Mundipharma Pharmaceuticals Limited - Formerly Napp Laboratories

OxyNorm^® concentrate 10 mg/ml oral solution

Each ml OxyNorm concentrate contains oxycodone base 9 mg as oxycodone hydrochloride 10 mg.

Excipients: Each ml of oral solution contains 0.1 mg sunset yellow (E110).

For a full list of excipients, see section 6.1.

Oral solution

OxyNorm concentrate is a clear orange oral solution.

For the treatment of severe pain.

Route of administration:

Oral use

Adults and elderly:

OxyNorm concentrate should be taken at 4-6 hourly intervals. The dosage is dependent on the severity of the pain and 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 5 mg 4-6 hourly. The dose should then be carefully titrated, every day if necessary, to achieve pain relief. 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 throughout the dosage interval. The need for escape medication more than twice a day indicates that the dosage of OxyNorm concentrate should be increased.

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 OxyNorm concentrate 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. For the long-term treatment of severe pain prolonged release formulations of oxycodone are available.

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.

Adults under 20 years and children:

Not recommended.

Any situation where opioids are contraindicated: 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 or within 2 weeks of discontinuation of their use.

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.

OxyNorm concentrate should not be used where there is a possibility of paralytic ileus occurring. Should paralytic ileus be suspected or occur during use, oxycodone should be discontinued immediately (see section 4.3). Due to an increased perioperative risk of ileus and respiratory depression OxyNorm concentrate should be used with caution pre-operatively and within the first 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 concentrate for 6 hours prior to the intervention. If further treatment with oxycodone is indicated then the dosage should be adjusted to the new post-operative requirement.

As with all opioid preparations, OxyNorm concentrate 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 other strong agonist opioids and 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. OxyNorm concentrate should be used with particular care in patients with a history of alcohol or drug abuse.

Abuse of oral dosage forms by parenteral administration can be expected to result in serious adverse events 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 opioid analgesic preparations without clinical assessment and careful retitration as necessary. Otherwise, a continuous analgesic action is not ensured.

OxyNorm concentrate contains sunset yellow which may cause allergic reactions.

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

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.

OxyNorm concentrate should not be used in pregnancy or the breast feeding mother.

Pregnancy

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.

Lactation

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

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 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:

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

Metabolism and nutrition disorders:

Common ( 1/100 to <1/10): anorexia.

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

Psychiatric disorders:

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

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

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.

Eye disorders:

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

Ear and labyrinth disorders:

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

Rare ( 1/10,000 to <1/1000): urticaria.

Renal and urinary disorders:

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

Uncommon (1/1,000 to <1/100): urinary retention.

Reproductive system and breast disorders:

Uncommon (1/1,000 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.

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 concentrate 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.

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.

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.

Pharmacotherapeutic group: Natural opium alkaloids

ATC code: N02A A05

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.

A pharmacokinetic study in healthy volunteers showed that OxyNorm liquid 1 mg/ml and OxyNorm concentrate 10 mg/ml exhibited an equivalent rate and extent of absorption following administration of a single dose of 10 mg. Mean peak plasma concentrations of 20 ng/ml are reached within 1 hour (range 0.5 – 2.5 hours) of administration.

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 and oxymorphone. Oxymorphone has some analgesic activity but is present in plasma in low concentrations and is not considered to contribute to oxycodone's pharmacological effect.

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

Saccharin Sodium

Sodium Benzoate

Citric Acid Monohydrate

Sodium Citrate

Hydrochloric Acid

Sodium Hydroxide

Purified Water

Sunset Yellow (E110)

Not applicable.

Four years.

Do not store above 30°C.

OxyNorm concentrate is supplied in 120 ml amber glass bottles with polyethylene/polypropylene caps. A graduated dropper or an oral syringe is also supplied.

OxyNorm concentrate may be mixed with a soft drink for ease of administration and to improve palatability.

Mundipharma Pharmaceuticals Ltd

Millbank House

Arkle Road

Sandyford

Dublin 18

Ireland

PA 1688/6/3

28 April 2000 / 27 April 2010

July 2011

® OxyNorm, MUNDIPHARMA and the 'mundipharma' device (logo) are Registered Trade Marks.

© 2011 Napp Pharmaceuticals Limited.