1 Name of Medicine
Oxycodone hydrochloride.
2 Qualitative and Quantitative Composition
Oxycodone-hameln 10 mg in 1 mL; 20 mg in 2 mL solution for injection or infusion contains 10 mg/mL of Oxycodone hydrochloride.
Oxycodone-hameln 50 mg in 1 mL solution for infusion contains 50 mg/mL of Oxycodone hydrochloride.
For the full list of excipients, see Section 6.1 List of Excipients.
3 Pharmaceutical Form
Oxycodone-hameln Injection, solution: is a clear colourless solution for injection.
4.1 Therapeutic Indications
Oxycodone-hameln solution for injection or infusion is indicated for the short-term management of severe pain for which other treatment options have failed, are contraindicated, not tolerated or are otherwise inappropriate to provide sufficient management of pain.
4.2 Dose and Method of Administration
Adults, elderly and children over 18 years.
Prior to initiation and titration of doses, (see Section 4.4 Special Warnings and Precautions for Use) for information on special risk groups such as females and the elderly. The lowest dose should be administered with careful titration to pain control. Oxycodone-hameln solution for injection or infusion should not be used in patients under 18 years, as there are no data on use in children under 18 years of age.
Routes of administration.
Oxycodone-hameln solution for injection or infusion 10 mg in 1 mL and 20 mg in 2 mL.
Intravenous injection or infusion, and subcutaneous injection or infusion.
Oxycodone-hameln solution for infusion 50 mg in 1 mL.
Intravenous infusion and subcutaneous infusion, suitable for use in a palliative care setting.
Posology.
The dose should be adjusted according to the severity of pain, the total condition of the patient and previous or concurrent medication.
Adults over 18 years.
Oxycodone-hameln solution for injection or infusion 10 mg in 1 mL and 20 mg in 2 mL.
The following starting doses are recommended for the 10 mg in 1 mL and 20 mg in 2 mL solution for injections, although the starting dose will vary with age, medical status, surgery, pre-existing opioid tolerance, concomitant medications, individual tolerability, severity of pain and the indication, and may require subsequent dosage adjustment. A gradual increase in dose may be required if analgesia is inadequate or if pain severity increases.
IV (injection).
Dilute to 1 mg/mL in 0.9% saline, 5% glucose or water for injections.
To establish analgesia, administer an intravenous bolus dose of 1 to 5 mg slowly over 1-2 minutes. Incremental bolus doses may be required at 5-10 min intervals, with monitoring of the patient. Previous studies have indicated that higher single bolus doses (5-15 mg) oxycodone have been associated with significant sedation and respiratory depression.
For maintenance analgesia, doses should not be administered more frequently than every 4 hours.
IV (infusion).
Dilute to 1 mg/mL in 0.9% saline, 5% glucose or water for injections. A starting dose of 2 mg/hour is recommended.
IV (PCA).
Dilute to 1 mg/mL in 0.9% saline, 5% glucose or water for injections. A starting PCA bolus dose of up to 0.03 mg/kg (e.g. 1-2 mg per 70 kg) should be administered with a minimum lock-out time of 5 minutes.
SC (injection).
Use as 10 mg/mL concentration. A starting dose of 5 to 10 mg is recommended, depending on age and medical status, repeated at 4-hourly intervals as required.
SC (infusion).
Dilute in 0.9% saline, 5% glucose or water for injections if required. For non-surgical pain in palliative care in opioid-tolerant patients, titrate gradually according to pain control.
Oxycodone-hameln solution for infusion 50 mg in 1 mL.
The use of Oxycodone-hameln solution for infusion 50 mg in 1 mL is indicated for opioid-tolerant patients in a palliative care setting. The following starting doses are recommended, although the starting dose will vary with age, medical status, surgery, pre-existing opioid tolerance, concomitant medications, individual tolerability, severity of pain and the indication, and may require subsequent dosage adjustment. A gradual increase in dose may be required if analgesia is inadequate or if pain severity increases. Oxycodone-hameln 50 mg in 1 mL solution for infusion should not be used for more than 4 consecutive weeks.
IV (infusion).
Dilute to 1 mg/mL in 0.9% saline, 5% glucose or water for injections. A starting dose of 2 mg/hour is recommended.
IV (PCA).
Dilute to 1 mg/mL in 0.9% saline, 5% glucose or water for injections. A starting PCA bolus dose of up to 0.03 mg/kg (e.g. 1-2 mg per 70 kg) should be administered with a minimum lock-out time of 5 minutes.
SC (infusion).
Dilute in 0.9% saline, 5% glucose or water for injections. Continuous subcutaneous infusion of a strong opioid is typically commenced via a syringe driver apparatus.
Transferring patients from oral to parenteral oxycodone.
The dose should be based on the following ratio: 2 mg of oral oxycodone is approximately equivalent to 1 mg of parenteral oxycodone. The approximate conversion ratio between oral and parenteral oxycodone is 2:1 (oral:parenteral), based on an oral liquid bioavailability of 46% (90% CI 41% to 51%). It is emphasised that this is a guide to the required dose only. Inter-patient variability requires that each patient is carefully titrated to the appropriate dose. For cancer patients transferring from oral oxycodone, or rotating from other opioid infusions, dosage requirements may be higher.
Transferring patients from IV morphine to IV oxycodone.
The dose should be based on the following ratio: 1 mg of IV oxycodone is approximately equivalent to 1 mg of IV morphine. The approximate conversion ratio between IV oxycodone and IV morphine is 1:1, based on the PCA study described under Pharmacodynamic Properties, Clinical trials. It is emphasised that this is a guide to the required dose only. Inter-patient variability requires that each patient is carefully titrated to the appropriate dose. For cancer patients transferring from oral oxycodone, or rotating from other opioid injections or infusions, the dosage requirements may be higher.
Elderly.
Elderly patients should be treated with caution. The lowest dose should be administered with careful titration to pain control.
As with other opioid initiation and titration, doses in elderly patients who are debilitated should be reduced to 1/3 to ½ of the usual doses.
Adults with mild to moderate renal impairment and mild hepatic impairment.
The plasma concentration in this patient population may be increased. Therefore, dose initiation should follow a conservative approach with careful titration to pain control (see Section 4.4 Special Warnings and Precautions for Use).
As with other opioid initiation and titration, doses in patients with renal impairment (CLcr < 60 mL/min) or hepatic impairment should be reduced to 1/3 to 1/2 of the usual doses.
Treatment goals and discontinuation.
Before initiating treatment with oxycodone, a treatment strategy including treatment duration and treatment goals, and a plan for end of the treatment, should be agreed together with the patient, in accordance with pain management guidelines. During treatment, there should be frequent contact between the physician and the patient to evaluate the need for continued treatment, consider discontinuation and to adjust dosages if needed. When a patient no longer requires therapy with oxycodone, it may be advisable to taper the dose gradually to prevent symptoms of withdrawal. In absence of adequate pain control, the possibility of hyperalgesia, tolerance and progression of underlying disease should be considered (see Section 4.4 Special Warnings and Precautions for Use).4.3 Contraindications
Hypersensitivity to opioids or any of the constituents of Oxycodone-hameln solution for injection or infusion, acute respiratory disease, severe respiratory disease, respiratory depression, cor pulmonale, cardiac arrhythmias, acute asthma or other obstructive airways disease, paralytic ileus, suspected surgical abdomen, severe renal impairment (creatinine clearance < 10 mL/min), moderate to severe hepatic impairment (see Section 4.4 Special Warnings and Precautions for Use, for information on special risk groups) acute abdominal pain, chronic constipation, delayed gastric emptying, acute alcoholism, coma, brain tumour, increased cerebrospinal or intracranial pressure, head injury (due to risk of raised intracranial pressure), severe CNS depression, convulsive disorders, delirium tremens, hypercarbia, concurrent administration of monoamine oxidase inhibitors or within 2 weeks of discontinuation of their use, anxiety states under the influence of alcohol or hypnotics and pregnancy.
4.4 Special Warnings and Precautions for Use
Hazardous and harmful use.
Oxycodone-hameln solution for injection or infusion contains the opioid oxycodone hydrochloride and is a potential drug of abuse, misuse and addiction. Addiction can occur in patients appropriately prescribed Oxycodone-hameln solution for injection or infusion at recommended doses.
The risk of addiction is increased in patients with a personal or family history of substance abuse (including alcohol and prescription and illicit drugs) or mental illness. The risk also increases the longer the drug is used and with higher doses. Patients should be assessed for their risks for opioid abuse or addiction prior to being prescribed Oxycodone-hameln solution for injection or infusion.
All patients receiving opioids should be routinely monitored for signs of misuse and abuse. Opioids are sought by people with addiction and may be subject to diversion. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the safe storage and proper disposal of any unused drug (see Section 6.4 Special Precautions for Storage; Section 6.6 Special Precautions for Disposal). Caution patients that abuse of oral or transdermal forms of opioids by parenteral administration can result in serious adverse events, which may be fatal.
Tolerance and physical and/or psychological dependence may develop upon repeated administration of opioids such as oxycodone. Repeated use of oxycodone can lead to Opioid Use Disorder (OUD). A higher dose and longer duration of opioid treatment can increase the risk of developing OUD. Abuse or intentional misuse of oxycodone may result in overdose and/or death. The risk of developing OUD is increased in patients with a personal or family history (parents or siblings) of substance use disorders (including alcohol use disorder), in current tobacco users or in patients with a personal history of other mental health disorders (e.g. major depression, anxiety and personality disorders).
Before initiating treatment with oxycodone and during the treatment, treatment goals and a discontinuation plan should be agreed with the patient (see Section 4.2 Dose and Method of Administration). Before and during treatment the patient should also be informed about the risks and signs of OUD. If these signs occur, patients should be advised to contact their physician.
Patients will require monitoring for signs of drug-seeking behaviour (e.g. too early requests for refills). This includes the review of concomitant opioids and psycho-active drugs (like benzodiazepines). For patients with signs and symptoms of OUD, consultation with an addiction specialist should be considered.
Patients should be advised not to share Oxycodone-hameln solution for injection or infusion with anyone else.
Respiratory depression.
Serious, life-threatening or fatal respiratory depression can occur with the use of opioids even when used as recommended. It can occur at any time during the use of Oxycodone-hameln solution for injection or infusion, but the risk is greatest during initiation of therapy or following an increase in dose. Patients should be monitored closely for respiratory depression at these times.
The risk of life-threatening respiratory depression is also higher in elderly, frail or debilitated patients, in patients with renal and hepatic impairment and in patients with existing impairment of respiratory function (e.g. chronic obstructive pulmonary disease; asthma).
Opioids should be used with caution and with close monitoring in these patients (see Section 4.2 Dose and Method of Administration). The use of opioids is contraindicated in patients with severe respiratory disease, acute respiratory disease and respiratory depression (see Section 4.3 Contraindications).
The risk of respiratory depression is greater with the use of high doses of opioids, especially high potency and modified release formulations, and in opioid naïve patients. Initiation of opioid treatment should be at the lower end of the dosage recommendations, with careful titration of doses to achieve effective pain relief. Careful calculation of equianalgesic doses is required when changing opioids or switching from immediate release to modified release formulations, (see Section 4.2 Dose and Method of Administration) together with consideration of pharmacological differences between opioids. Consider starting the new opioid at a reduced dose to account for individual variation in response.
Sleep related breathing disorders.
Opioids can cause sleep-related breathing disorders including central sleep apnoea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the total opioid dosage. Opioids may also cause worsening of pre-existing sleep apnoea (see Section 4.8 Adverse Effects (Undesirable Effects)).
Risks from concomitant use of benzodiazepines or other CNS depressants, including alcohol.
Concomitant use of opioids and benzodiazepines or other CNS depressants, including alcohol, may result in sedation, respiratory depression, coma and death.
Because of these risks, concomitant prescribing of Oxycodone-hameln solution for injection or infusion with CNS depressant medicines, such as other opioid analgesics, benzodiazepines, gabapentinoids, cannabis, sedatives, hypnotics, tricyclic antidepressants, antipsychotics, antihistamines, centrally-active anti-emetics and other CNS depressants, should be reserved for patients for whom other treatment options are not possible.
If a decision is made to prescribe Oxycodone-hameln solution for injection or infusion concomitantly with any of the medicines, the lowest effective dose should be used, and the duration of treatment should be as short as possible. Patients should be followed closely for signs and symptoms of respiratory depression and sedation. Patients and their caregivers should be made aware of these symptoms. Patients and their caregivers should also be informed of the potential harms of consuming alcohol while taking Oxycodone-hameln solution for injection or infusion.
Use of opioids in chronic (long-term) non-cancer pain (CNCP).
Opioid analgesics have an established role in the treatment of acute pain, cancer pain and palliative and end-of-life care. Current evidence does not generally support opioid analgesics in improving pain and function for most patients with chronic non-cancer pain. The development of tolerance and physical dependence and risks of adverse effects, including hazardous and harmful use, increase with the length of time a patient takes an opioid. The use of opioids for long-term treatment of CNCP is not recommended.
The use of an opioid to treat CNCP should only be considered after maximised non-pharmacological and non-opioid treatments have been tried and found ineffective, not tolerated or otherwise inadequate to provide sufficient management of pain. Opioids should only be prescribed as a component of comprehensive multidisciplinary and multimodal pain management.
Opioid therapy for CNCP should be initiated as a trial in accordance with clinical guidelines and after a comprehensive biopsychosocial assessment has established a cause for the pain and the appropriateness of opioid therapy for the patient (see Hazardous and harmful use, above). The expected outcome of therapy (pain reduction rather than complete abolition of pain, improved function and quality of life) should be discussed with the patient before commencing opioid treatment, with agreement to discontinue treatment if these objectives are not met.
Owing to the varied response to opioids between individuals, it is recommended that all patients be started at the lowest appropriate dose and titrated to achieve an adequate level of analgesia and functional improvement with minimum adverse reactions. Immediate-release products should not be used to treat chronic pain, but may be used for a short period in opioid-naïve patients to develop a level of tolerance before switching to a modified-release formulation. Careful and regular assessment and monitoring is required to establish the clinical need for ongoing treatment. Discontinue opioid therapy if there is no improvement of pain and/or function during the trial period or if there is any evidence of misuse or abuse. Treatment should only continue if the trial has demonstrated that the pain is opioid responsive and there has been functional improvement. The patient's condition should be reviewed regularly and the dose tapered off slowly if opioid treatment is no longer appropriate (see Section 4.4 Special Warnings and Precautions for Use, Ceasing opioids).
Tolerance, dependence and withdrawal.
Neuroadaptation of the opioid receptors to repeated administration of opioids can produce tolerance and physical dependence. Tolerance is the need for increasing doses to maintain analgesia. Tolerance may occur to both the desired and undesired effects of the opioid.
Physical dependence, which can occur after several days to weeks of continued opioid usage, results in withdrawal symptoms if the opioid is ceased abruptly or the dose is significantly reduced. Withdrawal symptoms can also occur following the administration of an opioid antagonist (e.g. naloxone) or partial agonist (e.g. buprenorphine).
Withdrawal can result in some or all of the following symptoms: dysphoria, restlessness/agitation, lacrimation, rhinorrhoea, yawning, sweating, chills, myalgia, mydriasis, irritability, anxiety, increasing pain, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhoea, increased blood pressure, increased respiratory rate and increased heart rate.
When discontinuing Oxycodone-hameln solution for injection or infusion in a person who may be physically-dependent, the drug should not be ceased abruptly but withdrawn by tapering the dose gradually (see Section 4.4 Special Warnings and Precautions for Use, Ceasing opioids).
Accidental ingestion/exposure.
Accidental ingestion or exposure of Oxycodone-hameln solution for injection or infusion, especially by children, can result in a fatal overdose of oxycodone. Patients and their caregivers should be given information on safe storage and disposal of unused Oxycodone-hameln solution for injection or infusion (see Section 6.4 Special Precautions for Storage; Section 6.6 Special Precautions for Disposal).
Hyperalgesia.
Hyperalgesia may occur with the use of opioids, particularly at high doses. Hyperalgesia may manifest as an unexplained increase in pain, increased levels of pain with increasing opioid dosages or diffuse sensitivity not associated with the original pain. Hyperalgesia should not be confused with tolerance (see Section 4.4 Special Warnings and Precautions for Use, Tolerance, dependence and withdrawal). If opioid induced hyperalgesia is suspected, the dose should be reduced and tapered off if possible. A change to a different opioid may be required.
Ceasing opioids.
Abrupt discontinuation or rapid decreasing of the dose in a person physically dependent on an opioid may result in serious withdrawal symptoms and uncontrolled pain (see Section 4.4 Special Warnings and Precautions for Use, Tolerance, dependence and withdrawal). Such symptoms may lead the patient to seek other sources of licit or illicit opioids. Opioids should not be ceased abruptly in a patient who is physically dependent but withdrawn by tapering the dose slowly. Factors to take into account when deciding how to discontinue or decrease therapy include the dose and duration of the opioid the patient has been taking, the type of pain being treated and the physical and psychological attributes of the patient. A multimodal approach to pain management should be in place before initiating an opioid analgesic taper. During tapering, patients require regular review and support to manage any increase in pain, psychological distress and withdrawal symptoms.
There are no standard tapering schedules suitable for all patients and an individualised plan is necessary. In general, tapering should involve a dose reduction of no more than 10 percent to 25 percent every 2 to 4 weeks. If the patient is experiencing increased pain or serious withdrawal symptoms, it may be necessary to go back to the previous dose until stable before proceeding with a more gradual taper.
When ceasing opioids in a patient who has a suspected opioid use disorder, the need for medication assisted treatment and/or referral to a specialist should be considered.
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.
Use in renal impairment.
In renal impairment, the administration of Oxycodone-hameln solution for injection or infusion 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 function. Therefore, initiation of dosing in patients with renal impairment (CLcr < 60 mL/min) should be reduced to 1/3 to ½ of the usual dose with cautious titration.
Use in hepatic impairment.
In hepatic impairment, the administration of Oxycodone-hameln solution for injection or infusion 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 hepatic function. Therefore, initiation of dosing in patients with hepatic impairment should be reduced to 1/3 to ½ of the usual dose with cautious titration.
Use in the elderly.
The plasma concentrations of oxycodone are only nominally affected by age, being approximately 15% greater in elderly as compared with young subjects. There were no differences in adverse event reporting between young and elderly subjects.
As with other opioid initiation and titration, doses in elderly patients who are debilitated should be reduced to 1/3 to ½ of the usual doses.
Paediatric use.
Oxycodone-hameln solution for injection or infusion should not be used in patients under 18 years (see Section 4.2 Dose and Method of Administration, Adults, elderly and children over 18 years).
Effects on laboratory tests.
No data available.
Special risk patients.
As with all opioids, a reduction in dosage may be advisable in hypothyroidism. Use with caution in patients with hypotension, hypovolaemia, diseases of the biliary tract, pancreatitis, inflammatory bowel disorders, prostatic hypertrophy, adrenocortical insufficiency (Addison's disease), toxic psychosis, sleep apnoea, constipation and myxoedema. As with all opioid preparations, patients who are to undergo cordotomy or other pain-relieving neural blockade procedures should not receive Oxycodone-hameln solution for injection or infusion for 6 hours before surgery.
As with all opioid preparations, Oxycodone-hameln solution for injection or infusion 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. Should paralytic ileus be suspected or occur during use, Oxycodone-hameln solution for injection or infusion should be discontinued immediately. Oxycodone-hameln solution for injection or infusion should be used with caution pre- or intra-operatively and within the first 12-24 hours post-operatively. Oxycodone-hameln solution for infusion 50 mg/mL should not be used for more than 4 weeks consecutively.
Hepatobiliary disorders.
Oxycodone may cause dysfunction and spasm of the sphincter of Oddi, thus raising intrabiliary pressure and increasing the risk of biliary tract symptoms and pancreatitis. Therefore, oxycodone has to be administered with caution in patients with pancreatitis and diseases of the biliary tract.
Endocrine effects.
Opioids, such as oxycodone hydrochloride, 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 manifest from these hormonal changes.4.5 Interactions with Other Medicines and Other Forms of Interactions
Anticholinergic agents.
Concurrent use of oxycodone with anticholinergics or medications with anticholinergic activity (e.g. tricyclic antidepressants, antihistamines, antipsychotics, muscle relaxants, anti-Parkinson medications) may result in increased anticholinergic adverse effects, including 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 an increased risk of orthostatic hypotension.
CNS depressants.
Concurrent use of oxycodone with CNS depressants (include but are not limited to: sedatives (including benzodiazepines), antipsychotics, antidepressants, anxiolytics, centrally-active anti-emetics, cannabis, hypnotics, general anaesthetics, phenothiazines, other tranquillisers, alcohol, other opioids, gabapentinoids such as pregabalin, benzodiazepines and neuroleptic drugs, etc.), or related drugs increases the risk of profound sedation, respiratory depression, hypotension, death or coma because of additive CNS depressant effect (see Section 4.4 Special Warnings and Precautions for Use, Risks from concomitant use of benzodiazepines or other CNS depressants, including alcohol).
Intake of alcoholic beverages while being treated with Oxycodone-hameln solution for injection or infusion should be avoided because this may lead to more frequent undesirable effects such as somnolence and respiratory depression. Oxycodone hydrochloride containing products should be avoided in patients with a history of or present alcohol, drug or medicines abuse.
Coumarin derivatives.
Although there is little substantiating evidence, opiate agonists have been reported to potentiate the anticoagulant activity of coumarin derivatives.
CYP3A4 and CYP2D6 inducers and inhibitors.
Oxycodone is metabolised in part via the CYP2D6 and CYP3A4 pathways. The activities of these metabolic pathways may be inhibited or induced by various co-administered drugs or dietary elements, which may alter plasma concentrations. Oxycodone doses may need to be adjusted accordingly. 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. Concurrent administration of quinidine does not alter the pharmacodynamic effects of oxycodone. CYP3A4 inhibitors such as macrolide antibiotics (e.g. clarithromycin), azole antifungal agents (e.g. ketoconazole), protease inhibitors (e.g. ritonavir) and grapefruit juice may cause decreased clearance of oxycodone which could lead to an increase in oxycodone plasma concentrations. Oxycodone metabolism may be blocked by a variety of drugs (e.g. cimetidine, certain cardiovascular drugs, fluoxetine and other antidepressants and erythromycin), although such blockade has not yet been shown to be of clinical significance with Oxycodone-hameln solution for injection or infusion.
CYP3A4 inducers, such as rifampin, carbamazepine, phenytoin and St. John's wort, may induce the metabolism of oxycodone and cause increased clearance of the drug, resulting in a decrease in oxycodone plasma concentrations.
Oxycodone did not inhibit the activity of P450 isozymes 2D6, 3A4, 1A2, 2A6, 2C19 or 2E1 in human liver microsomes in vitro. Non-clinical data in vitro and in vivo indicate that oxycodone can act as a P-glycoprotein substrate and can induce over-expression of P-glycoprotein in rats.
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 drugs 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 drug 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.
Selective serotonin re-uptake inhibitor (SSRI) or a serotonin norepinephrine re-uptake inhibitor (SNRI).
Concurrent administration of oxycodone with serotonin agents, such as a selective serotonin re-uptake inhibitor (SSRI) or a serotonin norepinephrine re-uptake inhibitor (SNRI) may cause serotonin toxicity. The symptoms of serotonin toxicity may include mental-status changes (e.g. agitation, hallucinations, coma), autonomic instability (e.g. tachycardia, labile blood pressure, hyperthermia), neuromuscular abnormalities (e.g. hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g. nausea, vomiting, diarrhoea). Oxycodone should be used with caution and the dosage may need to be reduced in patients using these medications.4.6 Fertility, Pregnancy and Lactation
Effects on fertility.
In reproductive toxicology studies, no evidence of impaired fertility was seen in male or female rats at oxycodone doses of 8 mg/kg/day, with estimated exposure (plasma AUC) equivalent to 8 mg/day in men and 17 mg/day in women.
Despite these fertility studies in animals, prolonged use of opioids may result in impairment of reproductive function, including fertility and sexual dysfunction in both sexes, and irregular menses in women.
(Category C)
Australian Pregnancy Category C: Drugs which, owing to their pharmacological effects, have caused or may be suspected of causing harmful effects on the human fetus or neonate without causing malformations. These effects may be reversible.
Oxycodone used during pregnancy or labour may cause withdrawal symptoms and/or respiratory depression in the newborn infant. Oral administration of oxycodone during the period of organogenesis did not elicit teratogenicity or embryofoetal toxicity in rats or rabbits at doses up to 8 mg/kg/day in rats (equivalent to 17 mg/day in women, based on estimated plasma AUC values) or 125 mg/kg/day in rabbits.
Oral administration of oxycodone to rats from early gestation to weaning did not affect postnatal development parameters at doses up to 6 mg/kg/day (equivalent to 9 mg/day in women, based on estimated AUC values). In a study designed specifically to investigate the effect of pre-natal oxycodone on the hypothalamic-pituitary-adrenal axis in adolescent rats, intravenous administration of oxycodone 0.8 mg/kg/day (equivalent to 11 mg/day in pregnant women, based on estimated AUC values) had no effect on the corticosterone response, but delayed and enhanced the peak ACTH response to corticotrophin releasing hormone in males, but not females. The clinical significance of this observation is unknown.
There are no adequate and well-controlled studies with oxycodone in pregnant women. Because animal reproduction studies are not always predictive of human responses, oxycodone should not be used during pregnancy unless clearly needed. Prolonged use of oxycodone during pregnancy can result in neonatal opioid withdrawal syndrome. Oxycodone is not recommended for use in women during or immediately prior to labour. Infants born to mothers who have received opioids during pregnancy should be monitored for respiratory depression.
Oxycodone accumulates in human milk, with a median maternal milk:plasma ratio of 3:1 recorded in one study. Oxycodone (7.5 nanogram/mL) was detected in the plasma of one of forty-one infants 72 hours after Caesarean section. Opioids may cause respiratory depression in the newborn and withdrawal symptoms can occur in breastfeeding infants when maternal administration of an opioid analgesic is stopped. Oxycodone-hameln solution for injection or infusion should not be used in breastfeeding mothers unless the benefits outweigh the risks. Breastfed infants should be monitored for respiratory depression, sedation, poor attachment and gastrointestinal signs.4.7 Effects on Ability to Drive and Use Machines
Oxycodone may cause drowsiness and modify patients' reactions to a varying extent depending on the dosage and individual susceptibility. If affected, do not drive or operate machinery.
4.8 Adverse Effects (Undesirable Effects)
Reporting suspected adverse effects.
Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.
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.
Injectable formulation.
In a clinical trial where intravenous oxycodone was delivered via patient-controlled analgesia, 50 of 64 (78%) patients on oxycodone had at least one adverse drug reaction rated treatment-related or not determined. The very common adverse drug reactions included nausea (50%), vomiting (17%) and pruritus (14%), and the more common reactions included headache (6%), constipation (5%) and insomnia (5%). All of the adverse drug reactions were mild or moderate in intensity, except for one report of vomiting and one of nausea which were rated severe. One treatment-related serious adverse event (abdominal pain caused by postoperative constipation) was noted 17 days after intravenous oxycodone was ceased. In two smaller trials, the very common adverse reactions included headache, dizziness and somnolence.
Drowsiness often abates after a few days, and nausea and vomiting after use for a sustained period. Spasms in the bile duct and urinary tract may arise in predisposed individuals. The respiratory depressive effect is dose dependent.
Cardiac disorders.
Common: tachycardia.
Uncommon: palpitations (as part of withdrawal syndrome).
Ear and labyrinth disorders.
Common: vertigo.
Endocrine disorders.
Common: increased ADH release.
Eye disorders.
Common: miosis, visual impairment.
Gastrointestinal disorders.
Very common: nausea, vomiting, constipation.
Common: abdominal pain, diarrhoea, dry mouth, dyspepsia, flatulence, hiccup.
Uncommon: dental caries, dysphagia, eructation, gastrointestinal disorder, ileus.
General disorders and administration site conditions.
Common: asthenia, fatigue, chills, hot/warm, injection site hypersensitivity/pain, oedema, pain, pallor.
Uncommon: malaise, peripheral oedema, thirst.
Not known: drug withdrawal syndrome neonatal, opioid tolerance*, opioid withdrawal syndrome*.
Hepatobiliary disorders.
Uncommon: biliary spasm, cholestasis, hepatic enzyme increased, sphincter of Oddi dysfunction.
Immune system disorders.
Uncommon: anaphylactic reaction, anaphylactoid reaction, hypersensitivity.
Metabolism and nutrition disorders.
Common: decreased appetite.
Uncommon: dehydration.
Nervous system disorders.
Very common: dizziness, drowsiness, headache, somnolence.
Common: hypokinesia, stupor, tremor, lethargy.
Uncommon: amnesia, convulsion, grogginess, hypertonia, hypoaesthesia, muscle contractions involuntary, paraesthesia, speech disorder, syncope, dysgeusia (taste perversion).
Not known: hyperalgesia.
Psychiatric disorders.
Very common: euphoric mood.
Common: anxiety, confusional state, disorientation, insomnia, nervousness, thinking abnormal, depression.
Uncommon: affect lability, agitation, dysphoria, hallucination, libido decreased.
Not known: aggression, drug dependence* (see Section 4.4 Special Warnings and Precautions for Use).
Renal and urinary disorders.
Common: urinary retention.
Uncommon: urinary spasm.
Reproductive system and breast disorders.
Uncommon: amenorrhoea, erectile dysfunction, hypogonadism.
Respiratory, thoracic and mediastinal disorders.
Common: dyspnoea, hyperventilation.
Uncommon: bronchoconstriction, respiratory depression.
Not known: central sleep apnoea syndrome.
Skin and subcutaneous tissue disorders.
Very common: pruritus.
Common: hyperhidrosis, rash.
Uncommon: dry skin, urticaria.
Vascular disorders.
Common: hypotension, vasodilatation.
Uncommon: orthostatic hypotension.
Key: Very common (≥ 1/10); Common (≥ 1/100 to < 1/10); Uncommon (≥ 1/1000 to < 1/100); Rare (≥ 1/10,000 to < 1/1000); Very rare (< 1/10,000); Not known (cannot be estimated from the available data).
*The frequency of drug dependence, opioid tolerance and opioid withdrawal syndrome cannot be estimated from available evidence (e.g. clinical trials, spontaneous reporting, and the medical literature) and therefore is classified as "not known". 'Not known' should not be interpreted as an indication of the rarity of the occurrence of drug dependence, opioid tolerance and opioid withdrawal syndrome, but a reflection of the limitations in the available evidence that do not support a precise estimate of frequency.
Drug dependence.
The frequency in the above table regarding drug dependence reflects the current evidence, including cumulative data from clinical trials and additional post marketing sources, and indicates that the risk of drug dependence with opioids is highly variable depending upon: definition of drug dependence; duration of treatment; dose; individual patient risk factors; and clinical settings. 'Not known' should not be interpreted as an indication of the rarity of the occurrence of drug dependence, but a reflection of the limitations in the available evidence that do not support a precise estimate of frequency.
Repeated use of oxycodone may lead to drug dependence, even at therapeutic doses. The risk of drug dependence may vary depending on a patient's individual risk factors, dosage, and duration of opioid treatment (see Section 4.4 Special Warnings and Precautions for Use).
As an opioid, oxycodone exposes users to the risks of dependence (both physical and psychological), addiction, abuse, and misuse, as well as opioid use disorder and problematic opioid use. Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed oxycodone. Addiction can occur at recommended doses, and if the drug is misused or abused. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g. major depression). The frequency of drug dependence also increases with longer term use or higher doses of oxycodone. (See Section 4.4 Special Warnings and Precautions for Use.)
Opioid tolerance and opioid withdrawal syndrome.
The frequency of in the above table regarding opioid tolerance and opioid withdrawal syndrome reflects the high variability of risk depending upon: definition of tolerance and withdrawal syndrome; dose and duration of treatment; and assessment and monitoring methods (specific to withdrawal syndrome). 'Not known' should not be interpreted as an indication of the rarity of the occurrence of opioid tolerance and opioid withdrawal syndrome, but a reflection of the limitations in the available evidence that do not support a precise estimate of frequency. As an opioid, oxycodone exposes users to the risks of dependence (both physical and psychological), tolerance and withdrawal syndrome. (See Section 4.4 Special Warnings and Precautions for Use.)4.9 Overdose
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).
Symptoms.
Acute overdosage with oxycodone can be manifested by respiratory depression (reduced respiratory rate and/or tidal volume, cyanosis), extreme somnolence progressing to stupor or coma, hypotonia, miosis (dilated if hypoxia is severe), cold and/or clammy skin, and sometimes bradycardia, hypoglycemia, hypotension, pulmonary oedema, and death. Severe overdose may result in apnoea, pulmonary oedema, circulatory collapse and death. Toxic leukoencephalopathy has been observed with oxycodone overdose.
Treatment of oxycodone overdosage.
Primary attention should be given to immediate supportive therapy with the establishment of adequate respiratory exchange through the provision of a patent airway and institution of assisted or controlled ventilation. Adequate body temperature and fluid balance should be maintained. Oxygen, intravenous fluids, vasopressors and other supportive measures should be used as indicated, to manage the circulatory shock accompanying an overdose. Cardiac arrest or arrhythmias may require cardiac massage or defibrillation.
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. The patient should be under continued surveillance and doses of the antagonist should be repeated as needed to maintain adequate respiration.
For massive overdosage, associated with clinically significant respiratory or cardiovascular depression, 0.8 mg naloxone may be administered intravenously, repeating at 2-3 minute intervals as necessary, or by a titrated infusion of 2 mg in 500 mL of normal saline or 5% glucose (0.004 mg/mL). The infusion should be run at a rate related to 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. Monitoring for a further 24-48 hours is then recommended in case of possible relapse. Please see naloxone hydrochloride injection Product Information for further information.
In an individual physically dependent on, or tolerant to 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.
Toxicity.
Oxycodone toxicity may result from overdosage, but because of the great inter-individual variation in sensitivity to opioids, it is difficult to determine an exact dose of any opioid that is toxic or lethal. The toxic effects and signs of overdosage may be less pronounced than expected when pain and/or tolerance are manifest.5 Pharmacological Properties
5.1 Pharmacodynamic Properties
Mechanism of action.
Oxycodone is a full opioid agonist with no antagonist properties, whose principal therapeutic action is analgesia. It has 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).
Clinical trials.
Oxycodone solution for injection or infusion 10 mg in 1 mL.
A randomised, double-blind, parallel group study was performed to compare the tolerability, safety and efficacy of IV oxycodone with IV morphine in patients using patient-controlled analgesia (PCA) for acute postoperative pain. The intention to treat and safety populations included 133 patients (64 oxycodone, 69 morphine); 117 patients completed, 56 on oxycodone and 61 on morphine. Oxycodone 10 mg/mL or morphine solution for injection was diluted to 1 mg/mL with 0.9% saline, and 2 mg IV bolus doses were used during stabilisation. The PCA machine delivered bolus doses of 1 mg on demand, with a 5 minute lockout. The treatment duration was intended to be 24-72 hours.
The primary efficacy endpoint of the intensity of pain on movement or deep breathing at 24 hours post-operatively, using the BS-11 pain scores was 4.6 ± 2.6 for oxycodone and 4.1 ± 2.0 for morphine with a pain intensity difference of 0.55 (95% CI: -0.37 to 1.48). The 95% CI for the treatment difference was within the established equivalence limits (-1.5 to 1.5). See Table 1.
There was no significant difference in the median drug use, which was 69.0 mg (12-336 mg) for oxycodone and 54.0 mg (7-212 mg) for morphine in the PP population, and similar in the ITT population. The common adverse drug reactions were all known opioid side-effects, but respiratory depression was uncommon. Further details are provided under Adverse Effects (Undesirable Effects).
5.2 Pharmacokinetic Properties
Absorption.
The Tmax for subcutaneous administration was 0.25-0.5 hours. Considerable inter-individual variability was seen in pharmacokinetic studies.
Pharmacokinetic studies with oxycodone solution for injection or infusion in healthy subjects demonstrated an equivalent availability of oxycodone by intravenous (IV) and subcutaneous (SC) routes, when+ administered as a single bolus dose or continuous infusion over 8 hours.
Following absorption, oxycodone is distributed throughout the entire body. As expected, the Cmax for subcutaneous bolus was lower than for intravenous administration.
Distribution.
Approximately 45% is bound to plasma proteins.
Metabolism.
Oxymorphone has some analgesic activity but is present in plasma in low concentrations and is not considered to contribute to oxycodone's pharmacological effect.
Oxycodone hydrochloride is metabolised in the liver to form noroxycodone, oxymorphone, noroxymorphone, 6 α and β oxycodol and conjugated glucuronides. CYP3A4 and CYP2D6 are involved in the formation of noroxycodone and oxymorphone, respectively (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). The contribution of these metabolites to the analgesic effect is insignificant.
CYP2D6 is expressed as two phenotypes, extensive and poor metabolisers. Poor metabolisers, constituting about 5-10% of the White population, may have increased plasma concentrations of oxycodone because of the decreased oxidation by CYP2D6 and therefore a lower dosage may be needed. (See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.)
Excretion.
Oxycodone has an elimination half-life of between 3 - 5 hours, or approximately 4.5 hour. The plasma concentrations are only minimally affected by age, being 15% greater in the elderly compared with young subjects.
Patients with mild to severe hepatic or renal dysfunction may have an increase in elimination half-life compared with normal subjects, and therefore, may have higher plasma concentrations of oxycodone and noroxycodone, and lower concentrations of oxymorphone compared with normal subjects. This may be accompanied by an increase in drug effects. Considerable inter-individual variability may be seen in these patients.
5.3 Preclinical Safety Data
Genotoxicity.
Oxycodone was not genotoxic in bacterial gene mutation assays, but was positive in the mouse lymphoma assay. In assays of chromosomal damage, genotoxic effects occurred in the human lymphocyte chromosomal assay in vitro, but not in the in vivo bone marrow micronucleus assay in mice.
Carcinogenicity.
Carcinogenicity was evaluated in a 2-year oral gavage study conducted in Sprague-Dawley rats. Oxycodone did not increase the incidence of tumours in male and female rats at doses up to 6 mg/kg/day (equivalent to 6.8 mg/day in men and 24.6 mg/day in women, based on estimated AUC values). The doses were limited by opioid-related pharmacological effects of oxycodone.6 Pharmaceutical Particulars
6.1 List of Excipients
Oxycodone-hameln injection includes the following excipients: citric acid monohydrate, sodium citrate dihydrate, sodium chloride, hydrochloric acid, sodium hydroxide and water for injections.
6.2 Incompatibilities
Oxycodone-hameln solution for injection or infusion is formulated at acidic pH and is likely to be incompatible with alkaline pH formulations such as fluorouracil (5-FU) which may lead to precipitation. In addition, Oxycodone-hameln solution for injection or infusion has been shown to be chemically incompatible with prochlorperazine.
It is recommended that Oxycodone-hameln solution for injection or infusion should not be administered in combination with other parenteral formulations unless there is compatibility data to support the combination.
6.3 Shelf Life
In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.
6.4 Special Precautions for Storage
Store below 30°C and protect from light.
Instructions for storage and handling.
The solution for injection or infusion should be given immediately after opening the ampoule. The diluted solution should be used immediately after dilution. Once opened, any unused portion should be discarded. Inappropriate handling of the undiluted solution after opening of the original ampoule, or of the diluted solutions may compromise the sterility of the product. Oxycodone-hameln solution for injection or infusion is for single use in one patient only.
6.5 Nature and Contents of Container
Clear glass ampoules containing the following strengths of oxycodone hydrochloride:
10 mg in 1 mL and 20 mg in 2 mL in packs of 5 and 10 ampoules;
50 mg in 1 mL in packs of 5 and 10 ampoules.
Not all presentations may be marketed.
6.6 Special Precautions for Disposal
In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.
6.7 Physicochemical Properties
Chemical structure.
CAS number.
124-90-3.7 Medicine Schedule (Poisons Standard)
Schedule 8 - Controlled Drug.
Summary Table of Changes
