SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Tarim 40 mg/20 mg Prolonged-release Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each prolonged-release tablet contains 40 mg of oxycodone hydrochloride (equivalent to 36 mg oxycodone) and 20 mg of naloxone hydrochloride (as 21.8 mg naloxone hydrochloride dihydrate equivalent to 18 mg naloxone).

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Prolonged-release Tablet.

Pink, oblong, biconvex prolonged-release tablet with break scores on both side, with a length of 14.2 mm, a width of 6.7 mm and a height of 3.6 - 4.6 mm

The tablet can be divided into equal doses.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

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

Tarim is indicated in adults.

Posology and method of administration

Analgesia

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

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

Adults

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

Lower strengths are available to facilitate dose titration when initiating opioid therapy and for individual dose adjustment.

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

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

The maximum daily dose of Tarim 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 Tarim 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 Tarim, 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.

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

Some patients taking Tarim according to a regular time schedule require immediate-release analgesics as “rescue” medication for breakthrough pain. Tarim 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 Tarim requires upward adjustment. This adjustment should be made every 1-2 days in steps of 5 mg/2.5mg 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.

Tarim is taken at the determined dose 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.

For doses not realisable/practicable with this strength, other strengths of this medicinal product are available.

Analgesia Duration of use

Tarim should not be administered for longer than absolutely necessary. If long-term pain 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).

Elderly patients

As for younger adults the dose should be adjusted to the intensity of the pain and the sensitivity of the individual patient.

Renal impairment

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 not yet known. Caution should be exercised when administering Tarim to patients with renal impairment (see section 4.4).

Hepatic impairment

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 not yet known. Caution must be exercised when administering Tarim to patients with mild hepatic impairment (see section 4.4). In patients with moderate and severe hepatic impairment Tarim is contraindicated (see section 4.3).

Paediatric population

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

Method of administration For oral use.

Tarim is taken in the determined dose twice daily in a fixed time schedule.

The prolonged-release tablets may be taken with or without food with sufficient liquid.

The prolonged-release tablet can be divided into equal doses but must not be chewed or crushed.

4.3 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

Respiratory depression

The major risk of opioid excess is respiratory depression. Caution must be exercised when administering Tarim 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.

Hepatic or renal impairment

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

Diarrhoea

Diarrhoea may be considered as a possible effect of naloxone.

Long-term treatment

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

Tarim 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 Tarim may lead to physical dependence. Withdrawal symptoms may occur upon the abrupt cessation of therapy. If therapy with Tarim 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).

Psychological dependence (addiction)

There is potential for development of psychological dependence (addiction) to opioid analgesics, including Tarim. Tarim 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 not be chewed or crushed. 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 Tarim (see sections 4.5 and 4.7).

Alcohol

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

Paediatric population

Studies have not been performed on the safety and efficacy of Tarim 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.

Cancer

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 Tarim in this population is not recommended.

Surgery

Tarim 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 Tarim depends on a careful risk-benefit assessment for each individual patient.

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.

Doping

Athletes must be aware that this medicine may cause a positive reaction in ‘anti-doping’ tests. The use of Tarim as a doping agent may become a health hazard.

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 Tarim.

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

Clinically relevant changes in International Normalised 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. Tarim 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 Tarim 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 Tarim 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 Tarim is relatively low (see section 5.2).

Both oxycodone and naloxone pass through 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.

Tarim 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 Tarim 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 Tarim by the breastfeeding mother.

Breastfeeding should be discontinued during treatment with Tarim.

Fertility

There are no data with respect to fertility.

4.7 Effects on ability to drive and use machines

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

Undesirable effects are presented below in three sections: the treatment of pain, the active substance oxycodone hydrochloride and the treatment of another indication.

The following frequencies are the basis for assessing undesirable effects:

>1/10

>1/100 to <1/10 >1/1,000 to <1/100 >1/10,000 to <1/1,000 <1/10,000

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		Hyper sensitivity
Metabolism and nutritional disorders	Decreased appetite up to loss of appetite
Psychiatric disorders	Insomnia	Abnormal thinking Anxiety Confusion Depression Nervousnes s Restlessness		Euphoric mood Hallucinatio n Nightmares
Nervous system disorders	Dizziness Headache Somnolence	Convulsions1 Disturbance in attention Speech disorder Syncope Tremor		Paraesthesia Sedation

Eye disorders		Visual impairment
Ear and labyrinth disorders	Vertigo
Cardiac disorders		Angina pectoris2 Palpitations	Tachycardia
Vascular disorders	Hot flush	Decrease in blood pressure Increase in blood pressure
Respiratory, thoracic and mediastinal disorders		Dyspnoea Rhinorrhoea Cough	Yawning	Respiratory depression
Gastrointesti nal disorders	Abdominal pain Constipation Diarrhoea Dry mouth Dyspepsia Vomiting Nausea Flatulence	Abdominal distention	Tooth disorder	Eructation
Hepatobiliar y disorders		Hepatic enzymes increased Biliary colic
Skin and subcutaneous tissue disorders	Pruritus Skin reactions Hyperhidros is

Musculoskeletal and connective tissue disorders		Muscle spasms Muscle twitching, Myalgia
Renal and urinary disorders		Micturition urgency		Urinary retention
Reproductive system and breast disorders				Erectile dysfunction
General disorders and administrati on site conditions	Asthenic conditions Fatigue	Chest pain Chills Drug withdrawal syndrome Malaise Pain Peripheral oedema
Investigatio ns		Weight decreased	Weight increased
Injury, poisoning, and procedural complication s		Injury from accidents

¹ particularly in persons with epileptic disorder or predisposition to convulsions

particular 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 reactions
Metabolism and nutrition disorders		Dehydration	Increased appetite
Psychiatric disorders	Altered mood and personality changes Decreased activity Psychomoto r hyperactivit y	Agitation Perception disturbances (e.g. derealisation) Reduced libido Drug dependence
Nervous system disorders		Concentratio n impaired Migraine Dysgeusia Hypertonia Involuntary muscle contractions Hypoaesthesi a Abnormal co ordination
Ear and labyrinth		Hearing impaired

disorders
Vascular disorders		Vasodilation
Respiratory, thoracic and mediastinal disorders		Dysphonia
Gastrointestin al disorders	Hiccups	Dysphagia Ileus Mouth ulceration Stomatitis	Melaena Gingival bleeding
Hepatobiliary disorders				Cholestasis
Skin and subcutaneous tissue disorders		Dry skin	Urticaria
Renal and urinary disorders	Dysuria
Reproductive system and breast disorders				Amenorrhoea
General disorders and administration site conditions		Oedema Thirst Drug tolerance

Undesirable effects in the treatment of another indication

The list below reflects the adverse drug reactions seen with Tarim in a 12-week, randomised, placebo-controlled clinical trial comprising a total of 150 patients on Tarim and 154 patients on placebo with daily dosages between 10 mg/5 mg and 80 mg/40 mg oxycodone hydrochloride/naloxone hydrochloride. Adverse drug reactions associated with Tarim in pain were added with the frequency of not known.

System organ class MedDRA	Very Common	Common	Uncommon	Not known
Immune				Hypersensitiv

system disorders				ity
Metabolism and nutrition disorders		Decreased appetite up to loss of appetite
Psychiatric disorders		Insomnia Depression	Libido decreased Sleep attacks	Abnormal thinking Anxiety Confusion Nervousness Restlessness Euphoric mood Hallucination Nightmares
Nervous system disorders	Headache Somnolence	Dizziness, Disturbance in attention Tremor Paraesthesia	Dysgeusia	Convulsions1 Sedation Speech disorder Syncope
Eye disorders		Visual impairment
Ear and labyrinth disorders		Vertigo
Cardiac disorders				Angina pectoris2 Palpitations Tachycardia
Vascular disorders	Hot flush Blood pressure decreased Blood pressure increased
Respiratory thoracic and mediastinal disorders			Dyspnoea	Cough Rhinorrhoea Respiratory depression Yawning
Gastrointestina l disorders	Constipation, Nausea	Abdominal pain, Dry mouth Vomiting	Flatulence	Abdominal Distention Diarrhea Dyspepsia Eructation Tooth disorder
Hepatobiliary disorders		Hepatic enzymes increased3		Biliary colic
Skin and	Hyperhidorosis	Pruritus,

Depending on the history of the patient, an overdose of Tarim 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 measure (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: Nervous system; 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.

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.

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 Tarim Pharmacokinetic/pharmacodynamic relationships

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

All dose strengths of Tarim are interchangeable.

After oral administration of Tarim in 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 (C_max) 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 Tarim 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 Tarim is unlikely.

Elderly patients

Oxycodone

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

Naloxone

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

Naloxone-3-glucuronide

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

Patients with impaired hepatic function

Oxycodone

For AUCi_NF 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 C_max 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 t_1/2Z 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 AUC_t 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 C_max 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 t_1/2Z and the corresponding AUC_inf of naloxone were not calculated. The bioavailability comparisons for naloxone were therefore based on AUC_t values.

Naloxone-3-glucuronide

For AUC_inf 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 C_max 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 t_1/2Z 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 AUC_inf 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 C_max 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 AUC_t 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 C_max of naloxone, on average there was an increase to 1076% (90% C.l.: 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 t_1/2Z and the corresponding AUCi_NF 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 characterise the naloxone plasma profiles for the healthy subjects.

Naloxone-3-glucuronide

For AUC_inf 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 C_max 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 t_1/2Z of naloxone-3-glucuronide, on average there was no significant change between the renally impaired subjects and the healthy subjects.

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 foetuses were used in statistical evaluation, a dose related increase in developmental variations was observed (increased incidences of 27 presacral vertebrae, extra pairs of ribs). When these parameters were statistically evaluated using litters, only the incidence 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/foetotoxic, and does not affect perinatal/postnatal development. At very high doses (800 mg/kg/day) naloxone produced increased pup deaths in the immediate postpartum period at doses 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 to humans at therapeutic concentrations may be ruled out with adequate certainty.

6 PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Tablet core Polyvinyl acetate Povidone

Sodium laurilsulfate Silica, colloidal anhydrous Cellulose, microcrystalline Magnesium stearate

Tablet coating Polyvinyl alcohol Titanium dioxide (E171) Macrogol Talc

Iron oxide red (E172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

18 months

6.4 Special precautions for storage

Bottles: Do not store above 30°C Blister: Do not store above 25°C

6.5 Nature and contents of container

Blister

Child resistant aluminium/PVC/PE/PVDC blisters.

Child resistant aluminium/PVC/PE/PVDC perforated unit dose blisters.

Bottles

White high-density polyethylene (HDPE) bottles with white, tamper-evident child-resistant, closure made of polypropylene (PP).

Pack sizes

Blister: 10, 14, 20, 28, 30, 50, 56, 60, 90, 98, 100 prolonged-release tablets Unit dose blister: 56x1

Bottle: 50, 100, 200, 250 prolonged-release tablets Not all pack sizes may be marketed.

6.6 Special precautions for disposal

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

MARKETING AUTHORISATION HOLDER

TEVA UK LIMTED Brampton Road, Hampden Park, Eastbourne,

East Sussex BN22 9AG UNITED KINGDOM

8 MARKETING AUTHORISATION NUMBER(S)

PL 00289/1978

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

17/12/2015

10 DATE OF REVISION OF THE TEXT

17/12/2015