4.1. Therapeutic indications

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

Second line symptomatic treatment of patients with severe to very severe idiopathic restless legs syndrome after failure of dopaminergic therapy.

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

Targinact is indicated in adults.

4.2. Posology and method of administration

Posology

Analgesia

The analgesic efficacy of Targinact 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 naïve 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. Targinact 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 in steps of 5 mg/2.5 mg, twice daily, or where necessary 2.5mg/1.25 mg or 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. Slightly elevated (dose corrected) peak plasma concentrations should be taken into account when the 2.5 mg/ 1.25 mg tablet is used.

Targinact 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

Targinact is indicated for patients suffering from RLS for at least 6 months. RLS symptoms should be present daily and during daytime (≥ 4 days/week). Targinact 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 Targinact should be under the supervision of a clinician with experience in the management of restless legs syndrome.

Unless otherwise prescribed, Targinact should be administered as follows:

Adults

The usual starting dose is 5 mg/2.5 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.

Targinact 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. 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 these tablets to patients with mild hepatic impairment (see section 4.4). In patients with moderate and severe hepatic impairment Targinact 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 these tablets to patients with renal impairment (see section 4.4).

Paediatric population

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

Method of administration

Oral use.

These prolonged-release tablets are 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. These tablets must be swallowed whole, and not broken, chewed or crushed (see section 4.4).

Treatment goals and discontinuation

Before initiating treatment with Targinact, a treatment strategy including treatment duration and treatment goals, and a plan for end of the treatment, should be agreed together with the patient, in accordance with pain management guidelines. During treatment, there should be frequent contact between the physician and the patient to evaluate the need for continued treatment, consider discontinuation and to adjust dosages if needed. When a patient no longer requires therapy with oxycodone, it may be advisable to taper the dose gradually to prevent symptoms of withdrawal. In absence of adequate pain control, the possibility of hyperalgesia, tolerance and progression of underlying disease should be considered (see section 4.4).

Duration of use

These tablets should not be administered for longer than absolutely necessary.

Restless legs syndrome

At least every three months during therapy with Targinact patients should be clinically evaluated. Treatment should only be continued if Targinact is considered effective and the benefit is considered to outweigh adverse effects and potential harms in individual patients. Prior to continuation of RLS treatment beyond 1 year a discharge regimen by gradually tapering down of Targinact over a period of approximately one week should be considered to establish if continued treatment with Targinact is indicated.

When a patient no longer requires opioid therapy cessation of treatment by tapering down over a period of approximately one week is recommended in order to reduce the risk of a withdrawal reaction (see section 4.4).

4.3. Contraindications

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

• 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

4.4. Special warnings and precautions for use

Caution must be exercised when administering these tablets to patients with:

• Severely impaired respiratory function

• Sleep apnoea

• CNS depressants co-administration (see below and section 4.5)

• Monoamine oxidase inhibitors (MAOIs, see below and section 4.5)

• 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.

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 Targinact 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. In this respect, it is strongly recommended to inform patients and their caregivers to be aware of these symptoms (see section 4.5).

MAOIs

Targinact 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.

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 Targinact. 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 withdrawal syndrome.

Targinact is not suitable for the treatment of withdrawal symptoms.

There is no clinical experience with Targinact in the long-term treatment of RLS beyond 1 year (see section 4.2).

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 Targinact 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 Targinact may result in overdose and/or death. The risk of developing OUD is increased in patients with a personal or a family history (parents or siblings) of substance use disorders (including alcohol use disorder), in current tobacco users or in patients with a personal history of other mental health disorders (e.g. major depression, anxiety and personality disorders).

Before initiating treatment with Targinact and during the treatment, treatment goals and a discontinuation plan should be agreed with the patient (see section 4.2). 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.

Patients will require monitoring for signs of drug-seeking behaviour (e.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.

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 Targinact (see sections 4.5 and 4.7).

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

Studies have not been performed on the safety and efficacy of Targinact 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 these tablets in this population is not recommended.

These tablets are 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 these tablets depends on a careful risk-benefit assessment for each individual patient.

Prolonged release opioids should not be used for acute post-operative pain owing to the increased risk of persistent post-operative opioid use (PPOU) and opioid-induced ventilatory impairment (OIVI).

Any abuse of these tablets by drug addicts is strongly discouraged.

If abused parenterally, intranasally or orally by individuals dependent on opioid agonists, such as heroin, morphine, or methadone, these tablets are 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).

These tablets consist 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.

Opioids such as oxycodone may influence the hypothalamic-pituitary-adrenal or -gonadal axes. Some changes that can be seen include an increase in serum prolactin and decreases in plasma cortisol and testosterone. Clinical symptoms may manifest from these hormonal changes.

In patients under long-term opioid treatment the switch to Targinact may initially provoke withdrawal symptoms or diarrhoea.

Hyperalgesia that will not respond to a further dose increase of oxycodone may occur in particular in high doses. An oxycodone dose reduction or change in opioid may be required.

Hepatobiliary disorders

Oxycodone may cause dysfunction and spasm of the sphincter of Oddi, thus increasing the risk of biliary tract symptoms and pancreatitis. Therefore, oxycodone / naloxone has to be administered with caution in patients with pancreatitis and diseases of the biliary tract.

The use of Targinact may produce positive results in doping controls. The use of Targinact as a doping agent may become a health hazard.

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take Targinact.

4.5. Interaction with other medicinal products and other forms of interaction

The concomitant use of opioids with sedative medicines such as benzodiazepines or related drugs increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. The dose and duration of concomitant use should be limited (see section 4.4).

Drugs which depress the CNS include, but are not limited to: other opioids, gabapentinoids such as pregabalin, anxiolytics, hypnotics and sedatives (including benzodiazepines), anti-depressants, antipsychotics, anti-histamines and anti-emetics.

Concomitant administration of oxycodone with anticholinergics or medications with anticholinergic activity (e.g. tri-cyclic antidepressants, antihistamines, anti-psychotics, muscle relaxants, anti-Parkinson drugs) may result in increased anticholinergic adverse effects.

Targinact must be administered with caution in patients taking MAOIs or who have received MAOIs within the previous two weeks.

Concomitant administration of oxycodone with serotonin agents, such as a Selective Serotonin Re-uptake Inhibitor (SSRI) or a Serotonin Norepinephrine Re-uptake Inhibitor (SNRI) may cause serotonin toxicity. The symptoms of serotonin toxicity may include mental-status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular abnormalities (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhoea). Oxycodone should be used with caution and the dosage may need to be reduced in patients using these medications.

Alcohol may enhance the pharmacodynamic effects of Targinact; 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. Targinact 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 these tablets 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 Targinact 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 these 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. These tablets 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 taking these 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 these tablets by the breastfeeding mother. Breastfeeding should be discontinued during treatment with Targinact.

Fertility

No data on the effect of oxycodone and naloxone on human fertility are available. In rats, there was no effect on mating or fertility with Targinact treatment (see section 5.3).

4.7. Effects on ability to drive and use machines

Targinact has moderate influence on the ability to drive and use machines. This is particularly likely at the beginning of treatment, after dose increase or product rotation and if these tablets are 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 Targinact 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).

This medicine can impair cognitive function and can affect a patient's ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:

• The medicine is likely to affect your ability to drive.

• Do not drive until you know how the medicine affects you.

• It is an offence to drive while you have this medicine in your body over a specified limit unless you have a defence (called the 'statutory defence').

• This defence applies when:

o The medicine has been prescribed to treat a medical or dental problem; and

o You have taken it according to the instructions given by the prescriber and in the information provided with the medicine.

• Please note that it is still an offence to drive if you are unfit because of the medicine (i.e. your ability to drive is being affected)

Details regarding a new driving offence concerning driving after drugs have been taken in the UK may be found here: https://www.gov.uk/drug-driving-law

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

Immune system disorders

Uncommon:

Hypersensitivity

Metabolism and nutrition disorders

Common:

Decreased appetite up to loss of appetite

Psychiatric disorders

Common:

Insomnia

Uncommon:

Abnormal thinking, anxiety, confusional state, depression, libido decreased, nervousness, restlessness

Not known:

Euphoric mood, hallucination, nightmares, aggression, drug dependence (see section 4.4)

Nervous system disorders

Common:

Dizziness, headache, somnolence

Uncommon:

Convulsions (particularly in persons with epileptic disorder or predisposition to convulsions), disturbance in attention, dysgeusia, speech disorder, syncope, tremor, lethargy

Not known:

Paraesthesia, sedation

Eye disorders

Uncommon:

Visual impairment

Ear and labyrinth disorders

Common:

Vertigo

Cardiac disorders

Uncommon:

Angina pectoris (in particular in patients with history of coronary artery disease), palpitations

Rare:

Tachycardia

Vascular disorders

Common:

Hot flush

Uncommon:

Blood pressure decreased, blood pressure increased

Respiratory, thoracic and mediastinal disorders

Uncommon:

Dyspnoea, rhinorrhoea, cough

Rare:

Yawning

Not known:

Respiratory depression, central sleep apnoea syndrome (see section 4.4)

Gastrointestinal disorders

Common:

Abdominal pain, constipation, diarrhoea, dry mouth, dyspepsia, vomiting, nausea, flatulence

Uncommon:

Abdominal distension

Rare:

Tooth disorder

Not known:

Eructation

Hepatobiliary disorders

Uncommon:

Hepatic enzymes increased, biliary colic

Skin and subcutaneous tissue disorders

Common:

Pruritus, skin reactions, hyperhidrosis

Musculoskeletal and connective tissue disorders

Uncommon:

Muscle spasms, muscle twitching, myalgia

Renal and urinary disorders

Uncommon:

Micturition urgency

Not known:

Urinary retention

Reproductive system and breast disorders

Not known:

Erectile dysfunction

General disorders and administration site conditions

Common:

Asthenia, fatigue

Uncommon:

Chest pain, chills, malaise, pain, peripheral oedema, thirst

Not known:

Drug withdrawal syndrome

Investigations

Uncommon:

Weight decreased

Rare:

Weight increased

Injury, poisoning and procedural complications

Uncommon:

Injuries from accidents

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.

Infections and infestations

Rare:

Herpes simplex

Immune system disorders

Not known:

Anaphylactic reaction

Metabolism and nutrition disorders

Uncommon:

Dehydration

Rare:

Increased appetite

Psychiatric disorders

Common:

Altered mood and personality change, decreased activity, psychomotor hyperactivity

Uncommon:

Agitation, perception disturbances (e.g. derealisation)

Nervous system disorders

Uncommon:

Concentration impaired, migraine, hypertonia, involuntary muscle contractions, hypoaesthesia, abnormal coordination

Not known:

Hyperalgesia

Ear and labyrinth disorders

Uncommon:

Hearing impaired

Vascular disorders

Uncommon:

Vasodilatation

Respiratory, thoracic and mediastinal disorders

Uncommon:

Dysphonia

Gastrointestinal disorders

Common:

Hiccups

Uncommon:

Dysphagia, ileus, mouth ulceration, stomatitis

Rare:

Melaena, gingival bleeding,

Not known:

Dental caries

Hepatobiliary disorders

Not known:

Cholestasis, Sphincter of Oddi dysfunction

Skin and subcutaneous tissue disorders

Uncommon:

Dry skin

Rare:

Urticaria

Renal and urinary disorders

Common:

Dysuria

Reproductive system and breast disorders

Uncommon:

Hypogonadism

Not known:

Amenorrhoea

General disorders and administration site conditions

Uncommon:

Oedema

Not known:

Drug withdrawal syndrome neonatal, drug tolerance

Undesirable effects in the treatment of restless legs syndrome

The list below reflects the adverse drug reactions seen with Targinact in a 12-week, randomised, placebo-controlled clinical trial comprising a total of 150 patients on Targinact 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 these tablets in pain and not observed in RLS study population were added with the frequency of not known.

Immune system disorders

Not known:

Hypersensitivity

Metabolism and nutrition disorders

Common:

Decreased appetite up to loss of appetite

Psychiatric disorders

Common:

Insomnia, depression

Uncommon:

Libido decreased, sleep attacks

Not known:

Abnormal thinking, anxiety, confusional state, nervousness, restlessness, euphoric mood, hallucination, nightmares, drug dependence, aggression

Nervous system disorders

Very common:

Headache, somnolence

Common:

Dizziness, disturbance in attention, tremor, paraesthesia

Uncommon:

Dysgeusia

Not known:

Convulsions (particularly in persons with epileptic disorder or predisposition to convulsions), sedation, speech disorder, syncope, lethargy

Eye disorders

Common:

Visual impairment

Ear and labyrinth disorders

Common:

Vertigo

Cardiac disorders

Not known:

Angina pectoris (in particular in patients with history of coronary artery disease), palpitations, tachycardia

Vascular disorders

Common:

Hot flush, blood pressure decreased, blood pressure increased

Respiratory, thoracic and mediastinal disorders

Uncommon:

Dyspnoea

Not known:

Cough, rhinorrhoea, respiratory depression, yawning

Gastrointestinal disorders

Very common:

Constipation, nausea

Common:

Abdominal pain, dry mouth, vomiting

Uncommon:

Flatulence

Not known:

Abdominal distension, diarrhoea, dyspepsia, eructation, tooth disorder

Hepatobiliary disorders

Common:

Hepatic enzymes increased (alanine aminotransferase increased, gamma-glutamyltransferase increased),

Not known:

Biliary colic

Skin and subcutaneous tissue disorders

Very common:

Hyperhidrosis

Common:

Pruritus, skin reactions

Musculoskeletal and connective tissue disorders

Not known:

Muscle spasms, muscle twitching, myalgia

Renal and urinary disorders

Not known:

Micturition urgency, urinary retention

Reproductive system and breast disorders

Uncommon:

Erectile dysfunction

General disorders and administration site conditions

Very common:

Fatigue

Common:

Chest pain, chills, thirst, pain

Uncommon:

Drug withdrawal syndrome, oedema peripheral,

Not known:

Malaise, asthenia

Investigation

Not known:

Weight decreased, weight increased

Injury, poisoning and procedural complications

Uncommon:

Injuries from accidents

Drug dependence

The frequencies in the above table regarding drug dependence, drug withdrawal syndrome and drug tolerance reflects that although risk is low with short term and low dose use, it is highly variable.

Repeated use of Targinact can lead to drug dependence, even at therapeutic doses. The risk of drug dependence may vary depending on patient's individual risk factors, dosage and duration of opioid treatment (see section 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Symptoms of intoxication

Depending on the history of the patient, an overdose of Targinact 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, hypotonia, bradycardia as well as hypotension. Toxic leukoencephalopathy has been observed with oxycodone overdose. 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.