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.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Empty matrix (tablets) may be seen in the stool.

4.5       Interaction with other medicinal products and other forms of interaction

Interaction studies have only been performed in adults.

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, 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 4.43). 

Alcohol may enhance the pharmacodynamic effects of OxyContin; 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       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 no or limited amount of 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.

For animal studies see section 5.3.

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. 

For animal studies see section 5.3.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.

OxyContin should not be used during pregnancy.

Breastfeeding

Oxycodone is may be secreted in breast milk and may cause respiratory depression in the newborn. 

Oxycodone should, therefore, not be used in breast-feeding mothers.

Breastfeeding should be discontinued during treatment with OxyContin.

Fertility

Non-clinical toxicology studies in rats have not shown any effects upon fertility (see section 5.3).

4.7       Effects on ability to drive and use machines

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       Undesirable effects

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 section 4.9).  This is most likely to occur in elderly, debilitated or opioid-intolerant patients.

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

The adverse drug reactions seen during clinical trials and from spontaneous reports are listed below with the following frequencies:

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); very rare (<1/10,000); not known (cannot be estimated from the available data). 

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 OxyContin tablets or administration of an opioid antagonist may result in a withdrawal syndrome characterised by anxiety, irritability, chills, hot flushes, piloerection, joint pain, rhinorrhoea, diaphoresis, abdominal cramps and diarrhoea.  If the dose reduction regimen recommended in Section 4.2 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.

Paediatric population and adults under 20 years of age: