Not recommended.

4.3       Contraindications

Hypersensitivity to oxycodone or to any of the excipients listed in section 6.1.

Oxycodone must not be used in Aany situation where opioids are contraindicated: severe respiratory depression with hypoxia, elevated carbon dioxide levels in the blood (hypercarbia), head injury, paralytic ileus, acute abdomen, delayed gastric emptying, severe chronic obstructive airways lung disease, severe bronchial asthma, cor pulmonale, hypercarbia, known sensitivity to oxycodone, morphine or other opioids, hypersensitivity to any of the excipients, acute hepatic disease, concurrent administration of monoamine oxidase inhibitors or within 2 weeks of discontinuation of their use.

4.4       Special warnings and precautions for use

The major risk of opioid excess is respiratory depression.

Caution must be exercised when administering oxycodone to the debilitated elderly; patients with severely impaired pulmonary function, impaired hepatic or renal function; patients with myxoedema, hypothyroidism, Addison’s disease,  toxic psychosis, adrenocortical insufficiency, prostate hypertrophy, head injury (due to the risk of raised intracranial pressure), convulsive disorders, delirium tremens, disorders of consciousness, hypotension, hypovolaemia. Use with caution in opioid dependent patients, diseases of the biliary tract, biliary or ureteric colic, pancreatitis, obstructive and inflammatory bowel disorders, chronic obstructive airways disease, reduced respiratory reserve, alcoholism or patients taking MAO inhibitorsUse with caution in opioid dependent patients, in patients with toxic psychosis, raised intracranial pressure, convulsive disorders, delirium tremens, disorders of consciousness, hypotension, hypovolaemia, diseases of the biliary tract, biliary or ureteric colic, pancreatitis, obstructive and inflammatory bowel disorders, prostatic hypertrophy, adrenocortical insufficiency, hypothyroidism, chronic obstructive airways disease, severely impaired pulmonary function, reduced respiratory reserve, alcoholism, chronic renal and hepatic disease (see section 4.2), debilitated, elderly or infirm patients.  In patients in whom caution is required, a reduction in dosage may be advisable.

OxyNorm capsules should not be used where there is a possibility of paralytic ileus occurring.  Should paralytic ileus be suspected or occur during use, OxyNorm capsules should be discontinued immediately (see section 4.3).  Due to an increased perioperative risk of ileus and respiratory depression OxyNorm capsules should be used with caution pre-operatively and within the first 24 hours post-operatively.

OxyNorm should be used with caution pre-operatively and within the first 12-24 hours post-operatively.

As with all opioid preparations, patients about to undergo additional pain relieving procedures (e.g. surgery, plexus blockade) should not receive OxyNorm capsules for six hours prior to the intervention.  If further treatment with OxyNorm capsules is indicated then the dosage should be adjusted to the new post-operative requirement.

As with all opioid preparations, oxycodone products OxyNorm capsules 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.

The patient Patients may develop tolerance to the drug with chronic use and require progressively higher doses to maintain pain control.  There may also be cross-tolerance with other opioids.  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 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.

Oxycodone has an abuse profile similar to other strong opioid agonists and 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.  OxyNorm capsules should be used with particular caution care in patients with a history of alcohol or drug abuse.

The capsules should be swallowed whole, and not chewed or crushed.  Abuse of oral dosage forms by parenteral administration can be expected to result in serious adverse events, which may be fatal.

Concomitant use of alcohol and OxyNorm may increase the undesirable effects of OxyNorm; concomitant use should be avoided.

It should be emphasised that patients, once titrated to an effective dose of a certain opioid, should not be changed to other analgesic preparations without clinical assessment and careful retitration as necessary.  Otherwise, a continuous analgesic action is not ensured.

OxyNorm 5 mg capsules contain sunset yellow which may cause allergic reactions.

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 phenothiazines, tricyclic antidepressants, anaesthetics, hypnotics, sedatives, alcohol, muscle relaxants, other opioids, neuroleptic drugs, antihypertensives and SSRIs.  Oxycodone should be used with caution and the dosage may need to be reduced in patients using these medications. 

Monoamine oxidase inhibitors are known to interact with narcotic analgesics, producing 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 4.34).

Alcohol may enhance the pharmacodynamic effects of OxyNorm, concomitant use should be avoided.

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:

·         Itraconazole, a potent CYP3A4 inhibitor, administered 200 mg orally for five days, increased the AUC of oral oxycodone.  On average, the AUC was approximately 2.4 times higher (range 1.5 - 3.4).

·         Voriconazole, a CYP3A4 inhibitor, administered 200 mg twice-daily for four days (400 mg given as first two doses), increased the AUC of oral oxycodone.  On average, the AUC was approximately 3.6 times higher (range 2.7 - 5.6).

·         Telithromycin, a CYP3A4 inhibitor, administered 800 mg orally for four days, increased the AUC of oral oxycodone.  On average, the AUC was approximately 1.8 times higher (range 1.3 – 2.3).

·         Grapefruit Juice, a CYP3A4 inhibitor, administered as 200 ml three times a day for five days, increased the AUC of oral oxycodone.  On average, the AUC was approximately 1.7 times higher (range 1.1 – 2.1).

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:

·         St Johns Wort, a CYP3A4 inducer, administered as 300 mg three times a day for fifteen days, reduced the AUC of oral oxycodone.  On average, the AUC was approximately 50% lower (range 37-57%).

·         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.

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

Oxycodone is metabolised by the cytochrome P450 enzyme system (CYP2D6 and CYP3A4) but a full evaluation of interactions with other drugs metabolised by this route has not been undertaken.  Concurrent administration of quinidine, an inhibitor of cytochrome P450-2D6, resulted in an increase in oxycodone Cmax by 11%, AUC by 13% and t½ elim by 14%; also an increase in the metabolite noroxycodone level was observed.  The pharmacodynamic effects of oxycodone were not altered.  This interaction may be observed for other potent inhibitors of the cytochrome P450-2D6 enzyme such as paroxetine and fluoxetine.  Cimetidine and inhibitors or substrates of cytochrome P450-3A4 such as ketoconazole, voriconazole and erythromycin may inhibit the metabolism of oxycodone.

4.6      

Use of this medicinal product should be avoided to the extent possible in patients who are pregnant or lactating.OxyNorm capsules should not be used in pregnancy or the breast feeding mother.

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.

No clinical data on exposed pregnancies are available.

Studies in rats and rabbits with oral doses of oxycodone equivalent to 3 and 47 times an adult human dose of 160 mg/day respectively, did not reveal evidence of harm to the foetus due to oxycodone.

Oxycodone penetrates the placenta.  Oxycodone should not be used during pregnancy and labour due to impaired uterine contractility and the risk of neonatal respiratory depression.  Infants born to mothers who have received opioids during pregnancy should be monitored for respiratory depression.  Withdrawal symptoms may be observed in the newborn of mothers undergoing treatment with oxycodone.

Breast-feeding

Lactation

Oxycodone is may be secreted in breast milk and may cause respiratory depression in the newborn.  Oxycodone OxyNorm capsules should, therefore, not be used in breast-feeding mothers otherwise breast feeding has to be stopped.

4.7      

Oxycodone may impair the ability to drive and use machines.  Oxycodone may modify patients’ reactions to a varying extent depending on the dosage and individual susceptibility.  If affected, patients should not drive or operate machinery.

4.8      

The most commonly reported adverse reactions are nausea and constipation, both occurring in approximately 25 to 30 % of patients.  If nausea or vomiting are troublesome, oxycodone may be combined with an antiemetic.  Constipation should be anticipated as with any strong opioid, and treated appropriately with laxatives.  Should opioid related adverse events persist, they should be investigated for an alternative cause.

Adverse drug reactions are typical of full opioid agonists, and tend to reduce with time, with the exception of constipation.  Anticipation of adverse drug reactions and appropriate patient management can improve acceptability.

The most serious adverse reaction, as with other opioids, is respiratory depression (see Overdose section).  This is most likely to occur in elderly, debilitated or opioid-intolerant patients.

Adverse drug reactions seen during clinical trials and from spontaneous reports are listed below:

The following frequency categories form the basis for classification of the undesirable effects:

Immune system disorders:

Uncommon (≥1/1,000 to <1/100): hypersensitivity

Frequency unknown (cannot be estimated from the available data): anaphylactic responses.

Endocrine disorders:

Uncommon (≥1/1,000 to <1/100): syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Metabolism and nutrition disorders:

Common (≥1/100 to <1/10): decreased appetiteanorexia

Uncommon (≥1/1,000 to <1/100): dehydration, thirst, weight fluctuation.

Psychiatric disorders:

Common (≥1/100 to <1/10): abnormal dreams, abnormal thinking, anxiety, confusional state, depression, insomnia, nervousness

Uncommon  (≥1/1,000 to <1/100): agitation, abnormal thinking, decreased libido, depersonalisation, affect lability, euphoric mood, hallucinations, drug dependence (see section 4.4)

Frequency unknown: aggression.

Nervous system disorders:

Very common (≥1/10): somnolence, dizziness, headache.

Common (≥1/100 to <1/10): tremor.

Uncommon (≥1/1,000 to <1/100): amnesia, convulsion, hyperkinesia, hypertonia, hypoaesthesia, hypotonia, involuntary muscle contractions, speech disorder, stupor, paraesthesia, dysgeusia, syncope.

Frequency unknown: hyperalgesia.

Eye disorders:

Uncommon (≥1/1,000 to <1/100): abnormal vision, lacrimation disorder, miosis, visual impariment.

Ear and labyrinth disorders:

Uncommon (≥1/1,000 to <1/100): tinnitus, vertigo.

Cardiac disorders:

Uncommon (≥1/1,000  to <1/100): palpitations (in the context of withdrawal syndrome).

Vascular disorders:

Uncommon (≥1/1000 to <1/100): vasodilatation.

Rare (≥1/10,000 to <1/1000): hypotension, orthostatic hypotension.

Respiratory, thoracic and mediastinal disorders:

Common (≥1/100 to <1/10): dyspnoea, bronchospasm.

Uncommon (≥1/1,000 to <1/100): rhinitis, epistaxis, hiccup, voice alteration, respiratory depression.

Gastrointestinal disorders:

Very common (≥1/10): constipation, nausea, vomiting.

Common (≥1/100 to <1/10): abdominal pain, diarrhoea, dry mouth, dyspepsia.

Uncommon (≥1/1,000 to <1/100): dysphagia, flatulence, gastritis, mouth ulceration, eructation, ileus, stomatitis.

Frequency unknown (cannot be estimated from the available data): dental caries.

Hepato-biliary disorders:

Uncommon (≥1/1,000 to <1/100): hepatic enzymes increased.

Frequency unknown (cannot be estimated from the available data): biliary colic, cholestasis.

Skin and subcutaneous tissue disorders:

Very common (≥1/10): pruritus.

Common (≥1/100 to <1/10): rash, hyperhidrosis.

Uncommon (≥1/1,000 to <1/100): dry skin.

Rare (≥1/10,000 to <1/1,000): urticaria.

Renal and urinary disorders:

Common (≥1/100 to <1/10): urinary disorders.

Uncommon (≥1/1000 to <1/100): urinary retention.

Reproductive system and breast disorders:

Uncommon (≥1/1000 to <1/100): erectile dysfunction, decreased libido.

Frequency unknown (cannot be estimated from the available data): amenorrhoea.

General disorders and administration site conditions:

Common (≥1/100 to <1/10): asthenic conditions, fever.

Uncommon (≥1/1,000 to <1/100): chills, chest pain, drug withdrawal syndrome, gait disturbance, malaise, oedema, peripheral oedema, drug tolerance, thirst.

Tolerance may occur in patients treated with oxycodone, although this has not been a significant problem in the clinical trial programme.  Patients requiring marked dose escalation should have their pain control regimen carefully reviewed.

Abrupt withdrawal of OxyNorm capsules or administration of an opioid antagonist may result in a withdrawal syndrome characterised by anxiety, irritability, chills, hot flushes, piloerection, joint pain, rhinorrhea, diaphoresis, abdominal cramps and diarrhoea.  If the dose reduction regimen recommended in Section 4.4 results in a withdrawal syndrome, the dose should be slightly increased until the signs and symptoms disappear.  Dose reduction should then begin again with longer periods of time between each reduction.

4.9      

Acute overdosage with oxycodone can be manifested by respiratory depression, somnolence, progressing to stupor or, coma, hypotonia, misosisskeletal muscle flaccidity, miotic pupils, bradycardia, hypotension, and death.

Treatment of oxycodone overdosage:  A patent airway must be maintained.  The pure opioid antagonists such as naloxone are specific antidotes against symptoms from opioid overdose.  Other supportive measures should be employed as neededPrimary attention should be given to the establishment of a patent airway and institution of assisted or controlled ventilation.

In the case of massive overdosage, administer naloxone 0.8 mg intravenously. Repeat at 2-3 minute intervals as necessary, or by an infusion of 2 mg in 500 ml of normal saline or 5% dextrose (0.004 mg/ml).

The infusion should be run at a rate related to the previous bolus doses administered and should be in accordance with the patient’s response.  However, because the duration of action of naloxone is relatively short, the patient must be carefully monitored until spontaneous respiration is reliably re-established.

For less severe overdosage, administer naloxone 0.2 mg intravenously followed by increments of 0.1 mg every 2 minutes if required.

Naloxone should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to oxycodone overdosage.  Naloxone should be administered cautiously to persons who are known, or suspected, to be physically dependent on oxycodone.  In such cases, an abrupt or complete reversal of opioid effects may precipitate pain and an acute withdrawal syndrome.

Gastric contents may need to be emptied as this can be useful in removing unabsorbed drug.