SUMMARY OF PRODUCT CHARACTERISTICS. 1 ml of solution for injection/infusion includes 10 mg of oxycodone hydrochloride equivalent to 9 mg of oxycodone.

Transcription

1 SUMMARY OF PRODUCT CHARACTERISTICS 1. NAME OF THE MEDICINAL PRODUCT Oxycodone Orion 10 mg/ml solution for injection/infusion 2. QUALITATIVE AND QUANTITATIVE COMPOSITION 1 ml of solution for injection/infusion includes 10 mg of oxycodone hydrochloride equivalent to 9 mg of oxycodone. Excipient with known effect: sodium For the full list of excipients, see section PHARMACEUTICAL FORM Solution for injection/infusion Clear, colourless solution. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Severe pain, which can be adequately managed only with opioid analgesics. 4.2 Posology and method of administration Posology The dose should be adjusted according to the severity of pain, the general condition of the patient and previous or concomitant 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 worsens. Intravenous (Bolus): Dilute to concentration 1 mg/ml in 9 mg/ml (0.9%) saline, 50 mg/ml (5%) glucose or water for injections. Administer a bolus dose of 1 to 10 mg slowly for 1-2 minutes. The doses should not be administered more often than every 4 hour. Intravenous (Infusion): Dilute to 1 mg/ml in 9 mg/ml (0.9%) saline, 50 mg/ml (5%) glucose or water for injections. A starting dose of 2 mg/h is recommended. Intravenous (PCA (Patient controlled analgesia)): Dilute to 1 mg/ml in 9 mg/ml (0.9%) saline, 50 mg/ml (5%) glucose or water for injections. Bolus doses of 0.03 mg/kg should be administered with a minimum lock-out time of 5 minutes. Subcutaneous (bolus): Use as 10 mg/ml concentration. Starting dose of 5 mg repeated every 4 hour when needed is recommended.

2 Subcutaneous (infusion): When required dilute to 1 mg/ml in 9 mg/ml (0.9%) saline, 50 mg/ml (5%) glucose or water for injections. A starting dose of 7.5 mg is recommended in opioid naïve patients and the dose can be increased gradually according to the control of symptoms. Cancer patients transferring from oral oxycodone may require higher doses, see below. Intramuscular (bolus): Use as 10 mg/ml concentration. Bolus dose of 5 10 mg ( mg/kg) is administered intramuscularly at 3 4 hours intervals. If bolus doses are needed often, intravenous infusion or pain control infusion pump should be considered. Subcutaneous bolus injection or infusion or intramuscular bolus injection should be used as an alternative method of administration, when oral administration or intravenous administration is not possible. Switch 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 only a guide to determine the dose. Due to inter-patient variability dose should be determined individually. Switch between parenteral morphine and oxycodone: The dose should be based on the following ratio: 1 mg of parenteral morphine is equivalent to 1 mg of parenteral oxycodone. It must be emphasised that this is only a guide to determine the dose. Due to inter-patient variability dose should be determined individually. Oxycodone Orion solution for injection/infusion can be used with food and drink. For the use of alcohol during treatment, see section 4.5. Special populations Elderly patients Elderly patients should be treated with caution. The lowest dose should be administered with careful titration to pain control. Patients with renal or hepatic impairment Patients with mild hepatic and/or renal impairment should be treated with caution. The dose initiation should follow a conservative approach. The recommended adult starting dose should be reduced by 50% and each patient should be titrated to adequate pain control according to their clinical situation. Oxycodone Orion solution for injection/infusion is not recommended in patients with moderate to severe renal and/or hepatic impairment, unless the clinical need for analgesia outweighs the potential risks. Paediatric population The safety and efficacy of oxycodone in children under 18 years has not been established. No data are available. Method of administration Subcutaneous injection or infusion. Intravenous injection or infusion. Intramuscular injection. For instructions on dilution of the medicinal product before administration, see section 6.6. Duration of treatment Oxycodone should not be used for longer than necessary. Discontinuation of treatment

3 When a patient no longer requires therapy with oxycodone, it may be advisable to taper the dose gradually to prevent symptoms of withdrawal. 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 Secretion stagnation Severe respiratory depression with hypoxia Convulsions Coma Acute abdominal pain Severe hepatic impairment Anxiety during influence of alcohol or sedatives Paralytic ileus Hypercarbia Cor pulmonale Severe bronchial asthma Severe chronic obstructive lung disease. 4.4 Special warnings and precautions for use Addictive medicine. Observe highest precaution when prescribing this medicine. The major risk of opioid excess is respiratory depression. Caution must be exercised when administering oxycodone to the debilitated elderly; patients with severely impaired pulmonary function, impaired hepatic or renal function; patients with myxedema, hypothyroidism, Addison s disease, toxic psychosis, prostate hypertrophy, adrenocortical insufficiency, alcoholism, delirium tremens, diseases of the biliary tract, gallbladder or ureteric spasm, pancreatitis, inflammatory bowel, hypotension, hypovolaemia, head injury (due to risk of increased intracranial pressure) or patients taking MAO inhibitors. 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. The treatment should be stopped immediately in case of suspected ileus when using Oxycodone Orion 10 mg/ml solution for injection/infusion. Oxycodone should not be used in idiopathic or psychopathological pain conditions. The medicinal product can suppress the cough reflex. The patient may develop tolerance to the drug with chronic use and require progressively higher doses to maintain pain control. Prolonged use of this product may lead to physical dependence and a withdrawal syndrome may occur upon abrupt cessation of therapy. When a patient no longer requires therapy with oxycodone, it may be advisable to taper the dose gradually to prevent symptoms of withdrawal. Withdrawal symptoms may include yawning, mydriasis, lacrimation, rhinorrhoea, tremor, hyperhidrosis, anxiety, agitation, convulsions and insomnia. Abrupt withdrawal of treatment can cause withdrawal symptoms such as restlessness, runny eyes and nose, sweats and broken sleep within 24 hours. The symptoms may aggravate during the following 3 days. As with all opioids, development of tolerance to Oxycodone Orion cannot be excluded. In practice it has proved that development of tolerance only rarely is a problem in treatment of severe pain.

4 Hyperalgesia that will not respond to a further dose increase of oxycodone may very rarely occur, particularly in high doses. An oxycodone dose reduction or change to an alternative opioid may be required. Oxycodone Orion has an abuse profile corresponding to that of other strong opioids. As with other opioids Oxycodone Orion may be sought and abused by people with hidden or open dependence. The medicinal product should therefore be used with particular care in patients with a history of alcohol or substance abuse. Abuse of oral formulations for parenteral administration is expected to cause serious potentially lethal adverse reactions. Concomitant use of alcohol and Oxycodone Orion may increase the undesirable effects of Oxycodone Orion; concomitant use should be avoided. Oxycodone Orion should be used with caution pre- or intra-operatively and within the first hours post-operatively. Oxycodone Orion contains less than 1 mmol (23 mg) sodium per dose, i.e. essentially sodium- free. 4.5 Interaction with other medicinal products and other forms of interaction Other active substances, which have an effect on CNS (for instance other opioids, tranquillisers, hypnotics, antidepressants, sedatives, phenothiazines and neuroleptics) enhance the CNS depressant effect of oxycodone. Alcohol may enhance the pharmacodynamic effects of Oxycodone Orion, concomitant use should be avoided. Anticholinergics (e.g neuroleptics, antihistamines, antiemetics, antiparkinson drugs) can enhance the anticholinergic effects of oxycodone (such as constipation, dry mouth or micturition ). MAO inhibitors are known to interact with narcotic analgesics, producing CNS excitation or depression with hyper- or hypotensive crisis. Oxycodone Orion should be used with caution if the patient uses or has used monoamine oxidase (MAO) inhibitors during the last two weeks (see section 4.4). 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. CYP3A4 inhibitors, such as macrolide antibiotics (e.g. clarithromycin, erythromycin and telithromycin), azol-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 ). 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 ).

5 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 ). 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 ). CYP3A4 inducers, such as rifampicin, carbamazepin, 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. Clinically relevant changes in International Normalized Ratio (INR) in both directions have been observed in individuals if coumarin anticoagulants are co-applied with oxycodone. There are no studies investigating the effect of oxycodone on CYP catalysed metabolism of other drugs. 4.6 Fertility, pregnancy and lactation Use of this medicinal product should be avoided to the extent possible in patients who are pregnant or lactating. Pregnancy There are limited data from the use of oxycodone in pregnant women. Oxycodone crosses the placenta. Withdrawal symptoms may be observed in the newborn of mothers undergoing treatment with oxycodone. Infants born to mothers who have received opioids during the last 3 to 4 weeks before giving birth should be monitored for respiratory depression. Animal studies with oxycodone have not revealed any teratogenic or embryotoxic effects. Oxycodone should only be used during pregnancy if the benefit outweighs the possible risks to the unborn child or neonate. Breastfeeding Oxycodone may be secreted in breast milk and may cause respiratory depression in the newborn. Oxycodone should, therefore, not be used in breastfeeding mothers. Fertility There is no data available on fertility. 4.7 Effects on ability to drive and use machines Oxycodone Orion has influence on the ability to drive and use machines. It weakens the patients reactions especially at the beginning of the treatment and when dose is increased.

6 4.8 Undesirable effects The most common undesirable effects are constipation and nausea, which both occur in 25% 30% of the patients, given oxycodone orally. If nausea or vomiting is troublesome, oxycodone may be combined with antiemetic. As when using any other strong opioid, patients will most probably experience constipation, which can be treated with an appropriate laxative. If the undesirable effects concerning the use of opioids will be prolonged, patient has to be examined to exclude alternative reasons. Undesirable effects caused by pure opioid agonists (excluding constipation) abate normally, when the treatment is continued. Compliance can be improved by predicting undesirable effects and by adequate treatment. As with other opioids, the most serious undesirable effect is respiratory depression (see section 4.9). It occurs most commonly in elderly and infirm patients and in patients, who do not tolerate opioids. Dependence and tolerance will usually not cause problems, when the product is used in the treatment of severe pain. The following undesirable effects are possible. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Very common ( 1/10) Common ( 1/100 to <1/10) Uncommon ( 1/1,000 to <1/100) Rare ( 1/10,000 to <1/1,000) Very rare (<1/10,000) Not known (cannot be estimated from the available data) Immune system Metabolism and nutrition Psychiatric Nervous system Very common Common Uncommon Rare Very rare Hypersensitivity Allergic reaction, anafylactoid reaction, anaphylactic reaction Decreased Dehydration appetite Dizziness, somnolence, headache Anxiety, confusional state, nervousness, depression, abnormal thinking, insomnia Tremor Agitation, hallucinations, amnesia, affect lability, euphoria, drug dependence (see section 4.4) Convulsions, involuntary muscle contractions, hypertonia, hypoaesthesia, paraesthesia, speech disorder, Not known Aggression Hyperalgesia

7 Eye Cardiac Vascular Respiratory, thoracic and mediastinal Gastrointestinal Hepatobiliary Skin and subcutaneous tissue Renal and urinary Reproductive system and breast General and administration site conditions Very common Common Uncommon Rare Very rare syncope, vertigo Visual impairment, miosis Palpitations (in the context of withdrawal syndrome) Orthostatic Vasodilation, hypotension hypotension Dyspnoea Respiratory depression, bronchospasms Constipation, nausea, vomiting Pruritus Abdominal pain, anorexia, diarrhea, dyspepsia, dry mouth Rash, hyperhidrosis Oedema, faintness, sweating, chill, asthenic conditions Change in sense of taste, gastrointestinal disorder, flatulence, dysphagia, ileus, eructation Biliary colic, increased hepatic enzymes Urticaria, dryness of the skin Anuria, urethral spasm, urinary retention Amenorrhea, decreased libido, impotence Oedema peripheral, thirst, drug withdrawal syndrome, malaise, drug tolerance Not known Dental caries Cholestasis 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 national reporting system listed in Appendix V. 4.9 Overdose Acute overdose with oxycodone can be manifested by respiratory depression, somnolence progressing to stupor or coma, hypotonia, miosis, bradycardia, hypotension, and death.

8 Treatment of overdose Primary attention should be given to ensure a patent airway and to institute assisted or controlled ventilation to the patient. Ventilation and circulation should be maintained and assisted. In severe cases it should be considered to administer 0.8 mg naloxone intravenously. Dose is repeated at 2 3 minutes intervals. An infusion including 2 mg of naloxone in 500 ml saline or 50 mg/ml (5%) glucose (0.004 mg/ml) can also be administered to a patient. Infusion rate should be in relationship with earlier administered bolus doses, and it should be determined according to patient s response. The rate of the effect for naloxone is 1 2 minutes when administered intravenously, 2 5 minutes when administered subcutaneously or intramuscularly. The duration of action is depending on the dose and method of administration, being longer after intramuscular than intravenous administration. In adults the reported T 1/2 is minutes. Because the duration of action for naloxone is however comparatively short, the patient must be carefully monitored, until spontaneous respiration is reliably re-established. After this it is recommended to continue monitoring for hours because of possible recurrence. In case of a minor overdose administer 0.2 mg naloxone intravenously followed by 0.1 mg at a time every 2 minutes if required. Naloxone should not be administered if patient does not have a clinically significant respiratory or circulation depression caused by an overdose of oxycodone. 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. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: natural opium alkaloids, ATC code: N02AA05 Oxycodone is a full opioid agonist with no antagonist properties. The action of oxycodone is apparently mediated mainly by mu opioid reseptors, but the active substance has also been shown to have an affinity for delta and kappa opioid receptors. Oxycodone is similar to morphine in its action. The therapeutic effect is mainly analgesic, anxiolytic, antitussive and sedative. Opioids may influence the hypothalamic-pituitary-adrenal axis or hypothalamic-pituitary-gonadal axis. Possible changes include an increase in serum prolactin and decreases in plasma cortisol and testosterone. These changes in hormonal balance may manifest clinical symptoms. In vitro and animal studies indicate various effects of natural opioids, such as morphine, on components of the immune system. The clinical significance of these findings is unknown. Whether oxycodone, a semisynthetic opioid, has immunological effects similar to morphine is unknown. 5.2 Pharmacokinetic properties Pharmacokinetic studies in healthy subjects have demonstrated an equivalent availability of oxycodone from Oxycodone Orion injection/infusion when administered by the intravenous or subcutaneous routes, as a single bolus dose or a continuous infusion over 8 hours.

9 Distribution Following absorption, oxycodone is distributed throughout the entire body. Approximately 45% is bound to plasma protein. The elimination half-life of oxycodone is about 3 hours. The apparent volume of distribution of oxycodone is 2.5 ± 0.8 l/kg following intravenous administration. Oxycodone penetrates the placenta and can be found in breast milk. Biotransformation Oxycodone is metabolised in the liver to noroxycodone through N-demethylation and oxymorphone through O-demethylation. Noroxycodone is further metabolised to noroxymorphone, which glucuronides. Noroxycodone and noroxymorphone are formed primarily via CYP3A4 enzymes and oxymorphone via CYP2D6. It has been demonstrated, that 45±21% of the oxycodone dose is excreted to urine in metabolites formed via CYP3A4 by N-demethylation whereas 11±6% of the dose is metabolized via CYP2D6 by O-demethylation. In vitro interaction studies to noroxymorphone, in which human liver microsomes were used, did not show the substance to inhibit significantly the activity of CYP2D6 or CYP3A4. This indicates that noroxymorphone is not likely to effect on the metabolism of other drugs metabolised via CYP2D6 or CYP3A4. Noroxymorphone is demonstrated to bind to mu opioid receptors. Oxymorphone is shown to be active, but the analgesic effect of the metabolites is considered clinically insignificant. Elimination Oxycodone and its metabolites are excreted in both urine and faeces. The plasma concentrations of oxycodone are only minimally affected by age, being 15% greater in elderly (> 65 years old) as compared to young subjects. Female subjects have on average, plasma oxycodone concentrations up to 25% higher than males on a body weight adjusted basis. 5.3 Preclinical safety data Like other opioids, oxycodone was proved to be genotoxic in some in vitro studies (for instance in the mouse lymphoma assay). It has not been established to have genotoxic effect in the bacterial mutation tests or in the in vivo micronucleus assay in mice. There is insufficient data on the reproduction toxicity properties of oxycodone and there is no data available on fertility and postnatal effects following intrauterine exposure. Long-term studies on carcinogenicity have not been performed. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Citric acid monohydrate Sodium citrate Sodium chloride Hydrochloric acid (for ph adjustment) Sodium hydroxide (for ph adjustment) Water for injections 6.2 Incompatibilities If Oxycodone Orion product is given concurrently with cyclizine, and if the concentration of cyclizine in the mixed combination product is over 3 mg/ml, solution is unstable and it may be precipitated.

10 Combination solution should not be diluted with 9 mg/ml (0.9%) saline due to unstable solution, which may precipitate. Prochlorperazine is chemically incompatible with Oxycodone Orion injection/infusion. 6.3 Shelf life 1 ml, 2 ml: 3 years. 10 ml: 2 years. After opening use immediately. Any unused portion should be discarded. From a microbiological point of view the product should be used immediately. If not used immediately, in-use storage time and conditions are the responsibility of the user. 6.4 Special precautions for storage This medicinal product does not require any special temperature storage conditions. Store in the original package in order to protect from light. For storage conditions of the opened medicinal product, see section Nature and contents of container 1 ml filling volume in 2 ml glass ampoule with two yellow colour rings, 2 ml glass ampoule with two colour rings: upper ring is brown and lower ring is yellow or 10 ml in glass ampoules with two colour rings: upper ring is dark blue and lower ring is yellow. The ampoules are packed in a cardboard box containing 5 ampoules. Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling If needed, dilute with 9 mg/ml (0.9%) saline or 50 mg/ml (5%) glucose or water for injections. If Oxycodone Orion injection/infusion is used concurrently with cyclizine, mixed solution is diluted with water for injections. 9 mg/ml (0.9%) sodium chloride solution must not be used. If the concentration of cyclizine in the mixed combination is under 3 mg/ml, mixture is physically and chemically stable for 24 hours at room temperature. If the concentration of cyclizine in the mixture is over 3 mg/ml, solution is unstable and may be precipitated. Oxycodone Orion injection/infusion, undiluted or diluted to 9 mg/ml (0.9%) saline, 50 mg/ml (5%) glucose or water for injections is physically and chemically stable when in contact with polypropylene or polycarbonate syringes, polyethylene or PVC tubing and PVC, EVA, polyolefin / polyamide, low density polyethylene and polypropylene infusion bags, over 24 hours at room temperature. The injection/infusion, whether undiluted or diluted does not need to be protected from light, if it is used with the solution for infusion and equipment combinations used in these studies. Inappropriate handling of the undiluted solution after opening of the original ampoule, or of the diluted solutions may compromise the sterility of the product. Any unused product or waste material should be disposed of in accordance with local requirements.

11 7. MARKETING AUTHORISATION HOLDER Orion Corporation Orionintie 1 FI Espoo Finland 8. MARKETING AUTHORISATION NUMBER <[To be completed nationally]> 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION <[To be completed nationally]> 10. DATE OF REVISION OF THE TEXT 24 October 2016