TARGINACT Prolonged release tablet Ref.[50554] Active ingredients: Naloxone Oxycodone Oxycodone and Naloxone

The major risk of all opioid excess is respiratory depression. Caution must be exercised when administering TarginAct to elderly or infirm patients, patients with opioid-induced paralytic ileus, patients presenting severely impaired pulmonary function, 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.

Opioids, such as TarginAct, may cause sleep-related breathing disorders including central sleep apnoea (CSA) and sleep-related hypoxaemia. Opioid use may increase the risk of CSA in a dose-dependent manner in some patients. Opioids may also cause worsening of pre-existing sleep apnoea (see section 4.8). TarginAct is not recommended for patients who present with CSA.

Caution must also be exercised when administering TarginAct to patients with mild hepatic or renal impairment (see section 4.3).

Diarrhoea may occur as a possible effect of naloxone.

CNS depressant co-administration

Concomitant use of TarginAct and sedative medicines such as benzodiazepines or related medicines 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.

Tolerance, physical dependence and withdrawal

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

TarginAct 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 analgesic effect. Chronic administration of TarginAct may lead to physical dependence.

Withdrawal symptoms may occur upon the abrupt cessation of therapy. If therapy with TarginAct is no longer required, it may be advisable to reduce the daily dose gradually in order to avoid the occurrence of withdrawal syndrome.

There is potential for development of psychological dependence (addiction) to opioid analgesics. TarginAct should be used with particular care in patients with a history of alcohol and drug abuse. Any abuse of TarginAct by drug addicts is strongly discouraged. If abused parenterally, intranasally or orally by individuals dependent on opioid agonists, such as heroin, morphine, or methadone, TarginAct 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).

TarginAct consists 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. In opioid addicts, who abuse TarginAct, acute withdrawal symptoms will be induced or already existing symptoms will be intensified.

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). In addition, naloxone has a slower elimination rate when administered intranasally.

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.

There is no clinical experience in patients with cancer associated to peritoneal carcinomatosis or with subocclusive syndrome in advanced stages of digestive and pelvic cancers. Therefore, the use of TarginAct in this population is not recommended.

The empty prolonged-release tablet matrix may be visible in the stool.

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

TarginAct is not recommended for pre-operative use or within the first 12-24 hours postoperatively.

Paediatric population

There is no experience with the use of TarginAct in children.

No interaction studies have been performed in adults.

The concomitant use of opioids with sedative medicines such as benzodiazepines or related medicine 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). Medicines which depress the CNS include, but are not limited to: other opioids, gabapentinoids such as pregabalin, anxiolytics, hypnotics and sedatives (incl. benzodiazepines), antipsychotics, antidepressants, phenothiazines and alcohol.

Clinically relevant changes in International Normalized Ratio (INR or Quick-value) in both directions have been observed in individuals if oxycodone and warfarin are co-administered.

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.

In vitro metabolism studies indicate that no clinically relevant interactions are to be expected between oxycodone and naloxone.

Concomitant administration of oxycodone with anticholinergics or medications with anticholinergic activity (e.g. tricyclic antidepressants, antihistamines, antipsychotics, muscle relaxants, anti-Parkinson medicines) may result in increased anticholinergic adverse effects. Oxycodone is metabolised primarily via the CYP3A4 and partly via the CYP2D6 pathways. The activities of these metabolic pathways may be inhibited or induced by various coadministered medicines or dietary elements. TarginAct doses may need to be adjusted accordingly. CYP3A4 inhibitors, such as macrolide antibiotics (e.g. clarithromycin), azoleantifungal agents (e.g. ketoconazole), protease inhibitors (e.g. ritonavir) and grapefruit juice, may cause decreased clearance of oxycodone, which could lead to an increase in oxycodone plasma concentrations. CYP3A4 inducers, such as rifampin, carbamazepine, phenytoin and St. John’s Wort, may induce the metabolism of oxycodone and cause increased clearance of the medicine, resulting in a decrease in oxycodone plasma concentrations.

Medicines that inhibit CYP2D6 activity, such as paroxetine and quinidine, may cause decreased clearance of oxycodone, which could lead to an increase in oxycodone plasma concentrations.

In addition, the likelihood of clinically relevant interactions between paracetamol, acetylsalicylic acid or naltrexone and the combination of oxycodone and naloxone in therapeutic concentrations is minimal.

Pregnancy

TarginAct is not recommended for use in pregnancy or during labour. Both oxycodone and naloxone pass into the placenta.

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.

Breastfeeding

TarginAct should not be used in mothers breastfeeding their infants as oxycodone passes into the breast milk.

Fertility

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

TarginAct may impair the ability to drive and use machines. This is particularly likely at the beginning of treatment with TarginAct, after dose increase or product rotation and if TarginAct is combined with alcohol or other CNS depressant agents.

Patients stabilised on a specific dosage will not necessarily be restricted. Patients should consult with their medical practitioner as to whether driving or the use of machinery is permitted.

The reactions are listed as MeDRA preferred term by system organ class and absolute frequency.

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.

The following additional undesirable effects are known for the active substance oxycodone hydrochloride.

c. Description of selected adverse reactions

The opioid abstinence or withdrawal syndrome (see section 4.4 as well as section 4.2) is characterised by some or all of the following: restlessness, lacrimation, rhinorrhoea, yawning, perspiration, chills, myalgia and mydriasis. Other symptoms may also develop, which includes: irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhoea or increased blood pressure, increased respiratory rate or increased heart rate.

Adverse reactions from spontaneous reporting

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the “6.04 Adverse Drug Reactions Reporting Form”, found online under SAHPRA’s publications: https://www.sahpra.org.za/Publications/Index/8. Alternatively report to: ZADrugSafety@mundipharma.co.za.

Not applicable.