Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2023 Publisher: Napp Pharmaceuticals Ltd, Cambridge Science Park, Milton Road, Cambridge CB4 0GW
Additionally for restless legs syndrome:
Caution must be exercised when administering these tablets to patients with:
The primary risk of opioid excess is respiratory depression.
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.
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).
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.
During long-term administration, the patient may develop tolerance to the medicinal product and require higher doses to maintain the desired effect. Chronic administration of these tablets may lead to physical dependence. Withdrawal symptoms may occur upon the abrupt cessation of therapy. If therapy is no longer required, it may be advisable to reduce the daily dose gradually in order to avoid the occurrence of withdrawal syndrome (see section 4.2).
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).
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.
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 prolongedrelease 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.
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 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.
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.
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.
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.
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.
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).
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:
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
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.
Uncommon: Hypersensitivity
Common: Decreased appetite up to loss of appetite
Common: Insomnia
Uncommon: Abnormal thinking, anxiety, confusional state, depression, libido decreased, nervousness, restlessness
Rare: Drug dependence (see Section 4.4)
Not known: Euphoric mood, hallucination, nightmares, aggression
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
Uncommon: Visual impairment
Common: Vertigo
Uncommon: Angina pectoris (in particular in patients with history of coronary artery disease), palpitations
Rare: Tachycardia
Common: Hot flush
Uncommon: Blood pressure decreased, blood pressure increased
Uncommon: Dyspnoea, rhinorrhoea, cough
Rare: Yawning
Not known: Respiratory depression, Central sleep apnoea syndrome (see section 4.4)
Common: Abdominal pain, constipation, diarrhoea, dry mouth, dyspepsia, vomiting, nausea, flatulence
Uncommon: Abdominal distension
Rare: Tooth disorder
Not known: Eructation
Uncommon: Hepatic enzymes increased, biliary colic
Common: Pruritus, skin reactions, hyperhidrosis
Uncommon: Muscle spasms, muscle twitching, myalgia
Uncommon: Micturition urgency
Not known: Urinary retention
Not known: Erectile dysfunction
Common: Asthenia, fatigue
Uncommon: Chest pain, chills, drug withdrawal syndrome, malaise, pain, peripheral oedema, thirst
Uncommon: Weight decreased
Rare: Weight increased
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.
Rare: Herpes simplex
Not known: Anaphylactic reaction
Uncommon: Dehydration
Rare: Increased appetite
Common: Altered mood and personality change, decreased activity, psychomotor hyperactivity
Uncommon: Agitation, perception disturbances (e.g. derealisation)
Uncommon: Concentration impaired, migraine, hypertonia, involuntary muscle contractions, hypoaesthesia, abnormal coordination
Not known: Hyperalgesia
Uncommon: Hearing impaired
Uncommon: Vasodilatation
Uncommon: Dysphonia
Common: Hiccups
Uncommon: Dysphagia, ileus, mouth ulceration, stomatitis
Rare: Melaena, gingival bleeding,
Not known: Dental caries
Not known: Cholestasis, Sphincter of Oddi dysfunction
Uncommon: Dry skin
Rare: Urticaria
Common: Dysuria
Uncommon: Hypogonadism
Not known: Amenorrhoea
Uncommon: Oedema, drug tolerance
Not known: Drug withdrawal syndrome neonatal
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.
Not known: Hypersensitivity
Common: Decreased appetite up to loss of appetite
Common: Insomnia, depression
Uncommon: Libido decreased, sleep attacks
Not known: Abnormal thinking, anxiety, confusional state, nervousness, restlessness, euphoric mood, hallucination, nightmares, drug dependence, aggression
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
Common: Visual impairment
Common: Vertigo
Not known: Angina pectoris (in particular in patients with history of coronary artery disease), palpitations, tachycardia
Common: Hot flush, blood pressure decreased, blood pressure increased
Uncommon: Dyspnoea
Not known: Cough, rhinorrhoea, respiratory depression, yawning
Very common: Constipation, nausea
Common: Abdominal pain, dry mouth, vomiting
Uncommon: Flatulence
Not known: Abdominal distension, diarrhoea, dyspepsia, eructation, tooth disorder
Common: Hepatic enzymes increased (alanine aminotransferase increased, gammaglutamyltransferase increased),
Not known: Biliary colic
Very common: Hyperhidrosis
Common: Pruritus, skin reactions
Not known: Muscle spasms, muscle twitching, myalgia
Not known: Micturition urgency, urinary retention
Uncommon: Erectile dysfunction
Very common: Fatigue
Common: Chest pain, chills, thirst, pain
Uncommon: Drug withdrawal syndrome, oedema peripheral,
Not known: Malaise, asthenia
Not known: Weight decreased, weight increased
Uncommon: Injuries from accidents
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 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.
Not applicable.
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