PRODUCT INFORMATION
Chemists Own Paracetamol Plus Codeine & Calmative
(paracetamol 500mg, codeine phosphate hemihydrate 10mg, and doxylamine succinate5.1mg)
NAMEOFTHEMEDICINE
Paracetamol, Codeine phosphate hemihydrate and Doxylamine succinate
Paracetamol:
Chemicalname:N-(4-hydroxyphenyl)acetamide.Molecular formula:C8H9NO2
MW: 151.2.
CAS:103-90-2
Codeine Phosphate hemihydrate:
Chemicalname:(5R, 6S)-7, 8-didehydro-4,5-epoxy-3-methoxy-N-methylmorphinan-6-oldihydrogen orthophosphate hemihydrate.
Molecular formula:C18H21NO3•H3PO4.½H2OMW: 406.4.
CAS:41444-62-6
Doxylamine succinate:
Chemicalname:NN-Dimethyl-2-[-methyl--(2-piridyl)benzyloxy]ethylamine hydrogensuccinate.
Molecular formula:C17H22N2O•C4H6O4
MW388.5.
CAS:562-10-7
DESCRIPTION:
Codeine phosphate hemihydrate:Appearance is white, or almostwhite crystalline powder orsmall,colourlesscrystals. Solubilityis freelysolublein water, slightlysolubleorveryslightlysolublein ethanol (96%).
Paracetamol:Appearance is white or almostwhite crystalline powder. Solubilityis sparinglysolublein water, freelysolublein alcohol, veryslightlysolublein methylene chloride.
Doxylaminesuccinate:Appearanceiswhiteorcreamy-whitepowderwithacharacteristicodour. Solubilityis verysolublein water and freelysolublein ethanol(96%).
Thetabletcontainsthefollowingactiveingredients:paracetamol500mg,codeinephosphatehemihydrate10mg,anddoxylaminesuccinate5.1mg.Thetabletsalsocontainthefollowingexcipients:starchmaize,hyprolose,sodiumlaurylsulphate,pregelatinisedmaizestarch,silica colloidalanhydrous,talc-purified,stearicacid, povidone andmagnesiumstearate.
PHARMACOLOGY:
Pharmacodynamics/mechanismofaction.
Paracetamolisap-aminophenolderivativethatexhibitsanalgesicandantipyreticactivity.Itdoesnotpossessanti-inflammatoryactivity.Paracetamolisthoughttoproduceanalgesiathrough acentralinhibition of prostaglandinsynthesis.
Codeineactscentrally.Ithasananalgesiceffect,whichisthoughttobeduemainlytoitspartialmetabolicconversiontomorphine.Codeinehasaboutone-sixththeanalgesicactivityof morphine.
Doxylaminesuccinatecompeteswithhistamineatcentralandperipheralhistamine1-receptorsites,preventingthe histamine-receptor interactionandsubsequentmediatorrelease.
Doxylaminesuccinateisahighlylipophilicmoleculethatreadilycrossestheblood-brainbarrier. Doxylaminesuccinateishighlyselectiveforhistamine1-receptorsbuthaslittleeffect on histamine2 or histamine3 receptors. Also, Doxylamine succinate activates 5-hydroxytryptamine (serotonin) and-adrenergic receptorsandblockscholinergic receptors.Doxylamine has pronounced sedativeeffects.
Thecombinationofparacetamol,codeineanddoxylaminecanbeshowntogiveanenhancedanalgesic effect.
Pharmacokinetics:
Paracetamol:Paracetamolisreadilyabsorbedfromthegastrointestinaltractwithpeakplasmaconcentrationsoccurringabout10to60minutesafteroraladministration.Paracetamolisdistributedintomostbodytissues.Plasmaproteinbindingisnegligibleatusualtherapeuticdosesbutincreaseswithincreasingdoses.Theeliminationhalf-lifevariesfromabout 1 to 3 hours.
Paracetamolismetabolisedextensivelyintheliverandexcretedintheurinemainlyasinactiveglucuronideandsulfateconjugates.Lessthan5%isexcretedunchanged.Themetabolites of paracetamolinclude aminor hydroxylated intermediate which has hepatotoxicactivity.Thisintermediatemetaboliteisdetoxifiedbyconjugationwithglutathione,however,itcanaccumulatefollowingparacetamoloverdosage(morethan150mg/kgor10gtotalparacetamol ingested) and if leftuntreatedcan cause irreversible liverdamage.
Paracetamolismetaboliseddifferentlybyprematureinfants,newborns,infantsandyoungchildrencompared to adults, the sulfate conjugatebeingpredominant.
Codeine:Codeineanditssaltsarewellabsorbedfromthegastrointestinaltractanddoesnotinterferewiththeparacetamolabsorption.Peakplasmacodeineconcentrationsoccuratabout onehour after ingestion of codeine phosphate hemihydrate.Codeineis metabolisedbyO-andN-demethylationintheliver(viathecytochromeP450system)tomorphine(abouttenpercentofacodeinedoseisdemthylatedtomorphine),norcodeineandothermetabolitesincludingnormorphineandhydrocodone.Codeineanditsmetabolitesareexcretedalmostentirelybythekidney,mainlyasconjugateswithglucuronicacid.Approximately3%to16%ofadoseis eliminatedunchanged in theurine.
About8%ofpeoplemetabolisedrugspoorlyviaCYP2D6,andarelikelytoobtainreducedbenefitfrom codeinedueto reducedformation ofthe active metabolite, morphine.
Theplasmahalf-lifeofcodeinehasbeenreportedtobebetween3to4hoursafteroraladministration.
Doxylamine:Doxylamine is alsowellabsorbedfrom the gastrointestinaltract.Followingoraladministrationpeakplasma levels occur after2-3hours.It is metabolisedbythe liverandhas a half-life ofabout 10 hours in healthyadults. It is excreted in theurine asunchangeddoxylamine(60%) andmetabolites(nordoxylamineanddinordoxylamine). Themajor metabolic siteis the liver andmajor metabolic pathways are N-demethylation,N-oxidation, hydroxylation,N-acetylation,N-desalkylationandether cleavage.
CLINICALTRIALS
Systemic reviewscomparingparacetamol-codeinecombinationsversusparacetamolaloneconcludedthat in single-dose studiesaddition ofcodeineto paracetamolproduced acomparativelysmall but statisticallysignificantincrease in analgesic effect;however, therewasanincreased incidence of adverseeffectswiththe combination.
INDICATIONS:
Forthetemporaryreliefofacute moderate pain.
CONTRAINDICATIONS:
Chemists Own Paracetamol Plus Codeine & Calmative is contraindicated for use in patients who are
- CYP 2D6 ultra-rapid metabolisers (see PRECAUTIONS – CYP2D6 Metabolism)
- Younger than12 years (see Precautions – Paediatric use)
- Aged between 12 – 18 years in whom respiratory function might be compromised, including post tonsillectomy and/or adenoidectomy for obstructive sleep apnoea, due to an increased risk of developing serious and life-threatening adverse reactions (see PRECAUTIONS – Paediatric use)
- Breastfeeding (see Precautions – Use in lactation)
This medicine should not be given to patients with:
- knownhypersensitivityoridiosyncraticreactiontoparacetamol,codeinephosphatehemihydrateorotheropiates,doxylaminesuccinateortootherantihistaminesoftheethanolamine class oranyof the other ingredients.
- acuterespiratorydepression
- chronic constipation
- duringlabour when deliveryofapremature infantis anticipatedas it mayproducecodeine withdrawal symptoms in the neonate
- active alcoholism(as thismaypredispose patientsto paracetamolhepatoxicity)
- diarrhoeaduetopseudomembranouscolitisorpoisoning(untilthecausativeorganismortoxinhasbeeneliminatedfromthegastrointestinaltractsincecodeinemayslowtheirelimination,therebyprolongingthe diarrhoea)
- narrow-angleglaucoma
- stenosingpeptic ulcer
- symptomatic prostatic hypertrophy
- bladder neck obstruction
- pyloroduodenal obstruction
- patientstakingmonoamineoxidase inhibitors(MAOIs).
Refer to ‘Interactionswithother medicines’for additional information.
PRECAUTIONS:
CYP2D6 metabolism
Chemists Own Paracetamol Plus Codeine & Calmative is contraindicated for use in patients who are CYP2D6 ultra-rapid metabolisers.
Codeine is metabolised by the liver enzyme CYP2D6 into morphine, its active metabolite. If a patient has a deficiency or is completely lacking this enzyme an adequate analgesic effect will not be obtained. However, if the patient is an extensive or ultra-rapid metaboliser there is an increased risk of developing side effects of opioid toxicity even at commonly prescribed doses. These patients convert codeine into morphine rapidly resulting in higher than expected serum morphine levels. General symptoms of opioid toxicity include confusion, somnolence, shallow breathing, small pupils, nausea, vomiting, constipation and lack of appetite. In severe cases this may include symptoms of circulatory and respiratory depression, which may be life-threatening and very rarely fatal. Children are particularly susceptible due to their immature airway anatomy. Deaths have been reported in children with rapid metabolism who were given codeine for analgesia post adenotonsillectomy. Morphine can also be ingested by infants through breast milk, causing risk of respiratory depression to infants of rapid metaboliser mothers who take codeine.
The prevalence of codeine ultra-rapid metabolism by CYP2D6 in children is not known, but is assumed to be similar to that reported in adults. The prevalence of ultra-rapid metabolisers is estimated to be 1% in those of Chinese, Japanese and Hispanic descent, 3% in African Americans and 1%-10% in Caucasians. The highest prevalence (16%-28%) occurs in North African, Ethiopian and Arab populations.
(see also the sections on Pediatric Use and Use in Lactation)
Thismedicine should be usedwithcaution in patientswith:
- impairedhepatic function
- impairedrenalfunction
- decreasedrespiratoryreservee.g.asthmaorchronicobstructivepulmonarydisease(COPD)
- pre-existingrespiratorydepression. Chemists’ Own Paracetamol Plus Codeine & Calmative is contraindicated for use in patients with acute respiratory depression (see CONTRAINDCATIONS).
- raisedintracranial pressureorhead injury
- prostatic hypertrophy
- hypotension
- hypothyroidism
- epilepsy
It should also beused withcaution in patientswho:
- have ahistoryofdrugabuse
- are takingother respiratorydepressants or sedatives,includingalcohol
- have had recent gastrointestinaltract surgery
Codeine mayobscurethediagnosis orthecourse of gastrointestinaldiseases.Prolonged useofcodeinemayproduce physical and psychologicaldependence.
Thismedicinemaycausedrowsinessandmayincreasetheeffectsofalcohol.Drowsiness
maycontinuethefollowingday.Thoseaffectedshouldnotdriveoroperatemachinery;alcohol should beavoided.
Refer to ‘Interactionswithother medicines’for additional information
Alcoholconsumption:Activealcoholconsumption(threeormorealcoholicdrinksdaily)andtheuseofpainrelieverscontainingparacetamolmayincreasetheriskofliverdamageorstomachbleeding.Effectonabilitytodriveoroperatemachinery:Bothdoxylaminesuccinateandcodeinemaycausedrowsinessinsomepatients,thereforepatientsshouldbecautionedaboutoperatingvehiclesormachineryorengaginginactivitieswhichrequirethemtobefullyalert.Patientsshould be cautioned to abstain fromalcohol.
UseinPregnancy:
CategoryA.
Paracetamol,CodeineandDoxylaminehavebeentakenbyalargenumberofpregnantwomenandwomenofchildbearingagewithoutanyprovenincreaseinthefrequencyofmalformations or other direct or indirectharmfuleffects on the foetus havingbeen observed.
Chemists Own Paracetamol Plus Codeine & Calmativemaycauserespiratorydepressioninthenewborninfant.Useofcodeinepriortodeliverymayproducecodeinewithdrawalsymptomsintheneonate.
Chemists Own Paracetamol Plus Codeine & Calmative is contraindicated during labour when delivery of a premature infant is anticipated as it may produce codeine withdrawal symptoms in the neonate.
UseinLactation:
Paracetamol,codeineanddoxylaminesuccinateareexcretedinbreastmilk.Codeinemaycause respiratorydepression in newborninfant.
Chemists Own Paracetamol Plus Codeine & Calmative is contraindicated during breastfeeding (see also Precautions-CYP2D6 metabolism) due to risk of respiratory depression in the infant.
Analgesic doses excreted in breast milk are generally low. However, infants of breastfeeding mothers taking codeine may have an increased risk of morphine overdose if the mother is an ultrarapid metaboliser of codeine. Codeine is excreted into human breast milk. Codeine is partially metabolised by cytochrome P4502D6 (CYP2D6) into morphine, which is excreted into breast milk. If nursing mothers are CYP2D6 ultra-rapid metabolisers, higher levels of morphine may be present in their breast milk. This may result in symptoms of opioid toxicity in both mother and the breastfed infant. Life-threatening adverse events or neonatal death may occur even at therapeutic doses (see also Precautions – CYP2D6 metabolism).
Therefore, Chemists Own Paracetamol Plus Codeine & Calmative is contraindicated for use during breastfeeding. However, in circumstances where a breastfeeding mother requires codeine therapy, breastfeeding should be suspended and alternative arrangements should be made for feeding the infant for any period during codeine treatment.
Breastfeeding mothers should be told how to recognize signs of high morphine levels in themselves and their babies. For example, in a mother, symptoms include extreme sleepiness and trouble caring for the baby. In the baby, symptoms include signs of increased sleepiness (more than usual), difficulty breastfeeding, breathing difficulties, or limpness. Medical advice should be sought immediately.
Paediatric Use
Childrenmayexperienceparadoxicalexcitationwithdoxylamine.
Chemists’OwnParacetamolPlusCodeineCalmative is contraindicated for use in children
•Younger than 12 years
•Aged between 12 to 18 years in whom respiratory function might be compromised, including post tonsillectomy and/or adenoidectomy for obstructive sleep apnoea. Respiratory depression and death have occurred in some children who received codeine following tonsillectomy and/or adenoidectomy and had evidence of being ultra-rapid metabolisers of codeine due to a CYP2D6 polymorphism.
(see also PRECAUTIONS – CYP2D6 Metabolism)
Use in the elderly
Elderly patientsmayexperienceparadoxicalexcitationwithdoxylamine andaremorelikelytohavecentralnervoussystem(CNS)depressivesideeffects,includingconfusion. (See contraindications).
Theelderlyaremorelikelytohaveagerelatedrenalimpairmentandmaybemoresusceptible to the respiratorydepressant effects ofcodeine.
INTERACTIONSWITHOTHERMEDICINES:
The followinginteractions have been noted:
- Anticoagulantdrugs(warfarin)-dosagemayrequirereductionifparacetamolandanticoagulants are takenfor a prolongedperiod oftime
- Paracetamolabsorption isincreasedbysubstancesthatincreasegastricemptying,e.g.metoclopramide
- Paracetamolabsorptionisdecreasedbysubstancesthatdecreasegastricemptying,
e.g. propantheline, antidepressants with anticholinergic properties, and narcoticanalgesics
- Paracetamol mayincrease chloramphenicolconcentrations
- Theriskofparacetamoltoxicitymaybeincreasedinpatientsreceivingotherpotentiallyhepatotoxicdrugsordrugsthatinducelivermicrosomalenzymessuchasalcoholandanticonvulsantagents
- Paracetamolexcretionmaybeaffectedandplasmaconcentrationsalteredwhengivenwithprobenecid
- Cholestyraminereducestheabsorptionofparacetamolifgivenwithin1hourofparacetamol.
- CNSdepressants–concomitantuseofcodeinewithcentralnervoussystemdepressants(e.g.barbiturates,chloralhydrate,sedatives,alcoholandcentrallyactingmuscle relaxants) cancause additive CNSdepression
- Anticholinergics–concurrentuseofcodeinewithanticholinergicagentsmayincrease the risk ofsevere constipationand/or urinaryretention
- Antihypertensives–hypotensiveeffectsmaybepotentiatedwhenusedconcurrentlywithcodeine and lead toorthostatic hypotension
- Antiperistalticantidiarrhoeals(e.g.kaolin,pectinandloperamide)–concurrentusewithcodeine mayincrease the risk of severeconstipation
- Metoclopramide–codeinemayantagonisetheeffectsofmetoclopramideongastrointestinal activity
- Monoamineoxidaseinhibitors(MAOIs)–concurrentadministrationorusewithin14daysofceasingMAOIsmayenhancethepotentialrespiratorydepressanteffectsofcodeine
- Opioidanalgesics–concurrentuseofcodeineandotheropioidreceptorantagonistsisusuallyinappropriateasadditiveCNSdepression,respiratorydepressionandhypotensiveeffectsmayoccur
- SubstancesthatinhibitCYP2D6suchasquinidine,phenothiazinesandantipsychoticagentscaninterferewiththemetabolismofcodeinetomorphine,reducingtheanalgesic effectof codeine
- Tranquillisers,sedativesandhypnotics–codeinemaypotentiatetheeffectsofthesesubstances.
The followinginteractions withDoxylamine havebeennoted:
- centralnervoussystem(CNS)depressants(alcohol,sedatives,opioidanalgesics,hypnotics) – maycausean increase in sedationeffects
- monoamineoxidaseinhibitors(MAOIs)andtricyclicantidepressants(TCAs)–mayprolongand intensifytheanticholinergic andCNSdepressive effects
- dexchlorpheniraminewhentakenwithmonoamineoxidaseinhibitors(MAOIs)maycause adecreasein blood pressure
- chlorpheniraminewhentakenconcomitantlywithphenytoinmaycauseadecreaseinphenytoinelimination
ADVERSEEFFECTS:
Paracetamol:
Sideeffectsofparacetamolarerareandusuallymild,althoughhaematologicalreactionshavebeenreported. Skin rashesand hypersensitivityreactions occuroccasionally.Overdosagewithparacetamolifleftuntreatedcanresultinsevere,sometimesfatalliverdamage andrarely,acuterenaltubular necrosis.
Codeine:
Themostcommonadverseeffectsassociatedwithcodeinearenausea,vomiting,drowsiness,dizzinessandconstipation.
Othersideeffectsinclude:coughsuppression,respiratorydepression,euphoria,dysphoria,skinrashes,histaminerelease(hypotension,flushing oftheface,tachycardia,breathlessness)andother allergic reactions.
Doxylamine:
CentralNervousSystem(CNS) effects
CNSdepressive effects of Doxylamine include sedation andimpairedperformance(impaireddrivingperformance, poorworkperformance,incoordination,reducedmotorskills, andimpairedinformationprocessing).Performancemaybeimpairedintheabsenceofsedationandmaypersist themorningafter a night-time dose.
CNSstimulatoryeffectsofDoxylaminemayincludeanxiety,hallucinations,appetitestimulation,muscle dyskinesiasandactivationofepileptogenic foci.
HighdosesofDoxylaminemaycausenervousness,tremor,insomnia,agitation,andirritability.
Anticholinergic effects
Side effects of Doxylamine associatedwithcholinergic blockage include drynessofthe eyes,mouth andnose,blurredvision, urinaryhesitancyandretention, constipation andtachycardia.
DOSAGEANDADMINISTRATION:
Adults and Childrenover 12 years:Oneortwotabletswithwaterevery4-6hours ifnecessary.Donotexceed8tabletsin24hoursperiod.
Thismedicineshouldnotbetakenwithothermedicinescontainingparacetamolunlessadvised to do so byadoctoror pharmacist.
Chemists’OwnParacetamolPlusCodeineCalmativeis contraindicated for use in patients who are
•Aged below 12 years.
•Aged between 12 to 18 years in whom respiratory function might be compromised, including post tonsillectomy and/or adenoidectomy for obstructive sleep apnoea (see also CONTRAINDICATIONS and PRECAUTIONS – Paediatric use)
OVERDOSAGE:
Symptoms:Toxicsymptomsofparacetamoloverdoseincludevomiting,abdominalpain,hypotension,sweating,centralstimulationwithexhilarationandconvulsionsinchildren,drowsiness,respiratorydepression,cyanosisandcoma.Themostseriousadverseeffectofacuteoverdosageofparacetamolisadosedependent,potentiallyfatalhepaticnecrosis.Inadults,hepatotoxicitymayoccurafteringestionofasingledoseofparacetamol10to15g(20-30tablets);adoseof25g(50tablets)ormoreispotentiallyfatal.Symptomsduringthefirsttwodaysofacutepoisoningbyparacetamoldonotreflectthepotentialseriousnessoftheintoxication.Majormalfestationsofliverfailuresuchasjaundice,hypoglycaemiaandmetabolicacidosismaytakeatleastthreedaystodevelop.Patientsmaybeasymptomaticforseveraldaysfollowingtheingestionoflargedosesofparacetamolandlaboratoryevidenceofhepatotoxicitymaybedelayed up to one week.Non-fataldamage is usuallyreversible.
Codeine overdose produces central stimulation with exhilaration followed byvomiting,drowsiness, respiratorydepressionandcoma.Inchildren,convulsions mayoccur.
Ingestion oflargeamounts ofdoxylamineismost commonlyassociatedwithimpairedconsciousness,althoughseizuresandanticholinergicsymptomssuchastachycardiaandmydriasishavebeenreported.Rhabdomyolysishasbeennotedduringsomecasesofdoxylamine overdose, with anassociated risein plasma creatine kinaseandmyoglobinuria.
Ifanoverdoseistakenorsuspected,immediatelycontactthePoisonsInformationCentre(inAustralia,call131126;inNewZealandcall0800764766)foradvice,orgotoahospitalstraightawayevenifyoufeelwellbecauseoftheriskofdelayed,seriousliverdamagewithparacetamol.
PRESENTATION AND STORAGE CONDITIONS:
White capsule-shaped tablet, withcentralbreakline on one side.PackSize(s):20's, 40’s
Store below 25oC
AUST R 277276
POISONSCHEDULEOFTHEMEDICINE
S4 (Schedule 4) – Prescription only medicine
NAMEANDADDRESSOFTHESPONSOR:
Cipla Australia PtyLtd
Level 1, 132-136AlbertRoad,South Melbourne VIC 3205
NAMEANDADDRESSOFTHEDISTRIBUTOR:
Arrow Pharmaceuticals Pty Ltd.
15-17 Chapel street, Cremorne, VIC 3121
DATE OF FIRST INCLUSION ON THE AUSTRALIAN REGISTER OFTHERAPEUTICGOODS(theARTG)
1stJuly2016