Data Sheet
OXYCONTIN®
Oxycodone hydrochloride USP 5mg, 10mg, 20mg, 40mg, 80mg controlled release tablets
Presentation
OxyContin® 5mg tablets - Round, biconvex, pale blue, film-coated tablet with OC on one side and 5 on the other.
OxyContin® 10mg tablets - Round, biconvex, white, film-coated tablet with OC on one side and 10 on the other.
OxyContin® 20mg tablets - Round, biconvex, pink, film-coated tablet with OC on one side and 20 on the other.
OxyContin® 40mg tablets - Round, biconvex, yellow, film-coated tablet with OC on one side and 40 on the other.
OxyContin® 80mg tablets - Round, biconvex, green, film-coated tablet with OC on one side and 80 on the other.
Uses
Actions
Oxycodone is a full opioid agonist with no antagonist properties whose principal therapeutic action is analgesia. It has an affinity for kappa, mu and delta opiate receptors in the brain and spinal cord. Oxycodone is similar to morphine in its action. Other pharmacological actions of oxycodone are in the CNS (respiratory depression, antitussive, anxiolytic, sedative and miosis), smooth muscle (constipation, reduction in gastric, biliary and pancreatic secretions, spasm of sphincter of Oddi and transient elevations in serum amylase) and cardiovascular system (release of histamine and/or peripheral vasodilation, possibly causing pruritus, flushing, red eyes, sweating and/or orthostatic hypotension).
Pharmacokinetics
Elimination and Metabolism
Oxycodone 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.
Absorption
Compared with morphine, which has an absolute bioavailability of approximately 30%, oxycodone has a high absolute bioavailability of up to 87% following oral administration.
The absorption of oxycodone from OXYCONTIN tablets is biphasic, with an initial absorption of approximately 40% of the active medicine (T½ = 0.6 hrs) providing onset of analgesia within 1 hour in most patients, followed by a more controlled absorption, which determines the 12 hour duration of action (T½ = 6.2 hrs). The mean apparent half-life of OXYCONTIN is 6.5 hours and steady-state is achieved in about one day. The initial absorption occurs from the surface of the tablet, following dissolution of the film coat. The remaining medicine substance is absorbed from the matrix either by dissolution or diffusion from or through the tablet matrix.
Release of oxycodone from OXYCONTIN tablets is independent of pH under physiological conditions.
OXYCONTIN tablets have an oral bioavailability comparable with conventional oral oxycodone, but achieve maximal plasma concentrations at about 3 hours compared with 1-1.5 hours for conventional oral oxycodone. Peak and trough concentrations of oxycodone from OXYCONTIN tablets 10mg administered 12-hourly are similar to those achieved from conventional oxycodone 5mg administered 6-hourly.
OXYCONTIN tablets 5mg, 10mg, 20mg, 40mg and 80mg are dose-proportional 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.
Indications
The management of moderate to severe chronic pain unresponsive to non-narcotic analgesia.
Dosage and Administration
OXYCONTIN tablets 80mg should only be used in opioid-tolerant patients.
OXYCONTIN tablets are to be swallowed whole, and are not to be broken, chewed or crushed. Taking broken, chewed or crushed OXYCONTIN tablets could leads to a rapid release and absorption of a potentially toxic dose of oxycodone.
Adults, elderly and children over 12 years: Prior to initiation and titration of doses, refer to the Precautions section for information on special risk groups such as females and the elderly. OXYCONTIN tablets should be taken at 12-hourly intervals. The dosage is dependent on the severity of the pain, and the patient's previous history of analgesic requirements.
Increasing severity of pain will require an increased dosage of OXYCONTIN tablets using the 5mg, 10mg, 20mg, 40mg or 80mg tablet strengths, either alone or in combination, to achieve pain relief. The correct dosage for any individual patient is that which controls the pain and is well tolerated, for a full 12 hours. There is no ceiling dose and so patients should be titrated to pain relief unless unmanageable adverse medicine reactions prevent this. If higher doses are necessary increases should be made, where possible, in 25% - 50% increments. The need for escape medication more than twice a day indicates that the dosage of OXYCONTIN tablets should be increased.
The usual starting dose for opioid naïve patients or patients presenting with severe pain uncontrolled by weaker opioids is 10mg 12 hourly, or 5mg 12 hourly for patients with renal or hepatic impairment. The dose should then be carefully titrated, as frequently as once a day if necessary, to achieve pain relief.
Patients receiving oral morphine before OXYCONTIN therapy should have their daily dose based on the following ratio: 10mg or oral oxycodone is equivalent to 20mg of oral morphine. It must be emphasized 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.
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 medicine reactions were seen based on age, therefore adult doses and dosage intervals are appropriate.
Children under 12 years: Not recommended.
Patients receiving other oral oxycodone formulation may be transferred to OXYCONTIN at the same total daily dosage, equally divided into two 12-hourly OXYCONTIN doses.
For patients who are receiving an alternative opioid, the "oral oxycodone equivalent" of the analgesic presently being used should be determined. Having determined the total daily dosage of the present analgesic, the following equivalence table can be used to calculate the approximate daily oral oxycodone dosage that should provide equivalent analgesia. The total daily oral oxycodone dosage should then be equally divided into two 12 hourly OXYCONTIN doses.
| Multiplication Factors for Converting the Daily Dose | ||
|---|---|---|
| (Mg/Day Prior Opioid x Factor = Mg/Day Oral Oxycodone) | ||
| Oral Prior Opioid | Parenteral Opioid | |
| Oxycodone | 1 | - |
| Codeine | 0.15 | - |
| Fentanyl TTS | See below** | See below** |
| Hydromorphone | 4 | 20 |
| Pethidine | 0.1 | 0.4 |
| Methadone | 1.5 | 3 |
| Morphine | 0.5 | 3 |
* To be used for conversion to oral oxycodone. For patients receiving
high-dose parenteral opioids, a more conservative conversion is warranted. For
example, for high-dose parenteral morphine, use 1.5 instead of 3 as a
multiplication factor.
** Conversion from transdermal fentanyl to OXYCONTIN: 18 hours following the removal of the transdermal fentanyl patch, OXYCONTIN treatment can be initiated. Although there has been no systematic assessment of such conversion, a conservative oxycodone dose, approximately 10mg q12h of OXYCONTIN, should be initially substituted for each 25µg/hr fentanyl transdermal patch. The patient should be followed closely.
Contraindications
Hypersensitivity to opioids, acute respiratory depression, cor pulmonale, cardiac arrhythmias, acute asthma or other obstructive airways disease, paralytic ileus, suspected surgical abdomen, delayed gastric emptying, acute alcoholism, brain tumour, increased cerebrospinal or intracranial pressure, head injury, severe CNS depression, convulsive disorders, delirium tremens, hypercarbia, concurrent administration of monoamine oxidase inhibitors or within 2 weeks of discontinuation of their use. Not recommended for pre-operative use or for the first 24 hours post-operatively.
Warnings and Precautions
The major risk of opioid excess is respiratory depression. As with all opioids, a reduction in dosage may be advisable in hypothyroidism. Use with caution in opioid dependent patients and in patients with raised intracranial pressure, hypotension, hypovolaemia, diseases of the biliary tract, pancreatitis, inflammatory bowel disorders, prostatic hypertrophy, adrenocortical insufficiency, toxic psychosis, chronic pulmonary, renal and hepatic disease, myxedema and debilitated patients. As with all opioid preparations, patients who are to undergo cordotomy or other pain relieving surgical procedures should not receive OXYCONTIN tablets for 24 hours before surgery. Pain in the immediate pre-operative period, and any symptoms of opioid withdrawal, should be managed with short-acting analgesic agents. If further treatment with OXYCONTIN tablets is then indicated 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.
Use in chronic, non-malignant pain
The use of OXYCONTIN for the treatment of chronic pain which is not due to malignancy should be restricted to situations where:
- all other conservative methods of analgesia have been tried and have failed;
- the pain is having a significant impact on the patient's quality of life;
- there is no psychological contraindication, medicine seeking behaviour or history of medicine misuse.
Prior to long term prescription, a trial of OXYCONTIN or shorter acting opioid should be undertaken. Long term administration of OXYCONTIN should only occur if this trial demonstrates that the pain is opioid sensitive. Opioid naïve patients who require rapid dose escalation with no concomitant pain relief within the trial period should generally be considered inappropriate for long term therapy.
One doctor only should be responsible for the prescription and monitoring of the patient's opioid use.
Prescribers should consult appropriate clinical guidelines on the use of opioid analgesics in such patients (e.g. those published by the Australian Pain Society in the Medical Journal of Australia 1997;167:30-4).
Drug Dependence
As with other opioids, tolerance and physical dependence tend to develop upon repeated administration of oxycodone. There is potential for abuse of the medicine and for development of strong psychological dependence. OXYCONTIN should therefore be prescribed and handled with a high degree of caution appropriate to the use of a medicine with strong abuse potential.
Substance abuse is not, however, a problem in patients with severe pain in which oxycodone is appropriately indicated. On the other hand, in the absence of a clear indication for a strong opioid analgesic, medicine-seeking behaviour must be suspected and resisted, particularly in individuals with a history of, or propensity for, substance abuse. Withdrawal symptoms may occur following abrupt discontinuation of oxycodone therapy or upon administration of an opioid antagonist. Therefore, patients on prolonged therapy should be withdrawn gradually from the medicine if it is no longer required for pain control.
Oxycodone should be used with caution and under close supervision in patients with pain not due to malignancy who have a prior history of substance abuse. However, in such cases, prior psychological assessment is essential and the prescribing doctor should consider whether the benefit of treatment outweighs the risk of abuse.
OXYCONTIN consists of a dual-polymer matrix, intended for oral use only. Parenteral venous injection of the tablet constituents, especially talc, can be expected to result in local tissue necrosis, pulmonary granulomas and serious adverse reactions which may be fatal.
Special Risk Groups
Renal and hepatic impairment
In renal and hepatic impairment, the administration of OXYCONTIN tablets 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, initiation of dosing in patients with renal impairment (CLcr<60ml/min) or hepatic impairment should be reduced to 1/3 to ½ of the usual dose with cautious titration.
Elderly
The plasma concentrations of oxycodone are only nominally affected by age, being approximately 15% greater in elderly as compared to young subjects. There were no differences in adverse event reporting between young and elderly subjects.
Elderly, debilitated patients
As with other opioid initiation and titration, doses in elderly patients who are debilitated should be reduced 1/3 to ½ of the usual doses.
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. There were no significant male/female differences detected for efficacy or adverse events in clinical trials.
Driving and Operating Dangerous Machinery
Oxycodone may modify patients' reactions to a varying extent depending on the dosage and individual susceptibility. If their ability is impaired, patients should not drive or operate machinery.
Carcinogenicity/Mutagenicity
Oxycodone was not mutagenic in the Ames Salmonella and E.coli assays, but was positive in the mouse lymphoma assay. In assays of chromosomal damage, genotoxic effects occurred in the human lymphocyte chromosomal aberration assay in vitro, but not in the in vivo bone marrow micronucleus assay in mice.
Studies of oxycodone in animals to evaluate its carcinogenic potential have not been conducted.
Impairment of Fertility
Studies have not been performed to assess the effects of oxycodone on fertility.
Use in Pregnancy
Category C: Oxycodone penetrates the plasma, and when used during labour, may cause respiratory depression in the newborn. Reproduction studies have been performed in rats and rabbits by oral administration at doses up to 8.0mg/kg (48mg/m2) and 125.0mg/kg (1375mg/m2), respectively, which are 0.4 and 11 times the human dose of 160mg, based on Body Surface Area (BSA), respectively. The studies did not show evidence of harm to foetus. There are, however, no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human responses, this medicine should be used during pregnancy only if clearly needed.
Use in Lactation
Low concentrations of oxycodone have been detected in breast milk. Withdrawal symptoms can occur in breast-feeding infants when maternal administration of an opioid analgesic is stopped.
Adverse Effects
Adverse medicine reactions are typical of full opioid agonists, and tend to reduce with time, with the exception of constipation. Anticipation of adverse medicine reactions and appropriate patient management can improve acceptability.
Gastrointestinal
Common
Constipation, nausea, vomiting, dry mouth, anorexia, gastritis, hiccup, dyspepsia, abdominal pain and diarrhoea.
Uncommon
Colic, stomatitis, dysphagia, eructation, flatulence, gastrointestinal disorders, increased appetite, ileus and taste perversion.
Central Nervous System
Common
Headache, confusion, asthenia, faintness, dizziness, sedation, anxiety, abnormal dreams, nervousness, insomnia, thought abnormalities, somnolence and twitching.
Uncommon
Vertigo, hallucinations, drowsiness, disorientation, mood changes, restlessness, raised intracranial pressure, hypothermia, abnormal gait, agitation, depression, tinnitus, tremor, withdrawal syndrome (with or without seizures), amnesia, hyperkinesias, hypesthesia, hypertonia malaise, paresthesia, speech disorder, stupor, euphoria, dysphoria, seizures and vision abnormalities.
Genitourinary
Uncommon
Biliary or ureteric spasm, urinary retention, impotence, urinary abnormalities, urinary tract infections, amenorrhea and decreased libido.
Cardiovascular
Common
Orthostatic hypotension.
Uncommon
Palpitation (as part of withdrawal syndrome), bradycardia, supraventricular tachycardia, blood pressure and heart rate reductions, syncope, migraine, vasodilation, ST depression and chest pain.
Metabolic and Nutritional
Uncommon
Dehydration, oedema, hyponatraemia, peripheral oedema and thirst.
Respiratory
Common
Bronchospasm, dyspnoea, pharyngitis, voice alteration.
Uncommon
Respiratory depression.
Dermatological
Common
Rash.
Uncommon
Dry skin, exfoliative dermatitis, urticaria and other skin rashes.
General
Common
Sweating, pruritus, fever and chills.
Uncommon
Accidental injury, pain, neck pain, facial flushing, miosis, muscular rigidity, lymphadenopathy, allergic reaction, anaphylactic reaction and anaphylactoid reaction.
Key: ≥ 1% Common, ≤ 1% Uncommon
If nausea and vomiting are troublesome, oxycodone may be combined with an antiemetic. Constipation must be treated with appropriate laxatives. Overdose may produce respiratory depression. Compared with other opioids, oxycodone is associated with low histamine release although urticaria and pruritus may occur.
Interactions
Anticholinergic Agents
Concurrent use with oxycodone may result in an increased risk of severe constipation and/or urinary retention.
Antihypertensive Agents
Hypotensive effects of these medications may be potentiated when used concurrently with oxycodone, leading to increased risk of orthostatic hypotension.
CNS Depressants (including sedatives or hypnotics, general anaesthetics, phenothiazines, other tranquillisers, alcohol, other opioids and neuroleptic medicines, etc).
Concurrent use with oxycodone may result in increased respiratory depression, hypotension, profound sedation or coma. Caution is recommended and the dosage of one or both agents should be reduced.
Coumarin Derivatives
Although there is little substantiating evidence, opiate agonists have been reported to potentiate the anticoagulant activity of coumarin derivatives.
Metoclopramide
Concurrent use with oxycodone may antagonise the effects of metoclopramide on gastrointestinal motility.
Monoamine Oxidase Inhibitors (MAOIs)
Non-selective MAOIs intensify the effects of opioid medicines which can cause anxiety, confusion and significant respiratory depression. Severe and sometimes fatal reactions have occurred in patients concurrently administered MAOIs and pethidine. Oxycodone should not be given to patients taking non-selective MAOIs or within 14 days of stopping such treatment. As it is unknown whether there is an interaction between selective (MAOIs (e.g. selegiline) and oxycodone, caution is advised with this medicine combination.
Neuromuscular Blocking Agents
Oxycodone may enhance the effects of neuromuscular blocking agents resulting in increased respiratory depression.
Opioid Agonist Analgesics (including morphine, pethidine)
Additive CNS depressant, respiratory depressant and hypotensive effects may occur if two or more opioid agonist analgesics are used concurrently.
Opioid Agonist-antagonist Analgesics (including pentazocine, butorphanol, buprenorphine)
Mixed agonist/antagonist analgesics may reduce the analgesic effect of oxycodone and/or may precipitate withdrawal symptoms.
Oxycodone hydrochloride is metabolised in the intestines and liver to form noroxycodone, oxymorphone and other conjugated glucuronides. CYP3A4 and CYP2D6 are probably involved in the formation of noroxycodone and oxymorphone, respectively. The contribution of these metabolites to the analgesic effect is insignificant.
Metabolic interactions with medicines that involve the cytochrome P450 enzyme system (CYP3A4, CYP2D6) can cause the plasma concentration of oxycodone to increase. Quinidine, which is a potent CYP2D6 inhibitor, has blocked the formation of oxymorphone, while the oxycodone concentration increased marginally. Concurrent administration of quinidine does not alter the pharmacodynamic effects of oxycodone. The metabolic pathway may be blocked by a variety of medicines (e.g. cimetidine, certain cardiovascular medicines and antidepressants), although such blockade has not yet been shown to be of clinical significance with OXYCONTIN.
The potential effects of oxycodone on CYP enzyme have not been studied either in vitro or in vivo.
Overdosage
Symptoms
Acute overdosage with oxycodone can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted 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.
Administration of activated charcoal should be restricted to patients with an intact gag reflex or protected airway. A saline cathartic or sorbitol added to the first dose of activated charcoal may speed gastrointestinal passage of the product.
Oxygen, intravenous fluids, vasopressor and other supportive measures should be used as indicated.
If there are signs of clinically significant respiratory or cardiovascular depression, the use of an opioid antagonist should be considered. The opioid antagonist naloxone hydrochloride is a specific antidote against respiratory depression due to overdosage. Concomitant efforts at respiratory resuscitation should be carried out. Since the duration of action of oxycodone, particularly sustained release formulations, may exceed that of the antagonist, the patient should be under continued surveillance and doses of the antagonist should be repeated as needed to maintain adequate respiration.
In an individual physically dependent on opioids, the administration of the usual dose of opioid antagonist will precipitate an acute withdrawal syndrome. The severity of this syndrome will depend on the degree of physical dependence and the dose of antagonist administered. The use of opioid antagonists in such individuals should be avoided if possible. If an opioid antagonist must be used to treat serious respiratory depression in the physically dependent patient, the antagonist should be administered with extreme care by using dosage titration, commencing with 10 to 20% of the usual recommended initial dose.
Pharmaceutical Precautions
Storage
Store below 25°C. Shelf-life for all strengths is 3 years when stored at or below 25°C.
Medicine Classification
Controlled Drug B3.
Package Quantities
OXYCONTIN tablets 5mg (pale blue), 10mg (white), 20mg (pink), 40mg (yellow), 80mg (green): blister packs of 20 or 3 x 20 tablets.
Further Information
- Oxycodone hydrochloride is a white, crystalline odourless powder readily soluble in water, sparingly soluble in ethanol and nearly insoluble in ether. The chemical name is 4,5α-epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one hydrochloride (CAS No. 124-90-3). The molecular formula is C18H21NO4. HCl and molecular weight is 351.87.
- Inactive ingredients in OXYCONTIN tablets are: lactose, povidone, Eudragit RS 30D (solids), glycerol triacetate, stearyl alcohol, talc and magnesium stearate. All of the tablets are coated with hypromellose, titanium dioxide and macrogol 400. The tablet coatings also contain: hydroxypropylcellulose (10 & 80mg tablets); polysorbate 80 (20 & 40mg tablets); iron oxide red CI77491 (20mg tablets); iron oxide yellow CI77492 (40 & 80mg tablets); indigo carmine CI73015 aluminium lake (80mg tablets) and brilliant blue CI42090 (5mg tablets).
Name and Address
Distributed on behalf of Mundipharma New Zealand Limited by:
Pharmaco (NZ) Ltd
P O Box 4079
AUCKLAND
Ph: (09) 377-3336
Toll Free (Medical Enquiries): 0800 773 310
Date of Preparation
19 May 2008
(Aust P.I. 29.10.04)
® OXYCONTIN is a Registered Trademark