Document: Oxytia Depot prolonged-release tablet ENG SmPC change

• Oxytia Depot prolonged-release tablet SmPC
• Oxytia Depot prolonged-release tablet ENG SmPC

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SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

Oxytia Depot 5 mg prolonged-release tablets

Oxytia Depot 10 mg prolonged-release tablets

Oxytia Depot 15 mg prolonged-release tablets

Oxytia Depot 20 mg prolonged-release tablets

Oxytia Depot 30 mg prolonged-release tablets

Oxytia Depot 40 mg prolonged-release tablets

Oxytia Depot 60 mg prolonged-release tablets

Oxytia Depot 80 mg prolonged-release tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Oxytia Depot 5 mg prolonged-release tablets:

Each prolonged-release tablet contains 5 mg oxycodone hydrochloride corresponding to 4.5 mg of oxycodone.

Oxytia Depot 10 mg prolonged-release tablets:

Each prolonged-release tablet contains 10 mg oxycodone hydrochloride corresponding to 9 mg of oxycodone.

Oxytia Depot 15 mg prolonged-release tablets:

Each prolonged-release tablet contains 15 mgoxycodone hydrochloride corresponding to 13.5 mg of oxycodone.

Oxytia Depot 20 mg prolonged-release tablets:

Each prolonged-release tablet contains 20 mg oxycodone hydrochloride corresponding to 18 mg of oxycodone.

Oxytia Depot 30 mg prolonged-release tablets:

Each prolonged-release tablet contains 30 mg oxycodone hydrochloride corresponding to 27 mg of oxycodone.

Oxytia Depot 40 mg prolonged-release tablets:

Each prolonged-release tablet contains 40 mg oxycodone hydrochloride corresponding to 36 mg of oxycodone.

Oxytia Depot 60 mg prolonged-release tablets:

Each prolonged-release tablet contains 60 mg oxycodone hydrochloride corresponding to 54 mg of oxycodone.

Oxytia Depot 80 mg prolonged-release tablets:

Each prolonged-release tablet contains 80 mg oxycodone hydrochloride corresponding to 72 mg of oxycodone.

Excipientwith known effect:

The prolonged-release tablets contain lactose monohydrate.

Oxytia Depot 5 mg prolonged-release tablets:

Each prolonged-release tablet contains 31.6 mg lactose monohydrate

Oxytia Depot 10 mg prolonged-release tablets:

Each prolonged-release tablet contains 63.2 mg lactose monohydrate

Oxytia Depot 15 mg prolonged-release tablets:

Each prolonged-release tablet contains 63.2 mg lactose monohydrate

Oxytia Depot 20 mg prolonged-release tablets:

Each prolonged-release tablet contains 31.6 mg lactose monohydrate

Oxytia Depot 30 mg prolonged-release tablets:

Each prolonged-release tablet contains 63.2 mg lactose monohydrate

Oxytia Depot 40 mg prolonged-release tablets:

Each prolonged-release tablet contains 31.6 mg lactose monohydrate

Oxytia Depot 60 mg prolonged-release tablets:

Each prolonged-release tablet contains 63.2 mg lactose monohydrate

Oxytia Depot 80 mg prolonged-release tablets:

Each prolonged-release tablet contains 63.2 mg lactose monohydrate

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL form

Prolonged-release tablet.

Oxytia Depot 5 mg prolonged-release tablets:

Blue, round, biconvex tablets, 7 mm in diameter, with ‘OX 5’ debossed on one side.

Oxytia Depot 10 mg prolonged-release tablets:

White, round, biconvex tablets, 9 mm in diameter, with ‘OX 10’ debossed on one side.

Oxytia Depot 15 mg prolonged-release tablets:

Grey, round, biconvex tablets, 9 mm in diameter, with ‘OX 15’ debossed on one side.

Oxytia Depot 20 mg prolonged-release tablets:

Pink, round, biconvex tablets, 7 mm in diameter, with ‘OX 20’ debossed on one side.

Oxytia Depot 30 mg prolonged-release tablets:

Brown, round, biconvex tablets, 9 mm in diameter, with ‘OX 30’ debossed on one side.

Oxytia Depot 40 mg prolonged-release tablets:

Yellow, round, biconvex tablets, 7 mm in diameter, with ‘OX 40’ debossed on one side.

Oxytia Depot 60 mg prolonged-release tablets:

Red, round, biconvex tablets, 9 mm in diameter, with ‘OX 60’ debossed on one side.

Oxytia Depot 80 mg prolonged-release tablets:

Green, round, biconvex tablets, 9 mm in diameter, with ‘OX 80’ debossed on one side.

4. Clinical particulars

4.1 Therapeutic indications

Severe pain, which can be adequately managed only with opioid analgesics.

Oxytia Depot is indicated in adults and adolescents aged 12 years and older.

4.2 Posology and method of administration

Posology

The dosagedepends on theintensity of painand thepatient’s individualsusceptibilityto the treatment.The followinggeneraldosage recommendationsapply:

Adults and adolescents 12 years of age and older

Dose titration andadjustment

In general, theinitial dose for opioid naïvepatients is10 mgoxycodone hydrochloride given atintervals of 12 hours. Somepatients maybenefit froma startingdose of 5 mg to minimizethe incidenceof side effects.

Patients alreadyreceiving opioidsmaystarttreatmentwith higherdosages taking into account theirexperience withformeropioid therapies.

For doses not realisable/practicable with these strengths, other strengths are available.

According towell-controlled clinicalstudies 10-13 mgoxycodone hydrochloride correspond toapproximately20 mgmorphine sulphate,both inthe prolonged-release formulation.

Because of individualdifferences insensitivity for different opioids,it isrecommended thatpatients shouldstart conservativelywith Oxytia Depotprolonged-releasetablets after conversion fromother opioids,with 50-75% of thecalculated oxycodonedose.

Somepatients who takeOxytia Depotprolonged-release tabletsfollowing afixed schedule need rapidrelease analgesicsas rescue medicationin orderto controlbreakthrough pain. Oxytia Depot prolonged-releasetabletsare notindicated for thetreatmentof acute pain and/or breakthroughpain. Thesingle dose of therescue medicationshould amountto 1/6 of theequianalgesic dailydose of Oxytia Depotprolonged-releasetablets. Use of the rescue medicationmore thantwice dailyindicates thatthe dose of Oxytia Depot prolonged-release tablets needsto beincreased. Thedose should notbe adjustedmoreoften thanonce every 1-2 days until astable twicedaily administrationhas been achieved.

Following adose increase from10 mg to20 mgtakenevery 12 hours dose adjustments shouldbe madein steps of approximately onethird of thedaily dose. Theaim isa patient- specific dosagewhich, withtwice dailyadministration,allows for adequate analgesiawith tolerableundesirable effectsandas little rescuemedicationas possible as long as pain therapyis needed.

Even distribution(the samedose morningsand evenings)following afixed schedule (every 12 hours) isappropriate for the majorityofthe patients.For somepatientsit maybe advantageous todistribute thedoses unevenly. In general, thelowest effective analgesic dose should bechosen. For thetreatmentof non- malignant paina dailydose of 40 mgis generallysufficient; buthigher dosages maybe necessary.Patients withcancer- related painmayrequire dosages of 80 to 120 mg,which inindividual casescan be increasedto up to400 mg. If evenhigher doses arerequired, thedose should bedecided individualbalancingefficacy withthetoleranceand risk ofundesirableeffects.

Method of administration

For oral use.

Oxytia Depot prolonged-releasetablets shouldbe takentwice dailybased on afixed schedule atthe dosagedetermined.

The prolonged-releasetablets maybe takenwith or independentof mealswith asufficient amountof liquid.Oxytia Depot prolongedreleasetablets mustbe swallowed whole, notchewed.

Duration of administration

Oxytia Depot prolonged-releasetabletsshould notbe takenlongerthan necessary.If long- term treatmentis necessarydue tothe typeand severityof theillnesscarefuland regular monitoring isrequired todeterminewhether andto whatextent treatmentshould be continued.

Discontinuation of treatment

When a patient no longer requires therapy with oxycodone, it may be advisable to taper the dose gradually to prevent symptoms of withdrawal.

Paediatric population

There have been no studies in patients under 12 years of age, therefore oxycodone hydrochloride shouldnot be used in patients under 12 years.

Elderly patients

A dose adjustment is not usually necessary in elderly patients.

Patients with renal or hepatic impairment

The dose initiation should follow a conservative approach in these patients. The recommended adult starting dose should be reduced by 50% (for example a total daily dose of 10 mg orally in opioid naïve patients), and each patient should be titrated to adequate pain control according to their clinical situation.

Risk patients

Risk patients,for examplepatients withlow body weight orslow metabolismof medicinalproducts, shouldinitially receivehalf the recommendedadult dose ifthey areopioid naïve. Dose titrationshould beperformedin accordancewith theindividualclinicalsituation.

For instructions how to open the child resistant blisters, see section 6.6.

4.3 Contraindications

- Hypersensitivity to oxycodone or toany of theexcipients listed in section 6.1.

- Severe respiratorydepression withhypoxia and/orhypercapnia.

- Severe chronicobstructive pulmonarydisease.

- Cor pulmonale.

- Severe bronchialasthma.

- Elevated carbon dioxide levels in the blood.

- Paralyticileus.

- Acute abdomen,delayed gastricemptying.

4.4 Special warnings and precautions for use

Paediatric population

Oxytia Depot prolonged-releasetablets havenot beenstudiedin childrenyounger than12 years of age.The safetyand efficacyof the tabletshave notbeendemonstratedand the use in childrenyounger than12 years ofage istherefore notrecommended.

Elderly ordebilitatedpatients

The major risk of opioid excess is respiratory depression. Cautionis requiredin elderlyor debilitatedpatients,in patientswith severeimpairmentof lung, liveror kidney function,myxoedema,hypothyroidism,Addison’s disease(adrenal insufficiency),intoxication psychosis (e.g. alcohol),prostatic hypertrophy, adrenocortical insufficiency,alcoholism, known opioiddependence, deliriumtremens,pancreatitis, diseasesof thebiliary tract, inflammatory bowel disorders, biliaryor ureteric colic, hypotension, hypovolaemia,conditions withincreased brainpressure such as head injury, disturbancesof circulatoryregulation, epilepsyor seizure tendencyand inpatients takingMAO inhibitors.

Patients undergoingabdominal surgery

As with all opioid preparations, oxycodone products should be used with caution following abdominal surgery as opioids are known to impair intestinal motility and should not be used until the physician is assured of normal bowel function.

Patients withsevere hepaticimpairmentshould beclosely monitored.

Respiratory depression

Respiratory depressionis themostsignificant risk induced by opioidsand ismost likely to occur inelderly or debilitated patients.The respiratorydepressant effectof oxycodone can leadto increasedcarbon dioxideconcentrationsin bloodand hencein cerebrospinal fluid. In predisposedpatients opioidscan causesevere decreasein bloodpressure.

Long-term use, tolerance and withdrawal

The patient may develop tolerance to the drug with chronic use and require progressively higher doses to maintain pain control. Prolonged use of this product may lead to physical dependence and a withdrawal syndrome may occur upon abrupt cessation of therapy. When a patient no longer requires therapy with oxycodone, it may be advisable to taper the dose gradually to prevent symptoms of withdrawal. Withdrawal symptoms may include yawning, mydriasis, lacrimation, rhinorrhoea, tremor, hyperhidrosis, anxiety, agitation, convulsions and insomnia.

Hyperalgesia

Hyperalgesia that will not respond to a further dose increase of oxycodone may very rarely occur, particularly in high doses. An oxycodone dose reduction or change to an alternative opioid may be required.

Dependence potential

Oxytia Depotprolonged-releasetabletshaveaprimarydependencepotential. Oxycodone has an abuse profile similar to other strong agonist opioids. Oxycodone may be sought and abused by people with latent or manifest addiction disorders. There is potential for development of psychological dependence [addiction] to opioid analgesics, including oxycodone. However, when used as directedinpatientswithchronicpaintherisk ofdevelopingphysicalor psychologicaldependenceismarkedlyreducedor needstobeassessed inadifferentiated manner.Thereareno dataavailableon theactualincidenceofpsychologicaldependence in chronicpainpatients.In patientswithahistoryof alcoholanddrug abusethemedicinal productmustbeprescribedwithspecialcare.

Pre-operative use

Oxytia Depot prolongedrelease tabletsare not recommended for pre-operative use or within the first 12-24 hours post operatively.

Abusive parenteralvenous injection

In case of abusiveparenteral venous injection thetablet excipientsmay leadto necrosisof the localtissue, infection, increased risk of endocarditis, and valvular heart injury which may be fatal,granulomasof the lungor other serious, potentially fatal events.

Tablets mustnot bechewed or crushed

To avoiddamageto thecontrolledreleasepropertiesof thetabletsthe prolonged releasetablets mustbe swallowed whole, and notbroken, chewedor crushed. Theadministrationof broken, chewed or crushed controlled release oxycodonetablets leadsto rapidreleaseandabsorption of apotentiallyfataldose of oxycodone (seesection 4.9).

Alcohol

Concomitant use of alcohol and oxycodone hydrochloride prolonged-release tablets may increase the undesirable effects of oxycodone hydrochloride; concomitant use should be avoided.

Oxytia Depot contains lactose

This medicinalproduct containslactose. Patients withrare hereditaryproblemsof galactose intolerance, the Lapp lactase deficiency orglucose-galactosemalabsorptionshould nottake thismedicine.

4.5 Interaction with other medicinal products and other forms of interaction

There can be an enhanced CNS depressant effect during concomitant therapy with drugs which affect the CNS such as other opioids, sedatives, hypnotics, anti-depressants, antipsychotics, anaesthetics, muscle relaxants, antihistamines and antiemetics. MAO-inhibitors are known to interact with opioid analgesics. MAO-inhibitors causes CNS-excitation or depression associated with hypertensive or hypotensive crisis (see section 4.4). Oxycodone should be used with caution in patients administered MAO-inhibitors or who have received MAO-inhibitors during the last two weeks (see section 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 theanticholinergicundesirableeffects of oxycodone (such as constipation, dry mouthor micturitiondisorders).

Cimetidinecan inhibitthe metabolismof oxycodone.

Oxycodone is metabolised mainly by CYP3A4, with a contribution from CYP2D6. The activities of these metabolic pathways may be inhibited or induced by various co-administered drugs or dietary elements.

CYP3A4 inhibitors, such as macrolide antibiotics (e.g. clarithromycin, erythromycin and telithromycin), azol-antifungals (e.g. ketoconazole, voriconazole, itraconazole, and posaconazole), protease inhibitors (e.g. boceprevir, ritonavir, indinavir, nelfinavir and saquinavir), cimetidine and grapefruit juice may cause a reduced clearance of oxycodone that could cause an increase of the plasma concentrations of oxycodone. Therefore the oxycodone dose may need to be adjusted accordingly.

Some specific examples are provided below:

CYP3A4 inducers, such as rifampicin, carbamazepin, phenytoin and St John´s Wort may induce the metabolism of oxycodone and cause an increased clearance of oxycodone that could cause a reduction of the plasma concentrations of oxycodone. The oxycodone dose may need to be adjusted accordingly.

Some specific examples are provided below:

Drugs that inhibit CYP2D6 activity, such as paroxetine, fluoxetine and quinidine, may cause decreased clearance of oxycodone which could lead to an increase in oxycodone plasma concentrations.

The effect of otherrelevant isoenzymeinhibitorson the metabolismof oxycodone isnot known. Potentialinteractions shouldbe takeninto account.

Clinicallyrelevantchangesin InternationalNormalizedRatio (INR) inboth directions have beenobserved inindividuals ifcoumarinanticoagulants areco-applied with oxycodone hydrochloride.

There areno studies investigatingthe effectof oxycodone on CYP catalysed metabolism of other drugs.

4.6 Fertility, pregnancy and lactation

Use of this medicinal product should be avoided to the extent possible in patients who are pregnant or lactating.

Pregnancy

There are limited data from the use of oxycodone in pregnant women. Infants born to mothers who have received opioids during the last 3 to 4 weeks before giving birth should be monitored for respiratory depression. Withdrawal symptoms may be observed in the newborn of mothers undergoing treatment with oxycodone.

Breastfeeding

Oxycodone may be secreted in breast milk and may cause respiratory depression in the newborn. Oxycodone should, therefore, not be used in breastfeeding mothers.

4.7 Effects on ability to drive and use machines

Oxycodone may impair the ability to drive and use machines.

Withstable therapy,a generalbanon drivinga vehicleis notnecessary. Thetreating physician mustassess the individualsituation.

Oxycodone cancause respiratorydepression, miosis,bronchial spasms and spasms of the smoothmusclesand cansuppress the coughreflex.

The adverseevents consideredat leastpossiblyrelatedto treatmentare tabulatedbelow by systemorgan classand absolutefrequency.

Tolerance anddependence maydevelop.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in

[to be completed nationally].

4.9 Overdose

Symptoms and intoxication:

Miosis, respiratory depression,somnolence,reducedskeletal muscletone anddrop in blood pressure. In severe casescirculatory collapse,stupor, coma,bradycardia, non- cardiogenic lungoedema, hypotension, and deathmayoccur; abuseof high doses of strong opioids such as oxycodone canbe fatal.

Therapy of intoxications:

Primaryattention shouldbe givento theestablishmentof apatentairway andinstitution of assistedor controlledventilation

In the eventof overdosing intravenousadministrationof an opiateantagonist (e.g.0.4-2 mg intravenousnaloxone) maybe indicated.Administrationof single doses mustbe repeated dependingon the clinicalsituation atintervals of 2 to3 minutes.Intravenous infusion of 2 mgof naloxone in500 mlisotonic salineor 5% dextrosesolution (correspondingto 0.004 mgnaloxone/ml)is possible.The rateof infusion shouldbe adjusted tothe previousbolus injectionsand theresponse of the patient.

Gastric lavagecan betaken intoconsideration.Consideractivated charcoal(50 g for adults, 10 -15 g for children), ifa substantialamounthas been ingestedwithin 1 hour, provided theairway canbe protected.It maybe reasonableto assumethat late administrationof activated charcoalmaybe beneficialfor prolonged releasepreparations; howeverthere isno evidenceto supportthis.

For speeding up thepassage asuitable laxative(e.g. aPEG based solution)maybe useful.

Supportive measures(artificial respiration,oxygensupply, administrationof vasopressors andinfusion therapy)should, ifnecessary, beapplied inthe treatmentof accompanying circulatory shock. Upon cardiac arrestor cardiac arrhythmiascardiac massageor defibrillation maybe indicated.If necessary, assistedventilation as well as maintenance of water andelectrolytebalance.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeuticgroup: Naturalopium alkaloids

ATC-Code: N02A A05

Oxycodone shows anaffinity tokappa, muanddeltaopioid receptorsin thebrain and spinalcord. Itacts atthese receptorsas an opioidagonist withoutan antagonisticeffect. The therapeuticeffect ismainlyanalgesicand sedative.Compared torapid-release oxycodone,given aloneor in combinationwith othersubstances, theprolonged-release tabletsprovide painrelief for amarkedlylonger periodwithout increasedoccurrence of undesirable effects.

Endocrine system

Opioids may influence the hypothalamic-pituitary-adrenal or – gonadal axes. Some changes that can be seen include an increase in serum prolactin, and decreases in plasma cortisol and testosterone. Clinical symptoms may be manifest from these hormonal changes.

Other pharmacological effects

In- vitro and animal studies indicate various effects of natural opioids, such as morphine, on components of the immune system; the clinical significance of these findings is unknown. Whether oxycodone, a semisynthetic opioid, has immunological effects similar to morphine is unknown.

Clinical studies

The efficacy of Oxycodone prolonged-release tablets has been demonstrated in cancer pain, post-operative pain and severe non-malignant pain such as diabetic neuropathy, postherpetic neuralgia, low back pain and osteoarthritis. In the latter indication, treatment was continued for up to 18 months and proved effective in many patients for whom NSAIDs alone provided inadequate relief. The efficacy of Oxycodone prolonged-release tablets in neuropathic pain was confirmed by three placebo-controlled studies.

In patients with chronic non-malignant pain, maintenance of analgesia with stable dosing was demonstrated for up to three years.

5.2 Pharmacokinetic properties

Absorption:

The relativebioavailability ofOxytia Depotprolonged-release tabletsis comparableto that of rapidrelease oxycodonewith maximumplasma concentrationsbeing achievedapproximately3 hours after intakeof the prolonged-releasetablets comparedto 1 to 1.5 hours. Peak plasmaconcentrations andoscillations of the concentrationsof oxycodone fromthe prolonged-releaseand rapid-releaseformulations arecomparable when given atthe samedaily dose atintervals of 12 and 6 hours respectively.

A fat-richmealbeforetheintakeof thetablets does notaffect themaximumconcentration or theextent of absorption of oxycodone.

The tabletsmust notbe crushed, divided or chewedas this leadsto rapidoxycodone release and absorption of a potentially fatal dose of oxycodonedue to thedamageof the prolongedrelease properties.

Distribution:

The absolutebioavailability of oxycodone isapproximatelytwo thirds relativeto parenteraladministration.In steadystate, thevolumeof distribution of oxycodone amountsto 2.6 l/kg;plasmaprotein bindingto 38-45%;the eliminationhalf-life to4 to 6 hours andplasmaclearance to0.8 l/min.

Metabolism:

Oxycodone ismetabolised inthe intestineandliver to noroxycodone andoxymorphone as well as toseveral glucuronideconjugates. CYP3A4 and CYP2D6 are probably involved in the formation of noroxycodone andoxymorphone respectively. Oxymorphone has analgesic activity but is present in the plasma in low concentrations and is not considered to contribute to oxycodone´s pharmacological effect.

Elimination:

Oxycodone andits metabolitesare excretedvia urineand faeces.Oxycodonecrosses the placentaand isfound in breastmilk.

Linearity/non-linearity:

The prolonged-releasetablets arebioequivalent ina dose proportional mannerwith regardto theamountof active substanceabsorbedas well as comparable withregard tothe rateof absorption.

Elderly

The plasma concentration of oxycodone in elderly subjects is 15% greater when compared with young subjects.

Gender

Female subjects have, on average, plasma oxycodone concentrations up to 25% higher than males on a body weight adjusted basis. The reason for this difference is unknown.

Patients with renal impairment

Patients with mild, moderate and severe renal impairment showed 1.1-, 1.4- and 1.7- fold increased plasma concentrations respectively compared to patients with normal renal function. AUC increased on average 1.5-, 1.7- and 2.3-fold respectively compared to patients with normal renal function. The elimination half-life for oxycodone increased 1.5-, 1.2- and 1.4- fold respectively compared to patients with normal renal function.

Patients with hepatic impairment

Patients with mild, moderate and severe hepatic impairment showed 1.2-, 2.0- and 1.9- fold increased plasma concentrations respectively compared to patient with normal hepatic function. AUC increased on average 1.4-, 3.2- and 3.2- fold respectively compared to patients with normal hepatic function. The elimination half-life of oxycodone increased 1.1-, 1.8- and 1.8- fold respectively compared to patients with normal hepatic function.

5.3 Preclinical safety data

Teratogenicity

Oyxcodone had no effect on fertility and early embryonic development in male and female rats in doses of up to 8 mg/kg body weight and induced no malformations in rats in doses of up to 8 mg/kg and in rabbits in doses of 125 mg/kg bodyweight. However, in rabbits, when individual foetuses were used in statistical evaluation, a dose related increase in developmental variations was observed (increased incidences of 27 presacral vertebrae, extra pairs of ribs). When these parameters were statistically evaluated using litters, only the incidence of 27 presacral vertebrae was increased and only in the 125 mg/kg group, a dose level that produced severe pharmacotoxic effects in the pregnant animals. In a study on pre- and postnatal development in rats F1 body weights were lower at 6 mg/kg/d when compared to body weights of the control group at doses which reduced maternal weight and food intake (NOAEL 2 mg/kg body weight). There were neither effects on physical, reflexological, and sensory developmental parameters nor on behavioural and reproductive indices.

In a study of peri- and postnatal development in rats, maternal body weight and food intake parameters were reduced for doses ≥ 2 mg/kg/d compared to the control group. Body weights were lower in the F1 generation from maternal rats in the 6 mg/kg/d dosing group. There were no effects on physical, reflexological, or sensory developmental parameters or on behavioural and reproductive indices in the F1 pups (the NOEL for F1 pups was 2 mg/kg/d based on body weight effects seen at 6 mg/kg/d). There were no effects on the F2 generation at any dose in the study.

Carcinogenicity

Long-term carcinogenicity studies were not performed.

Mutagenicity

The results of in-vitro and in-vivo studies indicate that the genotoxic risk of oxycodone to humans is minimal or absent at the systemic oxycodone concentrations that are achieved therapeutically.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core:

Lactose monohydrate

Hypromellose

Povidone K30

Stearic acid

Magnesium stearate

Colloidal anhydrous silica

Tablet coating

5 mg:

Polyvinyl alcohol

Titanium dioxide (E171)

Macrogol 3350

Talc

Blue Indigo Carmine Aluminium Lake (E132)

Iron oxide, yellow (E172)

10 mg:

Titanium dioxide (E171)

Hypromellose

Macrogol 400

Polysorbate 80

15 mg:

Polyvinyl alcohol

Titanium dioxide (E171)

Macrogol 3350

Talc

Iron oxide, black (E172)

Iron oxide, yellow (E172)

20 mg:

Polyvinyl alcohol

Titanium dioxide (E171)

Macrogol 3350

Talc

Iron oxide, red (E172)

30 mg:

Polyvinyl alcohol

Macrogol 3350

Talc

Iron oxide, red (E172)

Iron oxide, black (E172)

Blue Indigo Carmine Aluminium Lake (E132)

40 mg:

Polyvinyl alcohol

Titanium dioxide (E171)

Macrogol 3350

Talc

Iron oxide, yellow (E172)

60 mg:

Polyvinyl alcohol

Macrogol 3350

Talc

Iron oxide, red (E172)

Carmine (E120)

Iron oxide, black (E172)

80 mg:

Polyvinyl alcohol

Macrogol 3350

Talc

Titanium dioxide (E171)

Blue Indigo Carmine Aluminium Lake (E132)

Iron oxide, yellow (E172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years.

6.4 Special precautions for storage

Blister packs:

Do not store above 25°C.

HDPE container:

This medicinalproduct does notrequire anyspecial storageconditions.

Child resistant blister packs (PVC/PVdC/Al/PET/paper).

Pack sizes:

5 mg: 1, 20, 28, 30, 50, 56, 60 and 100 prolonged-release tablets

10 mg, 20 mg, 40 mg, 80 mg: 1, 20, 28, 30, 50, 56, 60, 98 and 100 prolonged-release tablets

15 mg: 1, 20, 30, 56, 98 and 100 prolonged-release tablets

30 mg, 60 mg: 1, 20, 30, 50, 56, 98 and 100 prolonged-release tablets

Blister packs (PVC/Al) in cartons.

Pack sizes:

5 mg: 1, 20, 28, 30, 50, 56, 60 and 100 prolonged-release tablets

10 mg, 20 mg, 40 mg, 80 mg: 1, 20, 28, 30, 50, 56, 60, 98 and 100 prolonged-release tablets

15 mg: 1, 20, 30, 56, 98 and 100 prolonged-release tablets

30 mg, 60 mg: 1, 20, 30, 50, 56, 98 and 100 prolonged-release tablets

White, round, HDPE tablet containers with LDPE caps.

Pack size: 98 and 100 prolonged-release tablets

White, round, child-resistant, HDPE tablet containers with LDPE caps.

Pack size: 98 and 100 prolonged-release tablets

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements.

Instructions for use of child resistant blisters:

1. Do not push the tablet directly out of the pocket

2. Separate one blister cell from the strip at the perforations

3. Carefully peel off the backing to open the pocket

7. MARKETING AUTHORISATION HOLDER

<[To be completed nationally]>

{Name and address}

<{tel}>

<{fax}>

<{e-mail}>

8. MARKETING AUTHORISATION NUMBER(S)

<[To be completed nationally]>

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 19 March 2014

<[To be completed nationally]>

10. DATE OF REVISION OF THE TEXT

19 March 2014

<[To be completed nationally]>