Mundipharma Pharmaceuticals Limited - Formerly Napp Laboratories

OxyContin^® 5 mg, 10 mg, 20 mg, 40 mg and 80 mg prolonged release tablets

Each 5 mg tablet contains 4.5 mg of oxycodone as 5 mg oxycodone hydrochloride

Each 10 mg tablet contains 9.0 mg of oxycodone as 10 mg oxycodone hydrochloride

Each 20 mg tablet contains 18.0 mg of oxycodone as 20 mg oxycodone hydrochloride

Each 40 mg tablet contains 36.0 mg of oxycodone as 40 mg oxycodone hydrochloride

Each 80 mg tablet contains 72.0 mg of oxycodone as 80 mg oxycodone hydrochloride

Excipient:

Each 5 mg tablet contains 77.30 mg of lactose monohydrate

Each 10 mg tablet contains 69.25 mg of lactose monohydrate

Each 20 mg tablet contains 59.25 mg of lactose monohydrate

Each 40 mg tablet contains 35.25 mg of lactose monohydrate

Each 80 mg tablet contains 78.50 mg of lactose monohydrate

For a full list of excipients, see section 6.1.

Prolonged release tablets.

Each 5 mg tablet is light blue, round, convex of approximately 7 mm in diameter marked OC on one side and 5 on the other.

Each 10 mg tablet is white, round, convex of approximately 7 mm in diameter marked OC on one side and 10 on the other.

Each 20 mg tablet is pink, round, convex of approximately 7 mm in diameter marked OC on one side and 20 on the other.

Each 40 mg tablet is yellow, round, convex of approximately 7 mm in diameter marked OC on one side and 40 on the other.

Each 80 mg tablet is green, round, convex of approximately 9 mm in diameter marked OC on one side and 80 on the other.

For the treatment of severe pain. OxyContin is indicated in adults 20 years of age and over.

Route of administration

Oral use

Posology

Prescribers should consider concomitant treatment with antiemetics and laxatives for the prevention of nausea, vomiting and constipation.

Missed dose:

If a patient forgets to take a dose but remembers within 4 hours of the time the dose was due to be taken, the tablets can be taken straight away. The next dose should be taken at the normal time. Beyond 4 hours the prescriber may need to consider alternative rescue medicine until the next dose is due.

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.

Adults and the elderly:

OxyContin tablets should be taken at 12-hourly intervals. The dosage is dependent on the severity of the pain, the patient's previous history of analgesic requirements, the patient's body weight, and sex (higher plasma concentrations are produced in females).

The usual starting dose for debilitated elderly patients, opioid naïve patients or patients presenting with severe pain uncontrolled with weaker opioids is 10 mg 12-hourly. Some patients may benefit from a starting dose of 5 mg to minimise the incidence of side effects. The dose should then be carefully titrated, every day if necessary, to achieve pain relief. Given the time to reach steady state, patients' doses should only be titrated up after 24 hours and increases should be made, where possible, in 25% - 50% increments. The correct dosage for any individual patient is that which controls the pain and is well tolerated, for a full 12 hours. The need for escape medication more than twice a day indicates that the dosage of OxyContin tablets should be increased.

Conversion from oral morphine:

Patients receiving oral morphine before oxycodone therapy should have their daily dose based on the following ratio: 10 mg of oral oxycodone is equivalent to 20 mg of oral morphine. It must be emphasised that this is a guide to the dose of OxyContin tablets required. Inter-patient variability requires that each patient is carefully titrated to the appropriate dose.

Elderly patients:

Controlled pharmacokinetic studies in elderly patients (aged over 65 years) have shown that compared with younger adults the clearance of oxycodone is only slightly reduced. No untoward adverse drug reactions were seen based on age, therefore adult doses and dosage intervals are appropriate.

Non-malignant pain:

Treatment with oxycodone should be short and intermittent to minimise the risk of dependence. The need for continued treatment should be assessed at regular intervals. Patients should not usually require more than 160 mg per day.

Cancer-related pain:

Patients should be titrated up to a dose which achieves pain relief unless unmanageable adverse drug reactions prevent this.

Patients with renal or hepatic impairment:

Unlike morphine preparations, the administration of oxycodone does not result in significant levels of active metabolites. However, the plasma concentration of oxycodone in this patient population may be increased compared with patients having normal renal or hepatic function. Therefore dose initiation should follow a conservative approach in these patients, i.e. one-third to one half the usual dose with careful dose titration. There are no data in patients with severe renal and/or hepatic impairment. A reduced dosage may be appropriate in these patients but each patient should be titrated to adequate pain control according to their clinical response.

Paediatric population and adults under 20 years of age:

Not recommended. Experience in children is limited. Currently available data are described in sections 4.8, 5.1 and 5.2 but no recommendation on posology can be made.

Method of administration

OxyContin tablets are for oral use.

OxyContin tablets must be swallowed whole and are not to be broken, chewed or crushed. Taking broken, chewed or crushed OxyContin tablets may lead to a rapid release and absorption of a potentially fatal dose of oxycodone.

Any situation where opioids are contra-indicated: respiratory depression, head injury, paralytic ileus, acute abdomen, delayed gastric emptying, severe obstructive airways 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 (see section 4.5) or within 2 weeks of discontinuation of their use. The safety of OxyContin used pre-operatively and for up to 24 hours post-operatively has not been established and cannot be recommended.

The major risk of opioid excess is respiratory depression.

Use with caution in opioid dependent patients, 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.

Doses of OxyContin tablets in excess of 60 mg may cause fatal respiratory depression when administered to patients not previously exposed to opioids and should only be used in opioid-tolerant patients. Care should be taken in the prescription of daily oxycodone dosages of 120 mg or more.

OxyContin tablets should not be used where there is a possibility of paralytic ileus occurring. Should paralytic ileus be suspected or occur during use, OxyContin tablets should be discontinued immediately (see section 4.3). As with all opioid preparations, patients about to undergo additional pain relieving procedures (e.g. surgery, plexus blockade) should not receive oxycodone for 12 hours prior to the intervention. If further treatment with OxyContin tablets is indicated then the dosage should be adjusted to the new post-operative requirement.

As with all opioid preparations, OxyContin tablets 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 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.

Oxycodone has an abuse profile similar to that of 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 to opioid analgesics, including oxycodone. OxyContin tablets should be avoided in patients with a history of or present alcohol or drug abuse.

The prolonged release tablets must not be broken, chewed or crushed, as this may lead to an overdose (see section 4.2 and 4.9).

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

Abuse of oral dosage forms by parenteral administration can be expected to result in serious adverse events, such as local tissue necrosis, infection, pulmonary granulomas, increased risk of endocarditis and valvular heart injury, which may be fatal.

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.

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 with hyper- or hypotensive crisis (see section 4.3).

Alcohol may enhance the pharmacodynamic effects of OxyContin; concomitant use should be avoided.

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.

Pregnancy

There are no or limited amount of data from the use of oxycodone in pregnant women. 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. 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 secreted in breast milk and may cause respiratory depression in the newborn.

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).

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.

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 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:

The frequency, type and severity of adverse reactions in children and adults under 20 years of age are expected not to be different from adults 20 years and over.

For infants born to mothers receiving oxycodone see section 4.6.

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

Treatment of oxycodone overdosage: Primary 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. OxyContin tablets will continue to release and add to the oxycodone load for up to 12 hours after administration and the management of oxycodone overdosage should be modified accordingly.

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, particularly when a prolonged release formulation has been taken.

Pharmacotherapeutic group: Natural opium alkaloids, opioids, analgesics ATC code: N02AA05

Oxycodone is a full opioid agonist with no antagonist properties and has an affinity for kappa, mu and delta opiate receptors in the brain and spinal cord. The therapeutic effect is mainly analgesic, anxiolytic, antitussive and sedative. The mechanism of action involves CNS opioid receptors for endogenous compounds with opioid-like activity.

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 semi-synthetic opioid, has immunological effects similar to morphine is unknown.

Paediatric population

Overall the safety data obtained with oral oxycodone in 9 clinical, pharmacodynamic and pharmacokinetic studies including a total of 629 infants and children (aged 2 months to 17 years) demonstrate that oral oxycodone is tolerated well in paediatric patients with only minor adverse events affecting mainly the gastrointestinal and nervous system. The positive safety data obtained with oral oxycodone are confirmed by 9 studies performed with bucally, intramuscularly and intravenously administered oxycodone in a total of 1860 infants and children who also experienced only mild adverse events comparable to those observed with the use of oral oxycodone.

The dose of oxycodone administered parenterally to infants and children in clinical trials was in the range of 0.025 mg/kg to 0.1 mg/kg, with 0.1 mg/kg being the most frequently used dosage followed by 0.05 mg/kg. The dose of i.v. oxycodone was in the range of 0.025 mg/kg to 0.1 mg/kg, with 0.1 mg/kg being the most frequently used dosage followed by 0.05 mg/kg. The dose of i.m. oxycodone was in the range of 0.02 mg/kg to 0.1 mg/kg. The dose of orally administered oxycodone was in the range of 0.1 mg/kg (starting dose) to 1.24 mg/kg/day. Buccally administered dose of oxycodone was 0.1 mg/kg.

Overall, the adverse events in these studies of oxycodone in infants and children appear consistent with the known safety profile of oxycodone elaborated in the numerous clinical trials performed in adults and described in the SmPC. No new or unexpected safety signals were identified in these studies. All of the adverse events reported were consistent with the known safety profile of oxycodone as well as of other comparable strong opioids. However OxyContin is not recommended in children and adults below 20 years of age due to insufficient data on safety and efficacy.

Oxycodone has a high absolute bioavailability of up to 87% following oral administration. It has an elimination half-life of approximately 3 hours and is metabolised principally to noroxycodone via CYP 3A4 and and oxymorphone via CYP 2D6. Oxymorphone has some analgesic activity but is present in plasma in low concentrations and is not considered to contribute to oxycodone's pharmacological effect.

The release of oxycodone from OxyContin tablets is biphasic with an initial relatively fast release providing an early onset of analgesia followed by a more controlled release which determines the 12 hour duration of action. The mean apparent elimination half-life of OxyContin tablets is 4.5 hours which leads to steady-state being achieved in about one day.

Release of oxycodone from OxyContin tablets is independent of pH.

OxyContin tablets have an oral bioavailability comparable with conventional oral oxycodone, but the former achieve maximal plasma concentrations at about 3 hours rather than about 1 to 1.5 hours. Peak and trough concentrations of oxycodone from OxyContin tablets 10 mg administered 12-hourly are equivalent to those achieved from conventional oxycodone 5 mg administered 6-hourly.

All strengths of OxyContin are bioequivalent in terms of both rate and extent of absorption. Ingestion of a standard high-fat meal does not alter the peak oxycodone concentration or the extent of oxycodone absorption from OxyContin tablets.

Paediatric population

The pharmacokinetic properties of oral oxycodone in infants and children were examined in 3 studies including a total of 63 infants and children aged 0.5 to 7.6 years. In addition pharmacokinetics of buccal and sublingual oxycodone was studied in 30 children aged 0.5-7.5 years. These studies did not reveal significant different results in comparison to adults. Oral oxycodone was tolerated well in these pharmacokinetic studies with only minor adverse events.

Teratogenicity

Oxycodone has shown no effect on fertility or foetal development in rats and rabbits except at doses leading to toxic effects in the dams.

Carcinogenicity

No animal tests have been performed to examine the carcinogenic effects of oxycodone.

Mutagenicity

Oxycodone was not mutagenic in bacterial mutation tests or in in-vivo micronucleus assay(s) in mice. As is the case with other opioids, oxycodone was shown to be genotoxic in some in-vitro assays (e.g. mouse lymphoma assay).

Lactose monohydrate

Povidone

Ammoniomethacrylate Polymer Dispersion

Sorbic acid

Glyceryl triacetate

Stearyl Alcohol

Talc

Magnesium Stearate

Hypromellose (E464)

Hydroxypropylcellulose (10 & 80 mg tablets only)

Titanium Dioxide (E171)

Macrogol

Polysorbate 80 (20 & 40 mg tablets only)

Brilliant Blue (E133) (5 mg tablets only)

Iron oxide (E172) (20, 40 & 80 mg tablets only)

Indigo carmine (E132) (80 mg tablets only).

Not applicable.

Three years

Do not store above 25°C.

PVC blister packs with aluminium foil backing containing 28 or 56 tablets.

Not all pack sizes may be marketed.

No special requirements.

Mundipharma Pharmaceuticals Limited,

Millbank House,

Arkle Road,

Sandyford,

Dublin 18.

PA 1688/5/1 – 5

10, 20, 40 and 80 mg tablets: 28 May 1998 / 22 November 2007

5 mg tablets: 22 November 2002/22 November 2007

October 2011

® OxyContin, MUNDIPHARMA and the 'mundipharma' device are Registered Trade Marks

© 2008-2011 Napp Pharmaceuticals Ltd