OXYCODONE HYDROCHLORIDE/NALOXONE HYDROCHLORIDE

Posology Analgesia The analgesic efficacy of Oxycodone hydrochloride/Naloxone hydrochloride 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, these tablets 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. 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 depending on their previous opioid experience. The maximum daily dose of these tablets 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 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, 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 these tablets with a subsequent switch to another opioid, a worsening of the bowel function can be expected.

Some patients taking these prolonged-release tablets according to a regular time schedule require immediate-release analgesics as “rescue” medication for breakthrough pain. Oxycodone hydrochloride/Naloxone hydrochloride 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 dosage requires upward adjustment.

This adjustment should be made every 1-2 days. 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.

Oxycodone hydrochloride/Naloxone hydrochloride 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.

For doses not realisable/practicable with this strength, other strengths of this medicinal product are available. Restless legs syndrome Oxycodone hydrochloride/Naloxone hydrochloride is indicated for patients suffering from RLS for at least 6 months.

RLS symptoms should be present daily and during daytime (≥ 4 days/week). Oxycodone hydrochloride/Naloxone hydrochloride should be used after failure of previous dopaminergic treatment. Dopaminergic treatment failure is defined as inadequate initial response, a response that has become inadequate with time, occurrence of augmentation or unacceptable tolerability despite adequate doses.

Previous treatment with at least one dopaminergic medicinal product should have lasted in general 4 weeks. A shorter period might be acceptable in case of unacceptable tolerability with dopaminergic therapy. The dosage should be adjusted to the sensitivity of the individual patient.

Treatment of patients with restless legs syndrome with Oxycodone hydrochloride/Naloxone hydrochloride should be under the supervision of a clinician with experience in the management of restless legs syndrome. 5 mg of oxycodone hydrochloride/naloxone hydrochloride at 12 hourly intervals.

Titration on a weekly basis is recommended in case higher doses are required. The mean daily dose in the pivotal study was 20mg/10mg oxycodone hydrochloride/naloxone hydrochloride. Some patients may benefit from higher daily doses up to a maximum of 60 mg/30 mg oxycodone hydrochloride/naloxone hydrochloride.

Oxycodone hydrochloride/Naloxone hydrochloride 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 situation, may benefit from asymmetric dosing tailored to the individual patient.

In general, the lowest effective dose should be selected. For doses not realisable/practicable with this strength other strengths of this medicinal product are available. Analgesia / Restless legs syndrome 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. 2). The clinical relevance of a relative high naloxone exposure in hepatic […]

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.

4) Euphoric mood Hallucination Nightmares Aggression Nervous system disorders Dizziness Headache Somnolence Convulsions1 Disturbance in attention Dysgeusia Speech disorder Syncope Tremor Lethargy Paraesthesia Sedation 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 Rhinorrhoea Cough Yawning Respiratory depression Central sleep apnoea syndrome 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 disorders Pruritus Skin reactions Hyperhidrosis 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 administration site conditions Asthenia Fatigue Chest pain, Chills, Drug withdrawal syndrome Malaise Pain Oedema peripheral Thirst 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.

g. derealisation) Nervous system disorders Concentration impaired Migraine Hypertonia, Involuntary muscle contractions Hypoaesthesia Abnormal co- ordination Hyperalgesia 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 Dental caries Hepatobiliary disorders Cholestasis Sphincter of Oddi dysfunction Skin and subcutaneous tissue disorders Dry skin Urticaria Renal and urinary disorders Dysuria Reproductive system and breast disorders Hypogonadism Amenorrhoea General disorders and administration site conditions Oedema Drug tolerance Drug withdrawal syndrome neonatal Undesirable effects in the treatment of restless legs syndrome The list below reflects the adverse drug reactions seen with oxycodone/naloxone in a 12-week, randomised, placebo-controlled clinical trial comprising a total of 150 patients on oxycodone/naloxone 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 oxycodone/naloxone in pain and not observed in RLS study population were added with the frequency of not known. System organ class MedDRA Very Common Common Uncommon Not known Immune system disorders Hypersensitivity Metabolism and nutrition disorders Decreased appetite up to loss of appetite Psychiatric disorders Insomnia Depression Libido decreased Sleep attacks Abnormal thinking Anxiety Confusional state Nervousness Restlessness Euphoric mood Hallucination Nightmares Drug dependence Aggression Nervous system disorders Headache Somnolence Dizziness, Disturbance in attention Tremor Paraesthesia Dysgeusia Convulsions1 Sedation Speech disorder Syncope Lethargy 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 Gastrointestinal disorders Constipation Nausea Abdominal pain Dry mouth Vomiting Flatulence Abdominal distention Diarrhoea Dyspepsia Eructation Tooth disorder Hepatobiliary disorders Hepatic enzymes increased3 Biliary colic Skin and subcutaneous tissue disorders Hyperhidorosis Pruritus, Skin reactions Musculoskeletal and connective tissue disorders Muscle spasms Muscle twitching Myalgia Reneal and urinary disorders Micturition urgency Urinary retention Reproductive systems and breast disorders Erectile dysfunction General disorders and administration site conditions Fatigue Chest pain Chills Thirst Pain Drug withdrawal syndrome Oedema peripheral Malaise Asthenia Investigation 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 […]

5) - Tolerance, physical dependence and withdrawal (see below) - Psychological dependence [addiction], abuse profile and history of substance and/or alcohol abuse (see below) - Elderly or infirm - Head injury, intracranial lesions or increased intracranial pressure, reduced level of consciousness of uncertain origin - Epileptic disorder or predisposition to convulsions - Hypotension - Hypertension - Pancreatitis - Mild hepatic impairment - Renal impairment - Opioid-induced paralytic ileus - Myxoedema - Hypothyroidism - Addison’s disease (adrenal cortical insufficiency) - Prostate hypertrophy - Toxic psychosis - Alcoholism - Delirium tremens - Cholelithiasis - Pre-existing cardiovascular diseases Respiratory depression The primary risk of opioid excess is respiratory depression.

Sleep-related breathing disorders Opioids can cause sleep-related breathing disorders including central sleep apnoea (CSA) and sleep related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the total opioid dosage.

Opioid-induced ventilatory impairment and persistent post-operative opioid use Do not use for acute post-operative pain owing to the increased risk of persistent post-operative opioid use (PPOU) and opioid-induced ventilatory impairment (OIVI) Risk from concomitant use of sedative medicines such as benzodiazepines or related drugs: Concomitant use of opioids, including oxycodone hydrochloride and sedative medicines such as benzodiazepines or related drugs may result in sedation, respiratory depression, coma and death.

Because of these risks, concomitant prescribing with these sedative medicines should be reserved for patients for whom alternative treatment options are not possible. If a decision is made to prescribe Oxycodone hydrochloride/Naloxone hydrochloride concomitantly with sedative medicines, the lowest effective dose should be used, and the duration of treatment should be as short as possible.

The patients should be followed closely for signs and symptoms of respiratory depression and sedation. 5). MAOIs Oxycodone hydrochloride/Naloxone hydrochloride must be administered with caution in patients taking MAOIs or who have received MAOIs within the previous two weeks.

Caution is advised in treating restless legs syndrome patients with additional sleep apnoea syndrome with these tablets due to the additive risk of respiratory depression. No data about the risk exist because in the clinical trial patients with sleep apnoea syndrome were excluded.

Caution must also be exercised when administering these tablets to patients with mild hepatic or renal impairment. Careful medical monitoring is particularly necessary for patients with severe renal impairment. Diarrhoea may be considered as a possible effect of naloxone.

Opioid Use Disorder (abuse and dependence) Tolerance and physical and/or psychological dependence may develop upon repeated administration of opioids such as oxycodone. Repeated use of Oxycodone hydrochloride/Naloxone hydrochloride can lead to Opioid Use Disorder (OUD).

A higher dose and longer duration of opioid treatment can increase the risk of developing OUD. Abuse or intentional misuse of Oxycodone hydrochloride/Naloxone hydrochloride may result in overdose and/or death. g. major depression, anxiety and personality disorders).

2). Before and during treatment the patient should also be informed about the risks and signs of OUD. If these signs occur, patients should be advised to contact their physician. g. too early requests for refills). This includes the review of concomitant opioids and psycho-active drugs (like benzodiazepines).

For patients with signs and symptoms of OUD, consultation with an addiction specialist should be considered. Discontinuation of treatment and withdrawal syndrome Repeated use of Oxycodone hydrochloride/Naloxone hydrochloride may lead to physical dependence and a withdrawal syndrome may occur upon abrupt cessation of therapy.

2). Oxycodone hydrochloride/Naloxone hydrochloride is not suitable for the treatment of withdrawal symptoms. 2). 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.

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 […]

1. - 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.

Additionally for restless legs syndrome: - History of opioid abuse