4.1. Therapeutic indications

For the treatment of moderate to severe pain in patients with cancer and post-operative pain. For the treatment of severe pain requiring the use of a strong opioid.

4.2. Posology and method of administration

Route of administration:

Subcutaneous injection or infusion.

Intravenous injection or infusion.

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:

The following starting doses are recommended. A gradual increase in dose may be required if analgesia is inadequate or if pain severity increases.

i.v. (Bolus): Where necessary dilute to 1 mg/ml in 0.9% saline, 5% dextrose or water for injections. Administer a bolus dose of 1 to 10 mg slowly over one to two minutes.

Doses should not be administered more frequently than every four hours.

i.v. (Infusion): Dilute to 1 mg/ml in 0.9% saline, 5% dextrose or water for injections. A starting dose of 2 mg/hour is recommended.

i.v. (PCA): Dilute to 1 mg/ml in 0.9% saline, 5% dextrose or water for injections. Bolus doses of 0.03 mg/kg should be administered with a minimum lock-out time of five minutes.

s.c. (Bolus): Where necessary dilute to 10 mg/ml concentration using 0.9% saline, 5% dextrose or water for injection. A starting dose of 5 mg is recommended, repeated at four-hourly intervals as required.

s.c. (Infusion): Dilute to 1 mg/ml in 0.9% saline, 5% dextrose or water for injections if required. A starting dose of 7.5 mg/day is recommended in opioid naïve patients, titrating gradually according to symptom control. Cancer patients transferring from oral oxycodone may require much higher doses (see below).

Transferring patients between oral and parenteral oxycodone:

The dose should be based on the following ratio: 2 mg of oral oxycodone is equivalent to 1 mg of parenteral oxycodone. It must be emphasised that this is a guide to the dose required. Inter-patient variability requires that each patient is carefully titrated to the appropriate dose.

Conversion from morphine:

Patients switching from parenteral morphine to parenteral oxycodone therapy should do so on the basis of a one to one dose ratio. It must be emphasised that this is a guide to the dose of Oxycodone injection required. Inter-patient variability requires that each patient is carefully titrated to the appropriate dose.

Elderly:

Elderly patients should be treated with caution. The lowest dose should be administered with careful titration to pain control.

Patients with renal and hepatic impairment:

The dose initiation should follow a conservative approach in these patients. The recommended adult starting dose should be reduced by 50% (for example a total daily dose of 10mg orally in opioid naïve patients), and each patient should be titrated to adequate pain control according to their clinical situation.

Children under 18 years:

There are no data on the use of Oxycodone injection in patients under 18 years of age.

Use in non-malignant pain:

Opioids are not first-line therapy for chronic non-malignant pain, nor are they recommended as the only treatment. Types of chronic pain which have been shown to be alleviated by strong opioids include chronic osteoarthritic pain and intervertebral disc disease.

Method of administration

Subcutaneous injection or infusion

Intravenous injection or infusion

Treatment goals and discontinuation

Before initiating treatment with Oxycodone Injection, 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).

Duration of treatment

Oxycodone should not be used for longer than necessary.

4.3. Contraindications

Hypersensitivity to oxycodone or to any of the excipients listed in section 6.1.

Oxycodone must not be used in any situation where opioids are contraindicated:

• severe respiratory depression with hypoxia

• paralytic ileus

• acute abdomen

• severe chronic obstructive lung disease

• cor pulmonale

• severe bronchial asthma

• elevated carbon dioxide levels in the blood

• chronic constipation

4.4. Special warnings and precautions for use

Caution must be exercised when administering oxycodone to the debilitated elderly; patients with severely impaired pulmonary function, patients with impaired hepatic or renal function; patients with myxoedema, hypothyroidism, Addison's disease, toxic psychosis, prostate hypertrophy, adrenocortical insufficiency, alcoholism, delirium tremens, diseases of the biliary tract, pancreatitis, inflammatory bowel disorders, hypotension, hypovolaemia, raised intracranial pressure, head injury (due to risk of increased intracranial pressure) or patients taking benzodiazepines, other CNS depressants (including alcohol) or MAO inhibitors (see section 4.5).

The primary risk of opioid excess is respiratory depression.

Concomitant use of oxycodone and sedative medicines such as benzodiazepines or related drugs may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing with these sedative medicines should be reserved for patients for whom alternative treatment options are not possible.

If a decision is made to prescribe oxycodone concomitantly with sedative medicines, the lowest effective dose should be used, and the duration of treatment should be as short as possible (see also general dose recommendation in section 4.2).

The patients should be followed closely for signs and symptoms of respiratory depression and sedation. In this respect, it is strongly recommended to inform patients and their caregivers to be aware of these symptoms (see section 4.5).

Oxycodone injection must be administered with caution in patients taking MAOIs or who have received MAOIs within the previous two weeks (see section 4.5).

Oxycodone injection should not be used where there is a possibility of paralytic ileus occurring. Should paralytic ileus be suspected or occur during use, Oxycodone injection should be discontinued immediately.

Oxycodone injection should be used with caution pre- or intra-operatively and within the first 12-24 hours post-operatively.

As with all opioid preparations, oxycodone products 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.

For appropriate patients who suffer with chronic non-malignant pain, opioids should be used as part of a comprehensive treatment programme involving other medications and treatment modalities. A crucial part of the assessment of a patient with chronic non-malignant pain is the patient's addiction and substance abuse history.

If opioid treatment is considered appropriate for the patient, then the main aim of treatment is not to minimise the dose of opioid but rather to achieve a dose which provides adequate pain relief with a minimum of side effects.See section 4.2 for additional information on treatment goals and discontinuation.

Tolerance, Dependence and Opioid Use Disorder

Tolerance and physical and/or psychological dependence may develop upon repeated administration of opioids such as oxycodone.

Repeated use of Oxycodone may 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 a 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). 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). The prescriber should conduct a 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.

The patient may develop tolerance to the drug with chronic use and require progressively higher doses to maintain pain control. A withdrawal syndrome may occur upon abrupt cessation of therapy following prolonged use of this product. When a patient no longer requires therapy with oxycodone, it may be advisable to taper the dose gradually to prevent symptoms of withdrawal.

The opioid abstinence or withdrawal syndrome is characterised by some or all of the following: restlessness, lacrimation, rhinorrhoea, yawning, perspiration, chills, myalgia, mydriasis and palpitations. Other symptoms also may develop, including: irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhoea, or increased blood pressure, respiratory rate or heart rate.

Hyperalgesia that will not respond to a further dose increase of oxycodone may occur, particularly in high doses. An oxycodone dose reduction or change to an alternative opioid may be required.

As with other opioids, infants who are born to dependent mothers may exhibit withdrawal symptoms and may have respiratory depression at birth.

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

Oxycodone injection contains approximately 3mg sodium per ml i.e. essentially 'sodium-free'.

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.

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 central sleep apnoea (see section 4.8).

Hepatobiliary disorders

Oxycodone may cause dysfunction and spasm of the sphincter of Oddi, thus 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.

4.5. Interaction with other medicinal products and other forms of interaction

The concomitant use of opioids with sedative medicines such as benzodiazepines or related drugs increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. The dosage and duration of concomitant use should be limited (see section 4.4).

Drugs which affect the CNS include, but are not limited to: other opioids, gabapentinoids such as pregabalin, anxiolytics, hypnotics and sedatives (including benzodiazepines), antipsychotics, antidepressants, phenothiazines, anaesthetics, muscle relaxants, antihypertensives and alcohol. Oxycodone should be used with caution and the dosage may need to be reduced in patients using these medications.

Concomitant 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.

Concomitant administration of oxycodone with anticholinergics or medicines with anticholinergic activity (e.g. tricyclic anti-depressants, antihistamines, antipsychotics, muscle relaxants, anti-Parkinson drugs) may result in increased anticholinergic adverse effects. Oxycodone should be used with caution and the dosage may need to be reduced in patients using these medications.

MAO inhibitors are known to interact with narcotic analgesics. MAO inhibitors cause CNS excitation or depression associated with hypertensive or hypotensive crisis (see section 4.4). Oxycodone should be used with caution in patients administered MAO-inhibitors or who have received MAO inhibitors during the last two weeks (see section 4.4).

Alcohol may enhance the pharmacodynamic effects of Oxycodone, concomitant use should be avoided.

Oxycodone is metabolised mainly by CYP3A4, with a contribution from CYP2D6. The activities of these metabolic pathways may be inhibited or induced by various co-administered drugs or dietary elements. Oxycodone doses may need to be adjusted accordingly.

CYP3A4 inhibitors, such as macrolide antibiotics (e.g. clarithromycin, erythromycin and telithromycin), azole-antifungals (e.g. ketoconazole, voriconazole, itraconazole, and posaconazole), protease inhibitors (e.g. boceprevir, ritonavir, indinavir, nelfinavir and saquinavir), cimetidine and grapefruit juice may cause a reduced clearance of oxycodone that could cause an increase of the plasma concentrations of oxycodone. Therefore the oxycodone dose may need to be adjusted accordingly.

Some specific examples are provided below:

• Itraconazole, a potent CYP3A4 inhibitor, administered 200 mg orally for five days, increased the AUC of oral oxycodone. On average, the AUC was approximately 2.4 times higher (range 1.5 - 3.4).

• Voriconazole, a CYP3A4 inhibitor, administered 200 mg twice-daily for four days (400 mg given as first two doses), increased the AUC of oral oxycodone. On average, the AUC was approximately 3.6 times higher (range 2.7 - 5.6).

• Telithromycin, a CYP3A4 inhibitor, administered 800 mg orally for four days, increased the AUC of oral oxycodone. On average, the AUC was approximately 1.8 times higher (range 1.3 – 2.3).

• Grapefruit Juice, a CYP3A4 inhibitor, administered as 200 ml three times a day for five days, increased the AUC of oral oxycodone. On average, the AUC was approximately 1.7 times higher (range 1.1 – 2.1).

CYP3A4 inducers, such as rifampicin, carbamazepine, phenytoin and St John´s Wort may induce the metabolism of oxycodone and cause an increased clearance of oxycodone that could cause a reduction of the plasma concentrations of oxycodone. The oxycodone dose may need to be adjusted accordingly.

Some specific examples are provided below:

• St Johns Wort, a CYP3A4 inducer, administered as 300 mg three times a day for fifteen days, reduced the AUC of oral oxycodone. On average, the AUC was approximately 50% lower (range 37-57%).

• Rifampicin, a CYP3A4 inducer, administered as 600 mg once-daily for seven days, reduced the AUC of oral oxycodone. On average, the AUC was approximately 86% lower

Drugs that inhibit CYP2D6 activity, such as paroxetine and quinidine, may cause decreased clearance of oxycodone which could lead to an increase in oxycodone plasma concentrations.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are limited data from the use of oxycodone in pregnant women. Regular use in pregnancy may cause drug dependence in the foetus, leading to withdrawal symptoms in the neonate. If opioid use is required for a prolonged period in pregnant women, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

No studies on fertility or the post-natal effects of intrauterine exposure have been carried out. However, studies in rats and rabbits with oral doses of oxycodone equivalent to 3 and 47 times an adult dose of 160 mg/day, respectively, did not reveal evidence of harm to the foetus due to oxycodone. Oxycodone injection is not recommended for use in pregnancy nor during labour.

Breastfeeding

Oxycodone may be secreted in breast milk and may cause respiratory depression in the newborn. Oxycodone should therefore not be used in breast-feeding mothers.

Fertility

No human data on the effect of oxycodone on fertility are available. In rats there was no effect on mating or fertility with oxycodone treatment (see section 5.3).

4.7. Effects on ability to drive and use machines

Oxycodone may impair the ability to drive and use machines. Oxycodone may modify patients' reactions to a varying extent depending on the dosage and individual susceptibility. Therefore patients should not drive or operate machinery, if affected.

This medicine can impair cognitive function and can affect a patient's ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:

• The medicine is likely to affect your ability to drive

• Do not drive until you know how the medicine affects you

• It is an offence to drive while you have this medicine in your body over a specified limit unless you have a defence (called the 'statutory defence').

• This defence applies when:

o The medicine has been prescribed to treat a medical or dental problem; and

o You have used it according to the instructions given by the prescriber and in the information provided with the medicine and

• Please note it is still an offence to drive if you are unfit because of the medicine (i.e. your ability to drive is being affected).

Details regarding a new driving offence concerning driving after drugs have been taken in the UK may be found here: https://www.gov.uk/drug-driving-law

4.8. Undesirable effects

Adverse drug reactions are typical of full opioid agonists. Tolerance and dependence may occur (see section 4.4). Constipation may be prevented with an appropriate laxative. If nausea or vomiting are troublesome, oxycodone may be combined with an antiemetic.

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

Term

Frequency

Very common

≥ 1/10

Common

≥ 1/100 to <1/10

Uncommon

≥ 1/1,000 to <1/100

Rare

≥1/10,000 to <1/1,000

Very rare

<1/10,000

Frequency not known

Cannot be estimated from the available data

Immune system disorders:

Uncommon: hypersensitivity.

Frequency not known: anaphylactic reaction, anaphylactoid reaction.

Metabolism and nutrition disorders:

Common: decreased appetite.

Uncommon: dehydration.

Psychiatric disorders:

Common: anxiety, confusional state, depression, insomnia, nervousness, abnormal thinking, abnormal dreams

Uncommon: agitation, affect lability, euphoric mood, hallucinations, decreased libido, drug dependence (see section 4.4), disorientation, mood altered, restlessness, dysphoria

Frequency not known: aggression.

Nervous system disorders:

Very common: somnolence, dizziness, headache.

Common: tremor, lethargy, sedation.

Uncommon: amnesia, convulsion, hypertonia, hypoaesthesia, involuntary muscle contractions, speech disorder, syncope, paraesthesia, dysgeusia, hypotonia.

Frequency not known: hyperalgesia.

Eye disorders:

Uncommon: visual impairment, miosis.

Ear and labyrinth disorders:

Uncommon: vertigo.

Cardiac disorders:

Uncommon: palpitations (in the context of withdrawal syndrome), supraventricular tachycardia.

Vascular disorders:

Uncommon: vasodilatation, facial flushing.

Rare: hypotension, orthostatic hypotension.

Respiratory, thoracic and mediastinal disorders:

Common: dyspnoea, bronchospasm, cough decreased.

Uncommon: respiratory depression, hiccups.

Frequency not known: Central sleep apnoea syndrome.

Gastrointestinal disorders:

Very common: constipation, nausea, vomiting.

Common: abdominal pain, diarrhoea, dry mouth, dyspepsia.

Uncommon: dysphagia, flatulence, eructation, ileus, gastritis.

Frequency not known: dental caries.

Hepato-biliary disorders:

Uncommon: increased hepatic enzymes, biliary colic.

Frequency not known: cholestasis, sphincter of Oddi dysfunction

Skin and subcutaneous tissue disorders:

Very common: pruritus.

Common: rash, hyperhidrosis.

Uncommon: dry skin, exfoliative dermatitis.

Rare: urticaria.

Renal and urinary disorders:

Uncommon: urinary retention, ureteral spasm.

Reproductive system and breast disorders:

Uncommon: erectile dysfunction, hypogonadism.

Frequency not known: amenorrhoea.

General disorders and administration site conditions:

Common: asthenia, fatigue.

Uncommon: syndrome, malaise, oedema, peripheral oedema, , thirst, pyrexia, chills.

Frequency not known: drug withdrawal syndrome neonatal, opioid tolerance, opioid withdrawal syndrome.

Opioid Tolerance and Opioid Withdrawal Syndrome

The frequency of opioid tolerance and the frequency of 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” (see section 4.8). '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.

Description of selected adverse reactions

Drug dependence

The frequency above 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 occurrence of drug dependence, but a reflection of the limitations in available evidence that do not support a precise estimate of frequency.

Repeated use of Oxycodone can 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).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Symptoms of overdosage

Acute overdose with oxycodone can be manifested by miosis, respiratory depression, hypotension and hallucinations. Nausea and vomiting are common in less severe cases. Non-cardiac pulmonary oedema and rhabdomyolysis are particularly common after intravenous injection of opioid analgesics. Circulatory failure and somnolence progressing to stupor or coma, hypotonia, bradycardia, pulmonary oedema and death may occur in more severe cases. Toxic leukoencephalopathy has been observed with oxycodone overdose.

The effects of overdosage will be potentiated by the simultaneous ingestion of alcohol or other psychotropic drugs

Treatment of overdosage

Primary attention should be given to the establishment of a patent airway and institution of assisted or controlled ventilation. The pure opioid antagonists such as naloxone are specific antidotes against symptoms from opioid overdose. Other supportive measures should be employed as needed.

In the case of massive overdosage, administer naloxone intravenously (0.4 to 2mg for an adult and 0.01mg/kg body weight for children) if the patient is in a coma or respiratory depression is present. Repeat the dose at 2 minute intervals if there is no response. If repeated doses are required then an infusion of 60% of the initial dose per hour is a useful starting point. A solution of 10 mg made up in 50 ml dextrose will produce 200 micrograms/ml for infusion using an IV pump (dose adjusted to the clinical response). Infusions are not a substitute for frequent review of the patient's clinical state.

Intramuscular naloxone is an alternative in the event that IV access is not possible. As the duration of action of naloxone is relatively short, the patient must be carefully monitored until spontaneous respiration is reliably re-established. Naloxone is a competitive antagonist and large doses (4 mg) may be required in seriously poisoned patients.

For less severe overdosage, administer naloxone 0.2 mg intravenously followed by increments of 0.1 mg every 2 minutes if required.

The patient should be observed for at least 6 hours after the last dose of naloxone.

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.