SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Ormetone 5 mg/2.5 mg prolonged-release tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each prolonged-release tablet contains 5 mg of oxycodone hydrochloride equivalent to 4.5 mg oxycodone and naloxone hydrochloride dihydrate equivalent to 2.5 mg naloxone hydrochloride and 2.25 mg naloxone.

Excipient with known effect: Each prolonged-release tablet contains 16.0 mg lactose. For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Prolonged-release tablet

Light blue, round, convex, film-coated tablets with a nominal diameter of 7.2 mm.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Severe pain, which can be adequately managed only with opioid analgesics.

The opioid antagonist naloxone is added to counteract opioid-induced constipation by blocking the action of oxycodone at opioid receptors locally in the gut.

Ormetone is indicated in adults.

4.2 Posology and method of administration Posology

Analgesia

The analgesic efficacy of Ormetone is equivalent to oxycodone hydrochloride prolonged-release formulations.

The dosage should be adjusted to the intensity of pain and the sensitivity of the individual patient. Unless otherwise prescribed, Ormetone should be administered as follows:

Adults

The usual starting dose for an opioid naive patient is 10 mg/5 mg of oxycodone hydrochloride/naloxone hydrochloride at 12 hourly intervals.

Patients already receiving opioids may be started on higher doses of Ormetone depending on their previous opioid experience.

Ormetone 5 mg/2.5 mg is intended for dose titration when initiating opioid therapy and individual dose adjustment.

The maximum daily dose of Ormetone is 160 mg oxycodone hydrochloride and 80 mg naloxone hydrochloride. The maximum daily dose is reserved for patients who have previously been maintained on a stable daily dose of oxycodone/naloxone and who have become in need of an increased dose. Special attention should be given to patients with compromised renal function and patients with mild hepatic impairment if an increased dose is considered. For patients requiring higher doses of Ormetone, administration of supplemental prolonged-release oxycodone hydrochloride at the same time intervals should be considered, taking into account the maximum daily dose of 400 mg prolonged-release oxycodone hydrochloride. In the case of supplemental oxycodone hydrochloride dosing, the beneficial effect of naloxone hydrochloride on bowel function may be impaired.

After complete discontinuation of therapy with Ormetone with a subsequent switch to another opioid a worsening of the bowel function can be expected.

Some patients taking Ormetone according to a regular time schedule require immediate-release analgesics as “rescue” medication for breakthrough pain.

Ormetone is a prolonged-release formulation and therefore not intended for the treatment of breakthrough pain. For the treatment of breakthrough pain, a single dose of “rescue medication” should approximate one sixth of the equivalent daily dose of oxycodone hydrochloride. The need for more than two “rescues” per day is usually an indication that the dose of Ormetone requires upward adjustment. This adjustment should be made every 1-2 days in steps of 5 mg/2.5 mg twice daily, or where necessary 10 mg/5 mg, oxycodone hydrochloride/naloxone hydrochloride until a stable dose is reached. The aim is to establish a patient-specific twice daily dose that will maintain adequate analgesia and make use of as little rescue medication as possible for as long as pain therapy is necessary.

Ormetone is taken at the determined dosage twice daily according to a fixed time schedule. While symmetric administration (the same dose mornings and evenings) subject to a fixed time schedule (every 12 hours) is appropriate for the majority of patients, some patients, depending on the individual pain situation, may benefit from asymmetric dosing tailored to their pain pattern. In general, the lowest effective analgesic dose should be selected.

In non-malignant pain therapy, daily doses of up to 40 mg/20 mg oxycodone hydrochloride/naloxone hydrochloride are usually sufficient, but higher doses may be needed.

Elderly patients

As for younger adults the dosage should be adjusted to the intensity of the pain or RLS symptoms and the sensitivity of the individual patient.

Patients with impaired hepatic function

A clinical trial has shown that plasma concentrations of both oxycodone and naloxone are elevated in patients with hepatic impairment. Naloxone concentrations were affected to a higher degree than oxycodone (see section 5.2). The clinical relevance of a relative high naloxone exposure in hepatic impaired patients is yet not known. Caution must be exercised when administering Ormetone to patients with mild hepatic impairment (see section 4.4). In patients with moderate and severe hepatic impairment Ormetone is contraindicated (see section 4.3).

Patients with impaired renal function

A clinical trial has shown that plasma concentrations of both oxycodone and naloxone are elevated in patients with renal impairment (see section 5.2). Naloxone concentrations were affected to a higher degree than oxycodone. The clinical relevance of a relative high naloxone exposure in renal impaired patients is yet not known. Caution should be exercised when administering Ormetone to patients with renal impairment (see section 4.4).

Paediatric population

The safety and efficacy of Ormetone in children aged below 18 years has not been established. No data are available.

Method of administration

Oral use.

Ormetone is taken in the determined dosage twice daily in a fixed time schedule.

The prolonged-release tablets may be taken with or without food with sufficient liquid. The prolonged-release tablets must be swallowed whole, and not broken, chewed or crushed.

Duration of use

Ormetone should not be administered for longer than absolutely necessary. If longterm treatment is necessary in view of the nature and severity of the illness, careful and regular monitoring is required to establish whether and to what extent further treatment is necessary.

Analgesia

When the patient no longer requires opioid therapy, it may be advisable to taper the dose gradually (see section 4.4).

Contraindications

•    Hypersensitivity to the active substances or to any of the excipients listed in section 6.1,

•    Any situation where opioids are contraindicated,

•    Severe respiratory depression with hypoxia and/or hypercapnia,

•    Severe chronic obstructive pulmonary disease,

•    Cor pulmonale,

•    Severe bronchial asthma,

•    Non-opioid induced paralytic ileus,

•    Moderate to severe hepatic impairment.

4.4 Special warnings and precautions for use

The major risk of opioid excess is respiratory depression.

Caution must be exercised when administering Ormetone to elderly or infirm patients, patients with opioid-induced paralytic ileus, patients presenting severely impaired pulmonary function, patients with sleep apnoea, myxoedema, hypothyroidism, Addison’s disease (adrenal cortical insufficiency), toxic psychosis, cholelithiasis, prostate hypertrophy, alcoholism, delirium tremens, pancreatitis, hypotension, hypertension, pre-existing cardiovascular diseases, head injury (due to the risk of increased intracranial pressure), epileptic disorder or predisposition to convulsions, or patients taking MAO inhibitors.

Caution must also be exercised when administering Ormetone to patients with mild hepatic or renal impairment. A careful medical monitoring is particularly necessary for patients with severe renal impairment.

Diarrhoea may be considered as a possible effect of naloxone.

In patients under long-term opioid treatment with higher doses of opioids, the switch to Ormetone can initially provoke withdrawal symptoms. Such patients may require specific attention.

Ormetone is not suitable for the treatment of withdrawal symptoms.

During long-term administration, the patient may develop tolerance to the medicinal product and require higher doses to maintain the desired effect. Chronic administration of Ormetone may lead to physical dependence. Withdrawal symptoms may occur upon the abrupt cessation of therapy. If therapy with Ormetone is no longer required, it may be advisable to reduce the daily dose gradually in order to avoid the occurrence of withdrawal syndrome (see section 4.2).

There is potential for development of psychological dependence (addiction) to opioid analgesics, including Ormetone. Ormetone should be used with particular care in patients with a history of alcohol and drug abuse. Oxycodone alone has an abuse profile similar to other strong agonist opioids.

In order not to impair the prolonged-release characteristic of the prolonged-release tablets, the prolonged-release tablets must be taken whole and must not be broken, chewed or crushed. Breaking, chewing or crushing the prolonged-release tablets for ingestion leads to a faster release of the active substances and the absorption of a possibly fatal dose of oxycodone (see section 4.9).

Patients who have experienced somnolence and/or an episode of sudden sleep onset must refrain from driving or operating machines. Furthermore, a reduction of the dose or termination of therapy may be considered. Because of possible additive effects, caution should be advised when patients are taking other sedating medicinal products in combination with Ormetone (see sections 4.5 and 4.7).

Concomitant use of alcohol and Ormetone may increase the undesirable effects of Ormetone. Concomitant use should be avoided

Studies have not been performed on the safety and efficacy of oxycodone/naloxone in children and adolescents below the age of 18 years. Therefore, their use in children and adolescents under 18 years of age is not recommended.

There is no clinical experience in patients with cancer associated to peritoneal carcinomatosis or with sub-occlusive syndrome in advanced stages of digestive and pelvic cancers. Therefore, the use of Ormetone in this population is not recommended

Ormetone is not recommended for pre-operative use or within the first 12-24 hours post-operatively. Depending on the type and extent of surgery, the anaesthetic procedure selected, other co-medication and the individual condition of the patient, the exact timing for initiating post-operative treatment with Ormetone depends on a careful risk-benefit assessment for each individual patient.

Any abuse of Ormetone by drug addicts is strongly discouraged.

If abused parenterally, intranasally or orally by individuals dependent on opioid agonists, such as heroin, morphine, or methadone, the broken, chewed or crushed tablet is expected to produce marked withdrawal symptoms - because of the opioid receptor antagonist characteristics of naloxone - or to intensify withdrawal symptoms already present (see section 4.9).

Ormetone consists of a dual-polymer matrix, intended for oral use only. Abusive parenteral injections of the prolonged-release tablet constituents (especially talc) can be expected to result in local tissue necrosis and pulmonary granulomas or may lead to other serious, potentially fatal undesirable effects.

The empty prolonged-release tablet matrix may be visible in the stool.

Ormetone 5 mg/2.5 mg prolonged-release tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take Ormetone 5 mg/2.5 mg.

4.5 Interaction with other medicinal products and other forms of interaction

Substances having a CNS-depressant effect (e.g. other opioids, sedatives, hypnotics, antidepressants, phenothiazines, neuroleptics, antihistamines and antiemetics) may enhance the CNS-depressant effect (e.g. respiratory depression) of Ormetone.

Alcohol may enhance the pharmacodynamic effects of Ormetone; concomitant use should be avoided.

Clinically relevant changes in International Normalized Ratio (INR or Quick-value) in both directions have been observed in individuals if oxycodone and coumarin anticoagulants are co-applied.

Oxycodone is metabolised primarily via the CYP3A4 pathways and partly via the CYP2D6 pathway (see section 5.2). The activities of these metabolic pathways may be inhibited or induced by various co-administered drugs or dietary elements. Ormetone doses may need to be adjusted accordingly.

CYP3A4 inhibitors, such as macrolide antibiotics (e.g. clarithromycin, erythromycin, telithromycin), azole-antifungal agents (e.g. ketoconazole, voriconazole, itraconazole, posaconazole), protease inhibitors (e.g. ritonavir, indinavir, nelfinavir, saquinavir), cimetidine and grapefruit juice may cause decreased clearance of oxycodone which could lead to an increase in oxycodone plasma concentrations. A reduction in the dose of Ormetone and subsequent re-titration may be necessary.

CYP3A4 inducers, such as rifampicin, 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. Caution is advised and further titration may be necessary to reach an adequate level of symptom control.

Theoretically, medicinal products that inhibit CYP2D6 activity, such as paroxetine, fluoxetine and quinidine, may cause decreased clearance of oxycodone which could lead to an increase in oxycodone plasma concentrations. Concomitant administration with CYP2D6 inhibitors had an insignificant effect on the elimination of oxycodone and also had no influence on the pharmacodynamic effects of oxycodone.

In vitro metabolism studies indicate that no clinically relevant interactions are to be expected between oxycodone and naloxone.

The likelihood of clinically relevant interactions between paracetamol, acetylsalicylic acid or naltrexone and the combination of oxycodone and naloxone in therapeutic concentrations is minimal.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no data from the use of oxycodone/naloxone in pregnant women and during childbirth. Limited data on the use of oxycodone during pregnancy in humans reveal no evidence of an increased risk of congenital abnormalities. For naloxone, insufficient clinical data on exposed pregnancies are available. However, systemic exposure of the women to naloxone after use of oxycodone/naloxone prolonged-release tablets is relatively low (see section 5.2). Both oxycodone and naloxone pass into the placenta. Animal studies have not been performed with oxycodone and naloxone in combination (see section 5.3). Animal studies with oxycodone or naloxone administered as single drugs have not revealed any teratogenic or embryotoxic effects.

Long-term administration of oxycodone during pregnancy may lead to withdrawal symptoms in the newborn. If administered during childbirth, oxycodone may evoke respiratory depression in the newborn.

Ormetone should only be used during pregnancy if the benefit outweighs the possible risks to the unborn child or neonate.

Breastfeeding

Oxycodone passes into the breast milk. A milk-plasma concentration ratio of 3.4:1 was measured and oxycodone effects in the suckling infant are therefore conceivable. It is not known whether naloxone also passes into the breast milk. However, after use of oxycodone/naloxone prolonged-release tablets systemic naloxone levels are very low (see section 5.2). A risk to the suckling child cannot be excluded in particular following intake of multiple doses of Ormetone by the breastfeeding mother. Breastfeeding should be discontinued during treatment with Ormetone.

Fertility

There are no data with respect to fertility.

4.7 Effects on ability to drive and use machines

Ormetone has moderate influence on the ability to drive and use machines. This is particularly likely at the beginning of treatment with Ormetone, after dose increase or product rotation and if Ormetone is combined with other CNS-depressant agents.

Patients stabilised on a specific dosage will not necessarily be restricted. Therefore, patients should consult with their physician as to whether driving or the use of machinery is permitted.

Patients being treated with Ormetone and presenting with somnolence and/or sudden sleep episodes must be informed to refrain from driving or engaging in activities where impaired alertness may put themselves or others at risk of serious injury or death (e.g. operating machines) until such recurrent episodes and somnolence have resolved (see also sections 4.4 and 4.5).

4.8 Undesirable effects

The following frequencies are the basis for assessing undesirable effects:

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)

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Undesirable effects in the treatment of pain

System organ class MedDRA	Common	Uncommon	Rare	Not known
Immune system disorders		Hypersensitivit y
Metabolism and nutritional disorders	Appetite decreased up to loss of appetite
Psychiatric disorders	Insomnia	Abnormal thinking Anxiety Confusion Depression Nervousness Restlessness		Euphoric mood Hallucination Nightmares
Nervous system disorders	Dizziness Headache Somnolence	Convulsions1 Disturbance in attention Speech disorder Syncope Tremor		Paraesthesia Sedation
Eye disorder		Visual impairment
Ear and labyrinth disorder	Vertigo
Cardiac disorders		Angina pectoris2	Tachycardia

		Palpitations
Vascular disorders	Hot flush	Blood pressure decreased Blood pressure increased
Respiratory, thoracic and mediastinal disorders		Dyspnoea Rhinorrhoea Cough	Yawning	Respiratory depression
Gastrointestinal disorders	Abdominal pain Constipation Diarrhoea Dry mouth Dyspepsia Vomiting Nausea Flatulence	Abdominal distention	Tooth disorder	Eructation
Hepatobiliary disorders		Hepatic enzymes increased Biliary colic
Skin and subcutaneous tissue disorder	Pruritus Skin reactions Hyperhidrosis
Musculoskeleta l and connective tissue disorder		Muscle spasms Muscle twitching Myalgia
Renal and urinary disorders		Micturition urgency		Urinary retention
Reproductive system and breast disorders				Erectile dysfunction
General disorders and administration site conditions	Asthenic conditions Fatigue	Chest pain Chills Drug withdrawal syndrome Malaise Pain Oedema peripheral
Investigations		Weight decreased	Weight increased
Injury, poisoning, and procedural complications		Injuries from accidents

¹    particularly in persons with epileptic disorder or predisposition to convulsions

²    particularly in patients with history of coronary artery disease

For the active substance oxycodone hydrochloride, the following additional undesirable effects are known:

Due to its pharmacological properties, oxycodone hydrochloride may cause respiratory depression, miosis, bronchial spasm and spasms of nonstriated muscles as well as suppress the cough reflex.

System organ class MedDRA	Common	Uncommon	Rare	Not known
Infections and infestations			Herpes simplex
Immune system disorders				Anaphylactic responses
Metabolism and nutritional disorders		Dehydration	Appetite increased
Psychiatric disorders	Altered mood and personality changes Decreased activity Psychomotor hyperactivity	Agitation Perception disturbances (e-g- derealisation) Libido reduced Drug dependence
Nervous system disorders		Impaired concentration Migraine Dysgeusia Hypertonia Involuntary muscle contractions Hypoaesthesia Abnormal coordination
Ear and labyrinth disorders		Hearing impaired
Vascular disorders		Vasodilation
Respiratory, thoracic and mediastinal disorders		Dysphonia
Gastrointestinal disorders	Hiccups	Dysphagia Ileus Mouth ulceration Stomatitis	Melaena, Gingival bleeding
Hepatobiliary disorders				Cholestasis
Skin and subcutaneous tissue disorders		Dry skin	Urticaria
Renal and urinary	Dysuria

disorders
Reproductive system and breast disorders				Amenorrhoea
General disorders and administration site conditions		Oedema Thirst Drug tolerance

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 Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Symptoms of intoxication

Depending on the history of the patient, an overdose of Ormetone may be manifested by symptoms that are either triggered by oxycodone (opioid receptor agonist) or by naloxone (opioid receptor antagonist).

Symptoms of oxycodone overdose include miosis, respiratory depression, somnolence progressing to stupor, skeletal muscle flaccidity, bradycardia as well as hypotension. Coma, non-cardiogenic pulmonary oedema and circulatory failure may occur in more severe cases and may lead to a fatal outcome.

Symptoms of a naloxone overdose alone are unlikely.

Therapy of intoxication

Withdrawal symptoms due to an overdose of naloxone should be treated symptomatically in a closely-supervised environment.

Clinical symptoms suggestive of an oxycodone overdose may be treated by the administration of opioid antagonists (e.g. naloxone hydrochloride 0.4-2 mg intravenously). Administration should be repeated at 2-3 minute intervals, as clinically necessary. It is also possible to apply an infusion of 2 mg naloxone hydrochloride in 500 ml of 0.9% sodium chloride or 5% dextrose (0.004 mg/ml naloxone). The infusion should be run at a rate aligned to the previously administered bolus doses and to the patient’s response. Consideration may be given to gastric lavage.

Supportive measures (artificial ventilation, oxygen, vasopressors and fluid infusions) should be employed, as necessary, to manage the circulatory shock accompanying an overdose. Cardiac arrest or arrhythmias may require cardiac massage or defibrillation. Artificial ventilation should be applied if necessary. Fluid and electrolyte metabolism should be maintained.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Analgesics; Opioids; Natural opium alkaloids, ATC code: N02AA55

Mechanism of action

Oxycodone and naloxone have an affinity for kappa, mu and delta opiate receptors in the brain, spinal cord and peripheral organs (e.g. intestine). Oxycodone acts as opioid-receptor agonist at these receptors and binds to the endogenous opioid receptors in the CNS. By contrast, naloxone is a pure antagonist acting on all types of opioid receptors.

Pharmacodynamic effects

Because of the pronounced first-pass metabolism, the bioavailability of naloxone upon oral administration is <3%, therefore a clinically relevant systemic effect is unlikely. Due to the local competitive antagonism of the opioid receptor mediated oxycodone effect by naloxone in the gut, naloxone reduces the bowel function disorders that are typical for opioid treatment.

Clinical efficacy and safety

Opioids can influence the hypothalamic-pituitary-adrenal or gonadal axes. Among the changes observed are an increase of prolactin in the serum and a reduced level of cortisol and testosterone in the plasma. Clinical symptoms may occur because of these hormone changes.

Preclinical studies show differing effects of natural opioids on components of the immune system. The clinical significance of these findings is not known. It is not known whether oxycodone, a semi-synthetic opioid, has similar effects on the immune system to natural opioids.

Analgesia

In a 12-weeks parallel-group double-blinded study in 322 patients with opioid-induced constipation, patients who were treated with oxycodone hydrochloride-naloxone hydrochloride had on average one extra complete spontaneous (without laxatives) bowel movement in the last week of treatment, compared to patients who continued using similar doses of oxycodone hydrochloride prolonged release tablets (p<0.0001). The use of laxatives in the first four weeks was significantly lower in the oxycodone-naloxone group compared to the oxycodone monotherapy group (31% versus 55%, respectively, p<0.0001). Similar results were shown in a study with 265 non-cancer patients comparing daily doses of oxycodone hydrochloride/naloxone hydrochloride of 60 mg/30 mg to up to 80 mg/40 mg with oxycodone hydrochloride monotherapy in the same dose range.

5.2 Pharmacokinetic properties Oxycodone hydrochloride

Absorption

Oxycodone has a high absolute bioavailability of up to 87% following oral administration.

Distribution

Following absorption, oxycodone is distributed throughout the entire body. Approximately 45% is bound to plasma protein.

Oxycodone crosses the placenta and may be detected in breast milk.

Biotransformation

Oxycodone is metabolised in the gut and the liver to noroxycodone and oxymorphone and to various glucuronide conjugates. Noroxycodone, oxymorphone and noroxymorphone are produced via the cytochrome P450 system. Quinidine reduces the production of oxymorphone in man without substantially influencing the pharmacodynamics of oxycodone. The contribution of the metabolites to overall pharmacodynamic effect is insignificant.

Elimination

Oxycodone and its metabolites are excreted in both urine and faeces.

Naloxone hydrochloride Absorption

Following oral administration, naloxone has a very low systemic availability of < 3%. Distribution

Naloxone passes into the placenta. It is not known whether naloxone also passes into breast milk.

Biotransformation and elimination

After parenteral administration, the plasma half-life is approximately one hour. The duration of action depends upon the dose and route of administration, intramuscular injection producing a more prolonged effect than intravenous doses. It is metabolised in the liver and excreted in the urine. The principal metabolites are naloxone glucuronide, 6p-Naloxol and its glucuronide.

Oxycodone hydrochloride / naloxone hydrochloride combination (Ormetone)

Pharmacokinetic/pharmacodynamic relationships

The pharmacokinetic characteristics of oxycodone from oxycodone/naloxone hydrochloride prolonged-release tablets is equivalent to those of prolonged-release oxycodone hydrochloride tablets administered together with prolonged-release naloxone hydrochloride tablets.

All dosage strengths of Ormetone are interchangeable.

After the oral administration of oxycodone/naloxone hydrochloride prolonged-release tablets at the maximum dose to healthy subjects, the plasma concentrations of naloxone are so low that it is not feasible to carry out a pharmacokinetic analysis. To conduct a pharmacokinetic analysis naloxone-3-glucuronide as surrogate marker is used, since its plasma concentration is high enough to measure.

Overall, following ingestion of a high-fat breakfast, the bioavailability and peak plasma concentration (Cmax) of oxycodone were increased by an average of 16% and 30%, respectively, compared to administration in the fasting state. This was evaluated as clinically not relevant, therefore oxycodone/naloxone hydrochloride prolonged-release tablets may be taken with or without food (see section 4.2).

In vitro drug metabolism studies have indicated that the occurrence of clinically relevant interactions involving oxycodone/naloxone hydrochloride prolonged-release tablets is unlikely.

Elderly patients

Oxycodone

For AUCt of oxycodone, on average there was an increase to 118% (90% C.I.: 103, 135), for elderly compared with younger volunteers. For Cmax of oxycodone, on average there was an increase to 114% (90% C.I.: 102, 127). For Cmin of oxycodone, on average there was an increase to 128% (90% C.I.: 107, 152).

Naloxone

For AUCt of naloxone, on average there was an increase to 182% (90% C.I.: 123, 270), for elderly compared with younger volunteers. For Cmax of naloxone, on average there was an increase to 173% (90% C.I.: 107, 280). For Cmin of naloxone, on average there was an increase to 317% (90% C.I.: 142, 708).

Naloxone-3-glucuronide

For AUCt of naloxone-3-glucuronide, on average there was an increase to 128% (90% C.I.: 113, 147), for elderly compared with younger volunteers. For Cmax of naloxone-3-glucuronide, on average there was an increase to 127% (90% C.I.: 112, 144). For Cmin of naloxone-3-glucuronide, on average there was an increase to 125% (90% C.I.: 105, 148).

Patients with impaired hepatic function

Oxycodone

For AUCINF of oxycodone, on average there was an increase to 143% (90% C.I :

111, 184), 319% (90% C.I.: 248, 411) and 310% (90% C.I.: 241, 398) for mild, moderate and severe hepatically impaired subjects, respectively, compared with healthy volunteers. For Cmax of oxycodone, on average there was an increase to 120% (90% C.I.: 99, 144), 201% (90% C.I.: 166, 242) and 191% (90% C.I.: 158,

231) for mild, moderate and severe hepatically impaired subjects, respectively, compared with healthy volunteers. For t1/2Z of oxycodone, on average there was an increase to 108% (90% C.I.: 70, 146), 176% (90% C.I.: 138, 215) and 183% (90% C.I.: 145, 221) for mild, moderate and severe hepatically impaired subjects, respectively, compared with healthy volunteers.

Naloxone

For AUCt of naloxone, on average there was an increase to 411% (90% C.I.: 152, 1112), 11518% (90% C.I.: 4259, 31149) and 10666% (90% C.I.: 3944, 28847) for mild, moderate and severe hepatically impaired subjects, respectively, compared with healthy volunteers. For Cmax of naloxone, on average there was an increase to 193% (90% C.I.: 115, 324), 5292% (90% C.I: 3148, 8896) and 5252% (90% C.I.: 3124, 8830) for mild, moderate and severe hepatically impaired subjects, respectively, compared with healthy volunteers. Due to insufficient amount of data available t1/2Z and the corresponding AUCINF of naloxone were not calculated. The bioavailability comparisons for naloxone were therefore based on AUCt values.

Naloxone-3-glucuronide

For AUCINF of naloxone-3-glucuronide, on average there was an increase to 157% (90% C.I.: 89, 279), 128% (90% C.I.: 72, 227) and 125% (90% C.I.: 71, 222) for mild, moderate and severe hepatically impaired subjects, respectively, compared with healthy volunteers. For Cmax of naloxone-3-glucuronide, on average there was an increase to 141% (90% C.I.: 100, 197, 118% (90% C.I.: 84, 166) and a decrease to 98% (90% C.I.: 70, 137) for mild, moderate and severe hepatically impaired subjects, respectively, compared with healthy volunteers. For t1/2Z of naloxone-3-glucuronide, on average there was an increase to 117% (90% C.I.: 72, 161, a decrease to 77% (90% C.I.: 32, 121) and a decrease to 94% (90% C.I.: 49, 139) for mild, moderate and severe hepatically impaired subjects, respectively, compared with healthy volunteers.

Patients with impaired renal function

Oxycodone

For AUCINF of oxycodone, on average there was an increase to 153% (90% C.I.:

130, 182), 166% (90% C.I.: 140, 196) and 224% (90% C.I.: 190, 266) for mild, moderate and severe renally impaired subjects, respectively, compared with healthy volunteers. For Cmax of oxycodone, on average there was an increase to 110% (90% C.I.: 94, 129), 135% (90% C.I.: 115, 159) and 167% (90% C.I.: 142, 196) for mild, moderate and severe renally impaired subjects, respectively, compared with healthy volunteers. For t1/2Z of oxycodone, on average there was an increase to 149%, 123% and 142% for mild, moderate and severe renally impaired subjects, respectively, compared with healthy volunteers.

Naloxone

For AUCt of naloxone, on average there was an increase to 2850% (90% C.I.: 369, 22042), 3910% (90% C.I.: 506, 30243) and 7612% (90% C.I.: 984, 58871) for mild, moderate and severe renally impaired subjects, respectively, compared with healthy volunteers. For Cmax of naloxone, on average there was an increase to 1076% (90% C.I.: 154, 7502), 858% (90% C.I.: 123, 5981) and 1675% (90% C.I.: 240, 11676) for mild, moderate and severe renally impaired subjects, respectively, compared with healthy volunteers. Due to insufficient amount of data available t1/2Z and the corresponding AUCINF of naloxone were not calculated. The bioavailability comparisons for naloxone were therefore based on AUCt values. The ratios may have been influenced by the inability to fully characterize the naloxone plasma profiles for the healthy subjects.

Naloxone-3-glucuronide

For AUCINF of naloxone-3-glucuronide, on average there was an increase to 220% (90% C.I.: 148, 327), 370% (90% C.I.: 249, 550) and 525% (90% C.I.: 354, 781) for mild, moderate and severe renally impaired subjects, respectively, compared with healthy subjects. For Cmax of naloxone-3-glucuronide, on average there was an increase to 148% (90% C.I.: 110, 197), 202% (90% C.I.: 151, 271) and 239% (90% C.I.: 179, 320) for mild, moderate and severe renally impaired subjects, respectively, compared with healthy subjects. For t1/2Z of naloxone-3-glucuronide, on average there was no significant change between the renally impaired subjects and the healthy subjects.

Abuse

To avoid damage to the prolonged-release properties of the tablets, Ormetone must not be broken, crushed or chewed, as this leads to a rapid release of the active substances. In addition, naloxone has a slower elimination rate when administered intranasally. Both properties mean that abuse of Ormetone will not have the effect intended. In oxycodone-dependent rats, the intravenous administration of oxycodone hydrochloride / naloxone hydrochloride at a ratio of 2:1 resulted in withdrawal symptoms.

5.3 Preclinical safety data

There are no data from studies on reproductive toxicity of the combination of oxycodone and naloxone.

Studies with the single components showed that oyxcodone had no effect on fertility and early embryonic development in male and female rats in doses of up to 8 mg/kg body weight and induced no malformations in rats in doses of up to 8 mg/kg and in rabbits in doses of 125 mg/kg bodyweight. However, in rabbits, when individual fetuses were used in statistical evaluation, a dose-related increase in developmental variations was observed (increased incidence of 27 presacral vertebrae, extra pairs of ribs). When these parameters were statistically evaluated using litters, only the incidences of 27 presacral vertebrae was increased and only in the 125 mg/kg group, a dose level that produced severe pharmacotoxic effects in the pregnant animals. In a study on pre- and postnatal development in rats F1 body weights were lower at 6 mg/kg/d when compared to body weights of the control group at doses which reduced maternal weight and food intake (NOAEL 2 mg/kg body weight). There were neither effects on physical, reflexological, and sensory developmental parameters nor on behavioural and reproductive indices. The standard oral reproduction toxicity studies with naloxone show that at high oral doses naloxone was not teratogenic and/or embryo/fetotoxic, and does not affect perinatal/postnatal development.

At very high doses (800 mg/kg/day) naloxone produced increased pup deaths in the immediate post-partum period at dosages that produced significant toxicity in maternal rats (e.g., body weight loss, convulsions). However, in surviving pups, no effects on development or behaviour were observed.

Long-term carcinogenicity studies with oxycodone/naloxone in combination or oxycodone as a single entity have not been performed. For naloxone, a 24-months oral carcinogenicity study was performed in rats with naloxone doses up to 100 mg/kg/day. The results indicate that naloxone is not carcinogenic under these conditions.

Oxycodone and naloxone as single entities show a clastogenic potential in in vitro assays. No similar effects were observed, however, under in vivo conditions, even at toxic doses. The results indicate that the mutagenic risk of oxycodone/naloxone hydrochloride prolonged-release tablets to humans at therapeutic concentrations may be ruled out with adequate certainty.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core:

Microcrystalline cellulose, Lactose monohydrate, Ammonio methacrylate copolymer,

Povidone,

Talc,

Triacetin,

Stearyl alcohol, Magnesium stearate, Anhydrous colloidal silica

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

9 months

6.4 Special precautions for storage

Do not store above 25 °C.

6.5 Nature and contents of container

The prolonged-released tablets are available in child-resistant, perforated unit dose peel-off PVC/PVDC/PVC-Alu blisters in packs of 10 x 1, 20 x 1, 28 x 1, 30 x 1,

50 x 1, 56 x 1, 60 x 1, 98 x 1 and 100 x 1.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Any unused product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

Acino AG Am Windfeld 35 83714 Miesbach Germany

8    MARKETING AUTHORISATION NUMBER(S)

PL 21806/0094

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

17/02/2016

10    DATE OF REVISION OF THE TEXT

17/02/2016