Oxycodone Depot Teva Sweden
SUMMARYOF PRODUCTCHARACTERISTICS
1. NAMEOFTHEMEDICINALPRODUCT
Oxycodone Depot Teva Sweden5 mgprolonged-releasetablets
Oxycodone Depot
Teva Sweden10 mgprolonged-releasetablets
Oxycodone Depot Teva Sweden15 mgprolonged-releasetablets
Oxycodone Depot Teva Sweden20 mgprolonged-releasetablets
Oxycodone Depot Teva Sweden30 mgprolonged-releasetablets
Oxycodone Depot Teva Sweden40 mgprolonged-releasetablets
Oxycodone Depot Teva Sweden60 mgprolonged-releasetablets
Oxycodone Depot Teva Sweden80 mgprolonged-releasetablets
2. QUALITATIVEANDQUANTITATIVECOMPOSITION
Oxycodone Depot Teva Sweden5 mgprolonged-releasetablets:
Each prolonged-releasetabletcontains5 mgoxycodonehydrochloridecorrespondingto 4.5 mgof oxycodone.
Oxycodone Depot Teva Sweden10 mgprolonged-releasetablets:
Each prolonged-releasetabletcontains10 mgoxycodonehydrochloridecorrespondingto 9 mgof oxycodone.
Oxycodone Depot Teva Sweden15 mgprolonged-releasetablets:
Each prolonged-releasetabletcontains15 mgoxycodonehydrochloridecorrespondingto 13.5 mgof oxycodone.
Oxycodone Depot Teva Sweden20 mgprolonged-releasetablets:
Each prolonged-releasetabletcontains20 mgoxycodonehydrochloridecorrespondingto 18 mgof oxycodone.
Oxycodone Depot Teva Sweden30 mgprolonged-releasetablets:
Each prolonged-releasetabletcontains30 mgoxycodonehydrochloridecorrespondingto 27 mgof oxycodone.
Oxycodone Depot Teva Sweden40 mgprolonged-releasetablets:
Each prolonged-releasetabletcontains40 mgoxycodonehydrochloridecorrespondingto 36 mgof oxycodone.
Oxycodone Depot Teva Sweden60 mgprolonged-releasetablets:
Each prolonged-releasetabletcontains60 mgoxycodonehydrochloridecorrespondingto 54 mgof oxycodone.
Oxycodone Depot Teva Sweden80 mgprolonged-releasetablets:
Each prolonged-releasetabletcontains80 mgoxycodonehydrochloridecorrespondingto 72 mgof oxycodone.
Excipientwith known effect:
Theprolonged-releasetabletscontainlactosemonohydrate.
Oxycodone Depot Teva Sweden5 mgprolonged-releasetablets:
Each prolonged-releasetabletcontains31.6 mglactosemonohydrate
Oxycodone Depot Teva Sweden10 mgprolonged-releasetablets:
Each prolonged-releasetabletcontains63.2 mglactosemonohydrate
Oxycodone Depot Teva Sweden15 mgprolonged-releasetablets:
Each prolonged-releasetabletcontains63.2 mglactosemonohydrate
Oxycodone Depot Teva Sweden20 mgprolonged-releasetablets:
Each prolonged-releasetabletcontains31.6 mglactosemonohydrate
Oxycodone Depot Teva Sweden30 mgprolonged-releasetablets:
Each prolonged-releasetabletcontains63.2 mglactosemonohydrate
Oxycodone Depot Teva Sweden40 mgprolonged-releasetablets:
Each prolonged-releasetabletcontains31.6 mglactosemonohydrate
Oxycodone Depot Teva Sweden60 mgprolonged-releasetablets:
Each prolonged-releasetabletcontains63.2 mglactosemonohydrate
Oxycodone Depot Teva Sweden80 mgprolonged-releasetablets:
Each prolonged-releasetabletcontains63.2 mglactosemonohydrate
Forthefulllistofexcipients, seesection 6.1.
3. PHARMACEUTICALFORM
Prolonged-releasetablet.
Oxycodone Depot Teva Sweden5 mgprolonged-releasetablets:
Blue, round, biconvex tablets, 7 mmin diameter, with‘OX5’debossedon oneside.
Oxycodone Depot
Teva Sweden 10 mg prolonged-release tablets:
White, round, biconvex tablets, 9 mm in diameter, with ‘OX 10’ debossed on one side.
Oxycodone Depot
Teva Sweden15 mgprolonged-releasetablets:
Grey, round, biconvex tablets, 9mmin diameter, with‘OX15’debossed ononeside.
Oxycodone Depot
Teva Sweden20 mgprolonged-releasetablets:
Pink, round, biconvex tablets, 7 mmin diameter, with‘OX20’debossedon oneside.
Oxycodone Depot
Teva Sweden30 mgprolonged-releasetablets:
Brown, round, biconvex tablets, 9 mmin diameter, with ‘OX30’debossed on oneside.
Oxycodone Depot
Teva Sweden40 mgprolonged-releasetablets:
Yellow,round,biconvex tablets, 7 mmin diameter, with ‘OX40’debossed on oneside.
Oxycodone Depot
Teva Sweden60 mgprolonged-releasetablets:
Red, round, biconvex tablets, 9 mmin diameter, with‘OX60’debossedon oneside.
Oxycodone Depot
Teva Sweden80 mgprolonged-releasetablets:
Green,round,biconvex tablets, 9 mmin diameter, with ‘OX80’debossed on oneside.
4. CLINICALPARTICULARS
4.1 Therapeuticindications
Severepain, whichcan beadequatelymanaged onlywith opioid analgesics.
Oxycodone Depot Teva Swedenisindicatedinadultsand adolescentsaged 12 yearsand older.
4.2 Posology andmethod ofadministration
Posology
Thedosagedependsontheintensityofpainandthepatient’sindividualsusceptibilitytothetreatment. Thefollowinggeneraldosagerecommendationsapply:
Adultsandadolescents12yearsofage andolder
Dosetitrationandadjustment
Ingeneral,theinitialdoseforopioidnaïvepatientsis10 mgoxycodonehydrochloridegivenat intervalsof12 hours. Somepatientsmaybenefitfromastartingdoseof5mgto minimizethe incidenceofsideeffects.
Patientsalreadyreceivingopioidsmaystarttreatmentwithhigherdosagestakingintoaccounttheir experiencewithformeropioidtherapies.
Fordosesnotrealisable/practicablewiththesestrengths, otherstrengthsareavailable.
Accordingtowell-controlledclinicalstudies10-13mg oxycodonehydrochloridecorrespondto approximately20 mgmorphinesulphate,bothintheprolonged-releaseformulation.
Becauseofindividualdifferencesinsensitivityfordifferentopioids,itisrecommended thatpatients shouldstartconservativelywithOxycodone Depot Teva Swedenprolonged-releasetabletsafterconversionfromotheropioids,with 50-75%ofthecalculatedoxycodonedose.
SomepatientswhotakeOxycodone Depot Teva Swedenprolonged-releasetabletsfollowingafixedscheduleneedrapidrelease analgesicsasrescuemedicationinordertocontrolbreakthroughpain. Oxycodone Depot Teva Swedenprolonged-releasetabletsare notindicatedforthetreatmentofacutepain and/orbreakthroughpain.Thesingledoseoftherescue medicationshouldamountto1/6oftheequianalgesicdailydoseofOxycodone Depot Teva Swedenprolonged-releasetablets.Useof therescuemedicationmorethantwicedailyindicatesthatthedoseofOxycodone Depot Teva Swedenprolonged-releasetablets needstobeincreased.Thedoseshouldnotbeadjustedmoreoftenthanonceevery1-2 daysuntilastable twicedailyadministrationhasbeenachieved.
Followingadoseincreasefrom10mgto20mgtakenevery12 hoursdoseadjustmentsshouldbemade instepsofapproximatelyonethirdofthedailydose.Theaimisapatient-specificdosagewhich,with twicedailyadministration,allowsforadequateanalgesiawith tolerableundesirableeffectsandaslittle rescuemedicationaspossibleaslongaspain therapyisneeded.
Evendistribution(thesamedosemorningsandevenings)followingafixedschedule(every12 hours)is appropriateforthemajorityofthepatients.Forsomepatientsitmaybeadvantageoustodistributethedoses unevenly.In general,thelowesteffectiveanalgesicdoseshouldbechosen.Forthetreatmentofnon- malignantpainadailydoseof40 mgisgenerallysufficient;buthigherdosagesmaybenecessary.Patients withcancer-relatedpainmayrequiredosagesof80to120 mg,whichinindividualcasescanbeincreasedto up to400 mg.Ifevenhigherdosesarerequired,thedoseshouldbedecided individualbalancingefficacy withthetoleranceandriskofundesirableeffects.
Duration ofadministration
Oxycodone Depot Teva Swedenprolonged-releasetabletsshouldnotbetakenlongerthannecessary.Iflong-termtreatmentis necessaryduetothetypeandseverityoftheillnesscarefulandregularmonitoringisrequiredto determinewhetherandtowhatextenttreatmentshouldbecontinued.
Discontinuation oftreatment
Whenapatientno longerrequirestherapywithoxycodone, itmaybeadvisabletotaperthedosegraduallyto preventsymptomsofwithdrawal.
Paediatricpopulation
Therehavebeenno studiesin patientsunder12 yearsofage; thereforeoxycodonehydrochlorideshould notbeusedin patientsunder12 years.
Elderlypatients
Adoseadjustmentisnotusuallynecessaryinelderlypatients.
Patientswith renalorhepaticimpairment
Thedoseinitiation shouldfollowaconservativeapproach in thesepatients.Therecommended adultstarting doseshould bereduced by50%(forexampleatotaldailydoseof10 mgorallyinopioid naïvepatients), and each patientshouldbetitrated toadequatepain controlaccordingtotheirclinicalsituation.
Riskpatients
Riskpatients,forexamplepatientswithlowbodyweightorslowmetabolismofmedicinalproducts,should initiallyreceivehalftherecommendedadultdoseiftheyareopioidnaïve. Dosetitrationshouldbeperformed inaccordancewiththeindividualclinicalsituation.
Method ofadministration
Fororaluse.
Oxycodone Depot Teva Swedenprolonged-releasetabletsshouldbetakentwicedailybasedon afixed scheduleatthedosage determined.
Theprolonged-releasetabletsmaybetakenwithorindependentofmealswithasufficientamountof liquid.Oxycodone Depot Teva Swedenprolongedreleasetabletsmustbeswallowedwhole,notchewed.
Forinstructionshowto open thechildresistantblisters and HDPE containers, seesection 6.6.
4.3 Contraindications
- Hypersensitivityto the active substanceortoanyoftheexcipientslistedinsection 6.1.
- Severerespiratorydepressionwithhypoxiaand/orhypercapnia.
- Severechronicobstructivepulmonarydisease.
- Corpulmonale.
- Severebronchialasthma.
- Elevatedcarbon dioxidelevelsintheblood.
- Paralyticileus.
- Acuteabdomen,delayedgastricemptying.
4.4 Specialwarningsand precautionsforuse
Paediatricpopulation
Oxycodone Depot Teva Swedenprolonged-releasetabletshavenotbeenstudiedinchildrenyoungerthan12 yearsofage.The safetyandefficacyofthetabletshavenotbeendemonstratedandtheuseinchildrenyoungerthan12 yearsofageisthereforenotrecommended.
Elderlyordebilitatedpatients
Themajorriskofopioid excessisrespiratorydepression. Cautionisrequiredinelderlyordebilitated patients,inpatientswithsevereimpairmentoflung,liverorkidneyfunction,myxoedema, hypothyroidism,Addison’sdisease(adrenalinsufficiency),intoxicationpsychosis(e.g.alcohol), prostatichypertrophy, adrenocorticalinsufficiency,alcoholism, known opioiddependence,delirium tremens,pancreatitis,diseasesofthebiliarytract,inflammatoryboweldisorders,biliaryoruretericcolic, hypotension, hypovolaemia,conditionswithincreasedbrainpressuresuch asheadinjury, disturbances ofcirculatoryregulation,epilepsyorseizuretendencyandinpatientstakingMAOinhibitors.
Patientsundergoingabdominalsurgery
Aswithallopioidpreparations, oxycodoneproductsshould beused with cautionfollowingabdominal surgeryasopioidsareknown to impairintestinalmotilityand should notbeuseduntilthephysician is assured ofnormalbowelfunction.
Patientswithseverehepaticimpairmentshouldbecloselymonitored.
Respiratorydepression
Respiratorydepressionisthemostsignificantriskinducedbyopioidsandismostlikelytooccurin elderlyordebilitatedpatients.Therespiratorydepressanteffectofoxycodonecanleadtoincreased carbondioxideconcentrationsinbloodandhenceincerebrospinalfluid.In predisposedpatients opioidscancauseseveredecreaseinbloodpressure.
Long-termuse, toleranceand withdrawal
Thepatientmaydevelop tolerancetothedrugwithchronicuseand requireprogressivelyhigherdosesto maintain paincontrol. Prolonged useofthisproductmaylead to physicaldependenceand awithdrawal syndromemayoccuruponabruptcessation oftherapy. Whenapatientno longerrequirestherapywith oxycodone, itmaybeadvisabletotaperthedosegraduallytopreventsymptomsofwithdrawal.Withdrawal symptomsmayincludeyawning, mydriasis, lacrimation, rhinorrhoea,tremor, hyperhidrosis, anxiety, agitation,convulsionsandinsomnia.
Hyperalgesia
Hyperalgesiathatwillnotrespondto afurtherdoseincreaseofoxycodonemayveryrarelyoccur, particularlyinhigh doses.An oxycodonedosereduction orchangetoan alternativeopioid mayberequired.
Dependencepotential
Oxycodone Depot Teva Swedenprolonged-releasetabletshaveaprimarydependencepotential. Oxycodonehasan abuseprofilesimilarto otherstrongagonistopioids. Oxycodonemaybesoughtandabused bypeoplewith latentormanifest addiction disorders.Thereispotentialfordevelopmentofpsychologicaldependence[addiction]toopioid analgesics,includingoxycodone.However, whenusedasdirectedinpatientswithchronicpaintheriskof developingphysicalorpsychologicaldependenceismarkedlyreducedorneedstobeassessed ina differentiated manner.Thereareno dataavailableon theactualincidenceofpsychologicaldependencein chronicpainpatients.In patientswithahistoryofalcoholanddrugabusethemedicinalproductmustbe prescribedwithspecialcare.
Pre-operative use
Oxycodone Depot Teva Swedenprolongedreleasetabletsarenotrecommendedforpre-operativeuseorwithinthefirst12-24 hourspostoperatively.
Abusiveparenteralvenousinjection
In caseofabusiveparenteralvenousinjectionthetabletexcipientsmayleadtonecrosisofthelocal tissue,infection, increasedriskofendocarditis,and valvularheartinjurywhich maybefatal, granulomasofthelungorotherserious, potentiallyfatalevents.
Tabletsmustnotbechewedorcrushed
Toavoiddamagetothecontrolledreleasepropertiesofthetabletstheprolongedreleasetabletsmust beswallowedwhole,andnotbroken,chewedorcrushed.Theadministrationofbroken, chewedor crushed controlledreleaseoxycodonetabletsleadstorapidreleaseandabsorptionofapotentially fataldoseofoxycodone(seesection4.9).
Alcohol
Concomitantuseofalcoholand oxycodonehydrochlorideprolonged-releasetabletsmayincreasethe undesirableeffectsofoxycodonehydrochloride;concomitantuseshouldbeavoided.
Oxycodone Depot Teva Swedencontainslactose
Thismedicinalproductcontainslactose. Patientswithrarehereditaryproblemsofgalactose intolerance, theLapp lactasedeficiencyorglucose-galactosemalabsorptionshouldnottakethis medicine.
4.5 Interactionwith othermedicinalproductsand otherformsofinteraction
Therecan beanenhancedCNS depressanteffectduringconcomitanttherapywith drugswhich affectthe CNS such asotheropioids,sedatives, hypnotics, anti-depressants,phenothiazines, neuroleptic drugs, antipsychotics,anaesthetics, muscle relaxants,antihistaminesand antiemetics. MAO-inhibitorsareknown tointeractwith opioid analgesics. MAO-inhibitorscausesCNS-excitation ordepression associated with hypertensiveorhypotensivecrisis(see section4.4). Oxycodoneshould beused with cautionin patientsadministered MAO-inhibitorsorwho have received MAO-inhibitorsduringthelasttwo weeks(seesection 4.4).
Alcohol may enhance the pharmacodynamic effects of oxycodone; concomitant use should be avoided.
Anticholinergics (e.g. antipsychotics, antihistamines, antiemetics, antiparkinson drugs) can enhance the anticholinergic undesirable effects of oxycodone (such as constipation, dry mouth or micturition disorders).
Cimetidinecaninhibitthemetabolismofoxycodone.
OxycodoneismetabolisedmainlybyCYP3A4, with acontributionfromCYP2D6. Theactivitiesofthese metabolicpathwaysmaybeinhibited orinduced byvariousco-administered drugsordietaryelements.
CYP3A4 inhibitors, such asmacrolideantibiotics(e.g. clarithromycin, erythromycin and telithromycin), azol-antifungals(e.g. ketoconazole, voriconazole, itraconazole, and posaconazole), proteaseinhibitors(e.g. boceprevir,ritonavir, indinavir, nelfinavirand saquinavir), cimetidineand grapefruitjuicemaycausea reduced clearanceofoxycodonethatcould causean increaseoftheplasmaconcentrationsofoxycodone. Thereforetheoxycodonedosemayneed to beadjusted accordingly.
Somespecificexamplesareprovided below:
• Itraconazole,apotentCYP3A4 inhibitor, administered200 mgorallyforfivedays, increasedtheAUCoforaloxycodone. On average, theAUCwasapproximately2.4 timeshigher(range1.5 -3.4).
• Voriconazole,aCYP3A4 inhibitor, administered200mgtwice-dailyforfourdays(400 mggiven as firsttwo doses), increased theAUCoforaloxycodone.On average, theAUCwasapproximately3.6 timeshigher(range2.7 -5.6).
• Telithromycin, aCYP3A4 inhibitor, administered800mgorallyforfourdays, increasedtheAUCof oraloxycodone. Onaverage, theAUCwasapproximately1.8 timeshigher(range1.3 – 2.3).
• GrapefruitJuice, aCYP3A4 inhibitor, administeredas200 mlthreetimesadayforfivedays, increasedtheAUCoforaloxycodone. On average, theAUCwasapproximately1.7 timeshigher (range1.1– 2.1).
CYP3A4 inducers,suchasrifampicin,carbamazepin,phenytoinand StJohn´sWortmayinducethe metabolismofoxycodoneand causeanincreasedclearanceofoxycodonethatcould causeareductionofthe plasmaconcentrationsofoxycodone.Theoxycodonedosemayneed to beadjusted accordingly. Somespecificexamplesareprovided below:
• StJohnsWort, aCYP3A4 inducer, administeredas300 mgthreetimesadayforfifteendays,reducedtheAUCoforaloxycodone. On average, theAUCwasapproximately50%lower(range37-57%).
• Rifampicin, a CYP3A4 inducer, administered as 600 mg once-daily for seven days, reduced the AUC of oral oxycodone. On average, the AUC was approximately 86% lower.
DrugsthatinhibitCYP2D6activity, suchasparoxetine, fluoxetineand quinidine,maycausedecreased clearanceofoxycodonewhich couldlead to anincreasein oxycodoneplasmaconcentrations.
Theeffectofotherrelevantisoenzymeinhibitorsonthemetabolismofoxycodoneisnotknown. Potentialinteractionsshouldbetakenintoaccount.
ClinicallyrelevantchangesinInternationalNormalizedRatio(INR)inbothdirectionshavebeen observedinindividualsifcoumarinanticoagulantsareco-appliedwithoxycodonehydrochloride.
Thereareno studiesinvestigatingtheeffectofoxycodoneon CYP catalysedmetabolismofotherdrugs.
4.6 Fertility, pregnancy andlactation
Useofthismedicinalproductshouldbeavoided to theextentpossibleinpatientswho arepregnantor lactating.
Pregnancy
Therearelimited datafromtheuseofoxycodoneinpregnantwomen.Infantsborn to motherswho have received opioidsduringthelast3to 4 weeksbeforegivingbirth shouldbemonitored forrespiratory depression.Withdrawalsymptomsmaybeobserved in thenewborn ofmothersundergoingtreatmentwith oxycodone.
Breastfeeding
Oxycodonemaybesecreted in breastmilkand maycauserespiratorydepression in thenewborn. Oxycodone should, therefore, notbeused in breastfeedingmothers.
4.7 Effectsonabilityto driveand usemachines
Oxycodonemayimpairtheabilityto driveand usemachines.
Withstabletherapy,ageneralbanondrivingavehicleisnotnecessary.Thetreatingphysicianmust assesstheindividualsituation.
4.8 Undesirableeffects
Oxycodonecancauserespiratorydepression,miosis,bronchialspasmsandspasmsofthesmooth musclesandcansuppressthecoughreflex.
Theadverseeventsconsideredatleastpossiblyrelatedtotreatmentaretabulatedbelowbysystem organclassandabsolutefrequency.
|
Body System |
Very common (≥ 1/10) |
Common (≥ 1/100 to <1/10) |
Uncommon (≥ 1/1,000 to <1/100) |
Rare (≥1/10,000 to <1/1,000) |
Frequency unknown (Cannot be estimated from the available data) |
|
Blood and lymphatic system disorders |
|
|
|
lymphadenopathy |
|
|
Immune system disorders |
|
|
hypersensitivity |
|
anaphylactic responses |
|
Endocrine disorders |
|
|
syndrome of inappropriate antidiuretic hormone secretion |
|
|
|
Metabolism and nutrition disorders |
|
decreased appetite |
dehydration |
|
|
|
Psychiatric disorders |
|
anxiety, confusional state, depression, insomnia, nervousness. abnormal thinking, amnesia, isolated cases of speech disorders |
agitation, affect lability, euphoric mood, hallucinations, decreased libido, drug dependence (see section 4.4), depersonalisation, change in taste, visual disturbances, hyperacousis |
|
aggression |
|
Nervous system disorders |
somnolence, dizziness, headache |
asthenia, tremor |
amnesia, convulsion, hypertonia, both increased and decreased muscle tone, involuntary muscle contractions; hypoesthesia; coordination disturbances; malaise; speech disorder, syncope, paraesthesia, dysgeusia |
|
hyperalgesia |
|
Eye disorders |
|
|
visual impairment, lacrimation disorder, miosis |
|
|
|
Ear and labyrinth disorders |
|
|
vertigo |
|
|
|
Cardiac disorders |
|
|
Supraventricular tachycardia; palpitations (in the context of withdrawal syndrome) |
|
|
|
Vascular disorders |
|
|
vasodilatation |
hypotension, orthostatic hypotension |
|
|
Respiratory, thoracic and mediastinal disorders |
|
dyspnoea, bronchospasm |
increased coughing; pharyngitis; rhinitis; voice changes, respiratory depression |
|
|
|
Gastrointestinal disorders |
constipation, nausea, vomiting |
dry mouth, rarely accompanied by thirst; gastrointestinal disorders such as abdominal pain; diarrhoea; dyspepsia; loss of appetite |
oral ulcers; gingivitis; stomatitis; flatulence, dysphagia, eructation, ileus |
gum bleeding; increased appetite; tarry stool; tooth staining |
dental caries |
|
Hepato-biliary disorders |
|
|
increased hepatic enzymes |
|
cholestasis, biliary colic |
|
Skin and subcutaneous tissue disorders |
pruritus |
skin eruptions including rash, in rare cases increased photosensitivity, in isolated cases urticaria or exfoliative dermatitis, hyperhidrosis |
dry skin |
herpes simplex, urticaria |
|
|
Renal and urinary disorders |
|
micturition disturbances (increased urge to urinate) |
urinary retention |
haematuria |
|
|
Reproductive system and breast disorders |
|
|
reduced libido; erectile disfunction |
|
amenorrhoea |
|
General disorders and administration site conditions |
|
sweating, asthenic conditions |
accidental injuries; pain (e.g. chest pain); oedema; migraine; physical dependence with withdrawal symptoms; drug tolerance, chills, malaise, peripheral oedema, thirst. |
weight changes (increase or decrease); cellulitis |
|
Toleranceanddependencemaydevelop.
Reportingofsuspected adversereactions
Reportingsuspected adversereactionsafterauthorisation ofthemedicinalproductisimportant. Itallows continuedmonitoringofthebenefit/riskbalanceofthemedicinalproduct. Healthcareprofessionalsareasked to reportanysuspectedadversereactions viathe national reporting system listed in Appendix V.
4.9 Overdose
Symptoms and intoxication:
Miosis, respiratory depression, somnolence, reduced skeletal muscle tone and drop in blood pressure. In severe cases circulatory collapse, stupor, coma, hypotonia, bradycardia, non- cardiogenic lung oedema, hypotension, and death may occur; abuse of high doses of strong opioids such as oxycodone can be fatal.
Therapy of intoxications:
Primary attention should be given to the establishment of a patent airway and institution of assisted or controlled ventilation
In the event of overdosing intravenous administration of an opiate antagonist (e.g. 0.4-2 mg intravenous naloxone) may be indicated. Administration of single doses must be repeated depending on the clinical situation at intervals of 2 to 3 minutes. Intravenous infusion of 2 mg of naloxone in 500 ml isotonic saline or 5% dextrose solution (corresponding to 0.004 mg naloxone/ml) is possible. The rate of infusion should be adjusted to the previous bolus injections and the response of the patient.
Gastric lavage can be taken into consideration. Consider activated charcoal (50 g for adults, 10 -15 g for children), if a substantial amount has been ingested within 1 hour, provided the airway can be protected. It may be reasonable to assume that late administration of activated charcoal may be beneficial for prolonged release preparations; however there is no evidence to support this.
For speeding up the passage a suitable laxative (e.g. a PEG based solution) may be useful.
Supportive measures (artificial respiration, oxygen supply, administration of vasopressors and infusion therapy) should, if necessary, be applied in the treatment of accompanying circulatory shock. Upon cardiac arrest or cardiac arrhythmias cardiac massage or defibrillation may be indicated. If necessary, assisted ventilation as well as maintenance of water and electrolyte balance.
5. PHARMACOLOGICALPROPERTIES
5.1 Pharmacodynamicproperties
Pharmacotherapeuticgroup:Naturalopiumalkaloids
ATC-Code:N02AA05
Oxycodoneshowsanaffinitytokappa,muand deltaopioidreceptorsinthebrainand spinalcord.It actsatthesereceptorsasanopioidagonistwithoutanantagonisticeffect.Thetherapeuticeffectis mainlyanalgesicandsedative.Comparedtorapid-releaseoxycodone,givenaloneorincombination withothersubstances,theprolonged-releasetabletsprovidepainreliefforamarkedlylongerperiod withoutincreasedoccurrenceofundesirableeffects.
Endocrinesystem
Opioidsmayinfluencethehypothalamic-pituitary-adrenalor– gonadalaxes.Somechangesthatcanbeseen includean increaseinserumprolactin, and decreasesin plasmacortisolandtestosterone. Clinicalsymptoms maybemanifestfromthesehormonalchanges.
Otherpharmacologicaleffects
In-vitro and animalstudiesindicatevariouseffectsofnaturalopioids, such asmorphine, oncomponentsof theimmunesystem;theclinicalsignificanceofthesefindingsisunknown. Whetheroxycodone, a semisyntheticopioid, hasimmunologicaleffectssimilarto morphineisunknown.
Clinicalstudies
TheefficacyofOxycodoneprolonged-releasetabletshasbeen demonstrated in cancerpain, post-operative painand severenon-malignantpainsuchasdiabeticneuropathy, postherpeticneuralgia,lowbackpain and osteoarthritis.In thelatterindication,treatmentwascontinuedforup to18 monthsand proved effectivein manypatientsforwhomNSAIDsaloneprovidedinadequaterelief.TheefficacyofOxycodoneprolonged- releasetabletsin neuropathicpain wasconfirmed bythreeplacebo-controlled studies.
In patientswith chronicnon-malignantpain, maintenanceofanalgesiawith stabledosingwasdemonstrated forup tothreeyears.
5.2 Pharmacokineticproperties
Absorption:
TherelativebioavailabilityofOxycodone Depot Teva Swedenprolonged-releasetabletsiscomparabletothatofrapidrelease oxycodonewithmaximumplasmaconcentrationsbeingachievedapproximately3 hoursafterintakeof theprolonged-releasetabletscomparedto1 to1.5 hours. Peakplasmaconcentrationsandoscillationsof theconcentrationsofoxycodonefromtheprolonged-releaseandrapid-releaseformulationsare comparablewhen givenatthesamedailydoseatintervalsof12 and6hoursrespectively.
Afat-richmealbeforetheintakeofthetabletsdoesnotaffectthemaximumconcentration ortheextent ofabsorptionofoxycodone.
Thetabletsmustnotbecrushed, dividedorchewedasthisleadstorapidoxycodonereleaseand absorption ofapotentiallyfataldoseofoxycodonedueto thedamageoftheprolongedrelease properties.
Distribution:
Theabsolutebioavailabilityofoxycodoneisapproximatelytwothirdsrelativeto parenteral administration.In steadystate,thevolumeofdistributionofoxycodoneamountsto2.6 l/kg;plasma proteinbindingto38-45%;theeliminationhalf-lifeto4to6 hoursandplasmaclearanceto0.8l/min.
Biotransformation:
Oxycodoneismetabolisedintheintestineandliverto noroxycodoneandoxymorphoneaswellasto severalglucuronideconjugates. CYP3A4 and CYP2D6 areprobablyinvolved in theformation of noroxycodoneandoxymorphonerespectively. Oxymorphonehasanalgesicactivitybutispresentin theplasmainlowconcentrationsand isnotconsideredto contributeto oxycodone´spharmacological effect.
Elimination:
Oxycodoneanditsmetabolitesareexcretedviaurineandfaeces.Oxycodonecrossestheplacentaand isfoundinbreastmilk.
Linearity/non-linearity:
Theprolonged-releasetabletsarebioequivalentinadoseproportionalmannerwithregardtothe amountofactivesubstanceabsorbedaswellascomparablewithregardtotherateofabsorption.
Older people
Theplasmaconcentration ofoxycodonein elderlysubjectsis15%greaterwhen compared with young subjects.
Gender
Femalesubjectshave, onaverage, plasmaoxycodoneconcentrationsup to 25%higherthan maleson abody weightadjusted basis.Thereason forthisdifferenceisunknown.
Patientswith renalimpairment
Patientswith mild, moderateand severerenalimpairmentshowed 1.1-, 1.4-and 1.7-fold increased plasma concentrationsrespectivelycompared topatientswithnormalrenalfunction. AUCincreased onaverage1.5-, 1.7-and 2.3-fold respectivelycompared to patientswith normalrenalfunction.Theelimination half-lifefor oxycodoneincreased 1.5-, 1.2-and 1.4-fold respectivelycompared topatientswith normalrenalfunction.
Patientswith hepaticimpairment
Patientswith mild, moderateand severehepaticimpairmentshowed 1.2-, 2.0-and 1.9-fold increasedplasma concentrationsrespectivelycompared topatientwith normalhepaticfunction. AUCincreased onaverage 1.4-, 3.2-and 3.2-fold respectivelycompared topatientswith normalhepaticfunction.Theelimination half- lifeofoxycodoneincreased1.1-, 1.8-and 1.8-fold respectivelycompared topatientswith normalhepaticfunction.
5.3 Preclinicalsafety data
Teratogenicity
Oyxcodonehad no effecton fertilityand earlyembryonicdevelopmentin maleand femaleratsin dosesof up to 8 mg/kgbodyweightand induced no malformationsinratsin dosesofupto8 mg/kgand in rabbitsin dosesof125 mg/kgbodyweight. However,in rabbits,when individualfoetuseswereusedin statistical evaluation,adoserelatedincreasein developmentalvariationswasobserved(increasedincidencesof27 presacralvertebrae,extrapairsofribs).When theseparameterswerestatisticallyevaluatedusinglitters,only theincidenceof27 presacralvertebraewasincreasedand onlyin the125 mg/kg group, adoselevelthat produced severepharmacotoxiceffectsin thepregnantanimals. In astudyon pre-and postnataldevelopment in ratsF1 bodyweightswerelowerat6 mg/kg/d when compared tobodyweightsofthecontrolgroupat doseswhichreduced maternalweightandfoodintake(NOAEL 2 mg/kgbodyweight).Therewereneither effectson physical, reflexological, and sensorydevelopmentalparametersnoron behaviouraland reproductiveindices.
In astudyofperi-and postnataldevelopmentinrats,maternalbodyweightandfood intakeparameterswere reduced fordoses≥2mg/kg/d compared tothecontrolgroup. BodyweightswerelowerintheF1 generation frommaternalratsin the6mg/kg/d dosinggroup. Therewerenoeffectsonphysical,reflexological,or sensorydevelopmentalparametersoron behaviouraland reproductiveindicesintheF1 pups(theNOAEL for F1 pupswas2 mg/kg/d based on bodyweighteffectsseen at6 mg/kg/d). Therewereno effectson theF2 generationatanydosein thestudy.
Carcinogenicity
Long-termcarcinogenicitystudieswerenotperformed.
Mutagenicity
Theresultsofin-vitro and in-vivo studiesindicatethatthegenotoxicriskofoxycodoneto humansisminimal orabsentatthesystemicoxycodoneconcentrationsthatareachievedtherapeutically.
6. PHARMACEUTICALPARTICULARS
6.1 Listofexcipients
Tabletcore:
Lactosemonohydrate Hypromellose PovidoneK30
Stearicacid
Magnesiumstearate
Colloidalanhydroussilica
Tabletcoating
5 mg:
Polyvinylalcohol
Titaniumdioxide(E171)
Macrogol3350
Talc
Indigo CarmineAluminiumLake(E132)
Iron oxide, yellow(E172)
10 mg:
Titaniumdioxide(E171)
Hypromellose
Macrogol400
Polysorbate80
15 mg:
Polyvinylalcohol
Titaniumdioxide(E171)
Macrogol3350
Talc
Iron oxide, black(E172)
Iron oxide, yellow(E172)
20 mg:
Polyvinylalcohol
Titaniumdioxide(E171)
Macrogol3350
Talc
Iron oxide, red (E172)
30 mg:
Polyvinylalcohol
Macrogol3350
Talc
Iron oxide, red (E172)
Iron oxide, black(E172)
Indigo CarmineAluminiumLake(E132)
40 mg:
Polyvinylalcohol
Titaniumdioxide(E171)
Macrogol3350
Talc
Iron oxide, yellow(E172)
60 mg:
Polyvinylalcohol
Macrogol3350
Talc
Iron oxide, red (E172)
Carmine(E120)
Iron oxide, black(E172)
80 mg:
Polyvinylalcohol
Macrogol3350
Talc
Titaniumdioxide(E171)
Indigo CarmineAluminiumLake(E132)
Iron oxide, yellow(E172)
6.2 Incompatibilities
Notapplicable.
6.3 Shelflife
2 years.
6.4 Specialprecautionsforstorage
Blisterpacks:
Do notstoreabove25°C.
HDPE container:
This medicinal product does not require any special storage conditions.
6.5 Natureandcontentsofcontainer
Child- resistant blister packs (PVC/Al/PET/paper) and non-child-resistant blisterpacks(PVC/Al)incartons.
Packsizes:
5 mg: 14, 25, 28, 30, 56, 60, 98, 100 prolonged-releasetablets
10 mg, 20 mg, 40mg, 80mg:10, 14, 25, 28, 30, 50, 56, 60, 98, 100 prolonged-releasetablets
15 mg:28, 30, 56, 98,100prolonged-releasetablets
30 mg, 60 mg:10, 30, 56, 60, 100 prolonged-releasetablets
White,round,child-resistant, HDPE tabletcontainerswith LDPE caps.
Packsize:
5 mg, 10 mg: 98 and 100 prolonged-releasetablets
15 mg, 60 mg: 100 prolonged-releasetablets
20 mg, 40 mg, 80 mg: 50 and 100 prolonged-release tablets
Notallpacksizesmaybemarketed.
6.6 Specialprecautionsfordisposaland otherhandling
No specialrequirements.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Instructionsforuseofchildresistantblisters:
1. Do notpushthetabletdirectlyoutofthepocket
2. Separateoneblistercellfromthestrip attheperforations
3. Carefullypeeloffthebackingto openthepocket
Instructions for use of containers:
1. Push down firmly on the cap
2. Turn the cap anti-clockwise
3. The child-resistant cap should be replaced after use.
7. MARKETINGAUTHORISATIONHOLDER
<[To becompleted nationally]>
8. MARKETINGAUTHORISATIONNUMBER(S)
<[To becompleted nationally]>
9. DATEOF FIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION
Dateoffirstauthorisation:{DDmonth YYYY}>
<[To becompleted nationally]>
10. DATE OF REVISION OF THE TEXT
16 June 2016
15