Special Warning : אזהרת שימוש

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

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.

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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 Targin®. 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.


Targin® is not suitable for the treatment of withdrawal symptoms.
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 Targin® 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 Targin® 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 Targin® 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 psychoactive 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 Targin® (see sections 4.5 and 4.7).

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

Studies have not been performed on the safety and efficacy of Targin® 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 Targin® 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 Targin® depends on a careful risk-benefit assessment for each individual patient.

Any abuse of Targin® by drug addicts is strongly discouraged.

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

Biliary tract disorders
Oxycodone can cause an increase in intrabiliary pressure and spasm as a result of its effects on the sphincter of Oddi; therefore, monitor patients with diseases of the biliary tract (including pancreatitis) for worsening symptoms while administering oxycodone.

The use of Targin® may produce positive results in doping controls. The use of Targin® 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 Targin®.

Effects on Driving

4.7 Effects on ability to drive and use machines

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

Patients being treated with Targin® 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.
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.
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