DONELOXON

4). Analgesia The analgesic efficacy of Doneloxon 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, Doneloxon 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 Doneloxon depending on their previous opioid experience.

5 mg is intended for dose titration when initiating opioid therapy and individual dose adjustment. The maximum daily dose of Doneloxon 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 oxycodone/naloxone 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. Doneloxon 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 Doneloxon requires upward adjustment.

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.

Doneloxon 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. Restless legs syndrome (RLS) Doneloxon is indicated for patients suffering from RLS for at least 6 months. RLS symptoms should be present daily and during daytime (on at least 4 days per week).

Doneloxon 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 dose should be adjusted to the sensitivity of the individual patient.

Treatment of patients with restless legs syndrome with oxycodone/naloxone 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 20 mg/10 mg 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.

Doneloxon 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 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 dose 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 […]

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 System organ class MedDRA Common Uncommon Rare Not known Immune system disorders Hypersensitivity Metabolism and nutrition disorders Decreased appetite up to loss of appetite Psychiatric disorders Insomnia Abnormal thinking Anxiety Confusion Depression Libido decreased Nervousness Restlessness Drug dependence 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 Gastrointestinal disorders Abdominal pain Constipation Diarrhoea Dry mouth Dyspepsia Vomiting Nausea Flatulence Abdominal distention Tooth disorder Eructation System organ class MedDRA Common Uncommon Rare Not known 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 Drug withdrawal syndrome Chest pain Chills Malaise Pain Peripheral oedema Thirst Investigations Weight decreased Weight increased Injury, poisoning and procedural complications Injury 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. 4) 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 Central sleep apnoea syndrome 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 System organ class MedDRA Common Uncommon Rare Not known Renal and urinary disorders Dysuria Reproductive system and breast disorders Hypogonadism Amenorrhoea General disorders and administration site conditions Oedema Drug tolerance Drug withdrawal syndrome 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 doses 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 Confusion Nervousness Restlessness Euphoric mood Hallucination Nightmares Aggression Drug dependence Nervous system disorders Headache Somnolence Dizziness Disturbance in attention Tremor Paraesthesia Dysgeusia Convulsions1 Sedation Speech disorder Syncope Lethargy System organ class MedDRA Very common Common Uncommon Not known 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 distension Diarrhoea Dyspepsia Eructation Tooth disorder Hepatobiliary disorders Hepatic enzymes increased3 Biliary colic Skin and subcutaneous tissue disorders Hyperhidrosis Pruritus Skin reactions Musculoskeletal and connective tissue disorders Muscle spasm Muscle twitching Myalgia Renal and urinary disorders Micturition urgency Urinary retention Reproductive system and breast disorders Erectile dysfunction General disorders and administration site conditions Fatigue Chest pain Chills Thirst Pain Drug withdrawal syndrome Oedema […]

Respiratory depression The major risk of opioid excess is respiratory depression. Caution must be exercised when administering oxycodone/naloxone 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.

Caution is advised in patients taking MAO inhibitors or CNS depressants. Risk from concomitant use of sedative medicinal products such as benzodiazepines or related medicinal product Concomitant use of oxycodone/naloxone and sedative medicinal products such as benzodiazepines or related medicinal products may result in sedation, respiratory depression, coma and death.

Because of these risks, concomitant prescribing with these sedative medicinal products should be reserved for patients for whom alternative treatment options are not possible. If a decision is made to prescribe oxycodone/naloxone concomitantly with sedative medicinal products, 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). Caution is advised in treating restless legs syndrome patients with additional sleep apnoea syndrome with oxycodone/naloxone 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. Hepatic or renal impairment Caution must also be exercised when administering oxycodone/naloxone to patients with mild hepatic or renal impairment.

Careful medical monitoring is particularly necessary for patients with severe renal impairment. Hepatobiliary disorders Oxycodone may cause dysfunction and spasm of the sphincter of Oddi, thus raising intrabiliary pressure and increasing the risk of biliary tract symptoms and pancreatitis.

Therefore, oxycodone has to be administered with caution in patients with pancreatitis and diseases of the biliary tract. Diarrhoea Diarrhoea may be considered as a possible effect of naloxone. Drug dependence, tolerance and potential for abuse 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 Doneloxon may lead to Opioid Use Disorder (OUD). A higher dose and longer duration of opioid treatment can increase the risk of developing OUD. Abuse or intentional misuse of Doneloxon 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.

A comprehensive patient history should be taken to document concomitant medications, including over-the-counter medicines and medicines obtained on- line, and past and present medical and psychiatric conditions. Tolerance Patients may find that treatment is less effective with chronic use and express a need to increase the dose to obtain the same level of pain control as initially experienced.

Patients may also supplement their treatment with additional pain relievers. These could be signs that the patient is developing tolerance. The risks of developing tolerance should be explained to the patient. Overuse or misuse may result in overdose and/or death.

It is important that patients only use medicines that are prescribed for them at the dose they have been prescribed and do not give this medicine to anyone else. Patients should be closely monitored for signs of misuse, abuse, or addiction.

The clinical need for analgesic treatment should be reviewed regularly. Drug withdrawal syndrome Prior to starting treatment with any opioids, a discussion should be held with patients to put in place a withdrawal strategy for ending treatment with this medicine.

Drug withdrawal syndrome may occur upon abrupt cessation of therapy or dose reduction. When a patient no longer requires therapy, it is advisable to taper the dose gradually to minimise symptoms of withdrawal. Tapering from a high dose may take weeks to months.

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

If women take this drug during pregnancy, there is a risk that their newborn infants will experience neonatal […]

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