesecretion of ACTH,cortisol, andluteinizinghormone(LH)inhumans. Theyalsostimulateprolactin,growthhormone(GH)secretion, andpancreaticsecretion ofinsulin and glucagonsin humans andotherspecies,ratsanddogs.Thyroidstimulatinghormone(TSH)hasbeenshown to bebothinhibitedandstimulatedbyopioids.

ImmuneSystem

Codeinehasbeenshowntohave a varietyof effects oncomponentsoftheimmunesysteminin vitroandanimalmodels.Theclinicalsignificanceof thesefindings is unknown.

12.2Pharmacodynamics

Codeineconcentrations donotcorrelatewithbrainconcentrationorreliefofpain.

Theminimumeffectiveconcentrationvarieswidelyand isinfluencedbya varietyof factors,includingtheextentofpreviousopioiduse,ageandgeneralmedicalcondition.Effectivedoses intolerant patientsmay be significantlyhigherthanin opioid-naïvepatients.

12.3Pharmacokinetics

Absorption

Codeineisabsorbedfromthe gastrointestinal tractwithmaximumplasmaconcentration occurring60 minutespostadministration.

Food Effects

When 60mgcodeinesulfate was administered30 minutesafteringestinga highfat/highcaloriemeal,therewas nosignificantchange intherate and extentofabsorptionofcodeine.

Steady-state

Administrationof 15 mgcodeinesulfateeveryfour hoursfor 5daysresultedinsteady-stateconcentrationsofcodeine,morphine,morphine-3-glucuronide(M3G)and morphine-6-glucuronide(M6G)within48 hours.

Distribution

Codeinehasbeenreportedtohave an apparentvolume ofdistributionofapproximately3-6L/kg,indicatingextensivedistributionofthe drugintotissues.Codeinehaslow plasmaproteinbindingwithabout7-25% ofcodeinebound toplasmaproteins.

Metabolism

About70-80%oftheadministereddoseofcodeineismetabolized byconjugationwithglucuronicacid tocodeine-6-glucuronide(C6G)andviaO-demethylationtomorphine(about5-10%) and N-demethylationto norcodeine(about10%)respectively.UDP-glucuronosyltransferase (UGT)2B7 and 2B4arethe majorenzymesmediatingglucurodinationofcodeineto C6G.Cytochrome P450 2D6 is themajorenzyme responsibleforconversionofcodeinetomorphineand P4503A4 isthe majorenzymemediatingconversion ofcodeineto norcodeine.Morphine and norcodeinearefurthermetabolized byconjugationwithglucuronicacid.Theglucuronidemetabolites ofmorphinearemorphine-3-glucuronide(M3G)and morphine-6-glucuronide(M6G).Morphineand M6Gareknown to haveanalgesicactivityinhumans.Theanalgesicactivityof C6G inhumans is unknown.Norcodeineand M3Gare generallynotconsideredto possessanalgesicproperties.

Elimination

Approximately90% ofthetotaldoseofcodeineisexcretedthroughthekidneys,of whichapproximately10%isunchangedcodeine.Plasmahalf-lives of codeine anditsmetaboliteshavebeenreported tobe approximately3hours.

13NONCLINICALTOXICOLOGY

13.1Carcinogenesis,Mutagenesis,ImpairmentofFertility

Carcinogenesis:Twoyearcarcinogenicitystudieshave been conductedin F344/Nratsand B6C3F1mice.There was noevidenceof carcinogenicityin male andfemalerats,respectively, atdietarydosesup to 70 and 80mg/kg/dayof codeine(approximately2 timesthemaximumrecommendeddailydoseof 360mg/dayforadults ona mg/m2basis)fortwoyears.Similiarlytherewas no evidenceof carcinogenicityactivityin maleand femalemiceatdietarydoses upto 400mg/kg/dayof codeine(approximately5 timesthemaximumrecommended dailydoseof 360mg/dayfor adultson a mg/m2basis)fortwoyears.

Mutagenesis:Codeine wasnotmutatgenic intheinvitrobacterialreversemutationassayorclastogenicin thein vitro

Chinesehamsterovarycellchromosomeaberrationassay.

Impairmentoffertility:Noanimalstudieswereconductedto evaluatetheeffectof codeine on maleorfemalefertility.

13.3 Reproduction andDevelopmentalToxicology

Studies onthereproductive and developmentaleffectsof codeinehavebeenreported inthepublishedliterature inhamsters,rats,miceandrabbits.

Astudyin hamstersadministered150mg/kgbid ofcodeine(PO;approximately7 timesthemaximumrecommendeddailydoseof360 mg/day for adults ona mg/m2basis)reportedthedevelopmentof cranialmalformations(i.e.,meningoencephalocele) inseveralfetusesexamined;aswellasthe observationofincreases inthepercentageofresorptionsperlitterexamined.Doses of50 and 150mg/kg, bid resulted infetotoxicityas demonstratedbydecreasedfetalbodyweight.In an earlierstudyin hamsters,dosesof73-360mg/kglevel(PO;approximately2-8times themaximumrecommended dailydose of360 mg/day for adults onamg/m2basis),reportedlyproducedcranioschisisin all of thefetusesexamined.

In studiesin rats,dosesatthe 120 mg/kglevel(PO;approximately3 timesthemaximumrecommendeddailydose of 360mg/dayfor adultson a mg/m2basis), inthetoxicrangefortheadultanimal,wereassociatedwithanincreasein embryoresorptionatthetime ofimplantation.

Inpregnantmice, a single100mg/kgdose (SC;approximately1.4 times therecommended dailydose of360mg/dayforadults ona mg/mg2basis)reportedlyresulted indelayedossification intheoffspring.

Noteratogeniceffectswereobserved inrabbitsadministeredup to30 mg/kg(approximately2 times the maximumrecommended dailydose of360 mg/day for adults onamg/m2basis)ofcodeineduringorganogenesis.

16HOWSUPPLIED/STORAGEAND HANDLING

CodeineSulfateTablets,USP

15 mg:areavailableas awhite tooff-whitebiconvextabletwith“15”debossedon thescoredsideand“54 613”debossedon theotherside.

Unitdose,25tabletsperblistercardNDC 0054-8155-24:4 CardsperCarton

30 mg:areavailableas a white tooff-whitebiconvextabletwith“30”debossedon thescoredsideand“54783”debossedon theotherside.

Unitdose,25tabletsperblistercardNDC 0054-4156-24:4 CardsperCarton

NDC 0054-0244-25:Bottles of100Tablets

60 mg:areavailableas a white tooff-whitebiconvextabletwith“60”debossedon thescoredsideand“54412”debossedon theotherside.

NDC 0054-4157-25:Bottles of100Tablets

Storage

Storeat20°to 25°C (68°to77°F).[SeeUSPControlledRoomTemperature.]Protectfrommoistureandlight.

Dispensein well-closedcontainer as definedinthe USP/NF.

Blistersarenotchild-resistant.Usechild-resistantclosureif dispensingto outpatient.

Allopioidsareliable todiversionandmisuseboth bythegeneralpublic andhealthcareworkersand should behandledaccordingly.

17PATIENTCOUNSELINGINFORMATION

  • Advisepatientsthatcodeinesulfateis anarcoticpainrelieverand may be habitforming.Itshould betakenonlyas directed.
  • Advisepatientsthatsomepeoplehave a geneticvariationthatresults incodeinechanginginto morphinemorerapidlyand completelythanotherpeople.Mostpeople areunawareofwhethertheyare an ultra-rapidcodeinemetabolizeror not.Thesehigher-than-normallevelsofmorphineinthebloodmay leadtolife-threateningor fatalrespiratorydepressionorsigns ofoverdosesuch asextremesleepiness,confusion,or shallowbreathing.Childrenwiththisgeneticvariationwhowereprescribedcodeineaftertonsillectomyand/or adenoidectomyfor obstructivesleepapneamay be at greatestriskbased onreportsofseveraldeathsinthispopulation duetorespiratorydepression.Codeineiscontraindicatedinchildren whoundergo tonsillectomyand/oradenoidectomy.Advisecaregiversof childrenreceivingcodeinefor otherreasons tomonitorforsignsofrespiratorydepression.
  • Advisepatientsthatnursing motherstakingcodeinecanhavehighermorphinelevels intheirbreastmilkiftheyare ultra-rapidmetabolizers.Thesehigherlevelsof morphineinbreastmilkmaylead tolife-threateningorfatalsideeffectsin nursingbabies.Advisenursingmothersto watchforsigns ofmorphinetoxicityin theirinfantswhichincludesincreasedsleepiness(morethanusual),difficultybreastfeeding,breathingdifficulties,or limpness.

Instructnursingmothers totalktothebaby’s doctor immediatelyif theynoticethesesigns and,iftheycannot reachthedoctorrightaway, to take thebabyto anemergencyroomor call 911(orlocalemergencyservices).

  • Advisepatientsthatthedoseof codeinesulfateshouldnotbeadjustedwithoutconsultingwithyourphysician.
  • Advisepatientsthatcodeinemay cause drowsiness,dizziness, orlightheadednessand may impair thementaland/orphysicalabilitiesrequiredfortheperformanceofpotentiallyhazardoustasks suchas drivinga caroroperatingmachinery.
  • Advisepatientsstarted oncodeinesulfateor patientswhosedosehasbeenadjusted to refrainfromanypotentiallydangerousactivityuntilitisestablishedthattheyare notadverselyaffected.Advisepatientsnottocombinecodeinesulfatewithalcoholor othercentralnervoussystemdepressants(sleepaids,tranquilizers)exceptbytheordersoftheprescribingphysician,becausedangerousadditiveeffectsmay occur, resultingin seriousinjuryordeath.
  • Advisepatientsthatcodeinesulfateis apotentialdrugof abuse,andshouldbe protectedfromtheft.Itshouldneverbe given toanyoneotherthantheindividualforwhomitwasprescribed.
  • Advisepatientsto keepcodeinesulfatein asecure place outof thereach ofchildren.
  • Advisepatientsofthe potentialforsevereconstipationwhentakingcodeinesulfate;appropriatelaxativesand/orstoolsoftenersaswellasotherappropriatetreatmentsshouldbeinitiatedfromthe onsetoftherapy.
  • Advisepatientsofthe most commonadverseeventsthatmay occur whiletakingcodeinesulfate:drowsiness,lightheadedness,dizziness,sedation,shortnessof breath,nausea,vomiting,constipation,andsweating.
  • Ifpatientshavebeenreceivingtreatmentwithcodeinesulfateformorethan afewweeks and cessation oftherapyis indicated,theyshould becounseledon theimportance ofsafelytaperingthe dose andthatabruptlydiscontinuingthe medicationcouldprecipitatewithdrawalsymptoms. Thephysicianshouldprovidea dosescheduleto accomplish a gradualdiscontinuationofthemedication.
  • Women ofchildbearingpotentialwhobecome orareplanningtobecomepregnantshouldconsulta physicianpriortoinitiatingorcontinuingtherapywithcodeinesulfate.
  • Safe usein pregnancyhasnotbeenestablished.Prolonged use ofopioidanalgesicsduringpregnancymay causefetal/neonatalphysicaldependence, and neonatalwithdrawal may occur.

RoxaneLaboratories,Inc.