1. Name Of The Medicinal Product
Targinact® 5 mg/2.5 mg, 10 mg/5 mg, 20 mg/10 mg and 40 mg/20 mg prolonged-release tablets
2. Qualitative And Quantitative Composition
Targinact 5 mg/2.5 mg
Each prolonged-release tablet contains 5 mg of oxycodone hydrochloride equivalent to 4.5 mg oxycodone, and 2.73 mg of naloxone hydrochloride dihydrate equivalent to 2.5 mg naloxone hydrochloride and 2.25 mg naloxone.
Excipients: Each prolonged-release tablet contains 68.17 mg lactose anhydrous
Targinact 10 mg/5 mg
Each prolonged-release tablet contains 10 mg of oxycodone hydrochloride equivalent to 9.0 mg oxycodone, and 5.45 mg of naloxone hydrochloride dihydrate equivalent to 5.0 mg naloxone hydrochloride and 4.5 mg naloxone.
Excipients: Each prolonged-release tablet contains 61.04 mg lactose anhydrous
Targinact 20 mg/10 mg
Each prolonged-release tablet contains 20 mg of oxycodone hydrochloride equivalent to 18.0 mg oxycodone, and 10.9 mg of naloxone hydrochloride dihydrate equivalent to 10.0 mg naloxone hydrochloride and 9.0 mg naloxone
Excipients: Each prolonged-release tablet contains 51.78 mg lactose anhydrous
Targinact 40 mg/20 mg
Each prolonged-release tablet contains 40 mg of oxycodone hydrochloride equivalent to 36.0 mg oxycodone, and 21.8 mg of naloxone hydrochloride dihydrate equivalent to 20.0 mg naloxone hydrochloride and 18.0 mg naloxone
Excipients: Each prolonged-release tablet contains 103.55 mg lactose anhydrous
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Prolonged-release tablet
Targinact 5 mg/2.5 mg
Oblong, blue film-coated tablets, marked “OXN” on one side and “5” on the other side.
Targinact 10 mg/5 mg
Oblong, white film-coated tablets, marked “OXN” on one side and “10” on the other side.
Targinact 20 mg/10 mg
Oblong, pink film-coated tablets, marked “OXN” on one side and “20” on the other side.
Targinact 40 mg/20 mg
Oblong, yellow film-coated tablets, marked “OXN” on one side and “40” on the other side.
4. Clinical Particulars
4.1 Therapeutic Indications
Severe pain, which can be adequately managed only with opioid analgesics.
The opioid antagonist naloxone is added to counteract opioid-induced constipation by blocking the action of oxycodone at opioid receptors locally in the gut.
4.2 Posology And Method Of Administration
Targinact is for oral use.
Posology
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, Targinact 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.
Patients already receiving opioids may be started on higher doses of Targinact depending on their previous opioid experience.
Targinact 5 mg/2.5 mg is intended for dose titration when initiating opioid therapy and individual dose adjustment.
The maximum daily dose of Targinact is 80 mg oxycodone hydrochloride and 40 mg naloxone hydrochloride. For patients requiring higher doses of Targinact, administration of supplemental oxycodone hydrochloride prolonged-release 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 Targinact with a subsequent switch to another opioid a worsening of the bowel function can be expected.
Some patients taking Targinact 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 dose of Targinact requires upward adjustment. This adjustment should be made every 1-2 days in steps of twice daily 5 mg/2.5 mg, or where demanded 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.
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.
Children and adolescents (under 18 years)
Targinact is not recommended for use in children and adolescents below the age of 18 years due to a lack of data on safety and efficacy.
Elderly patients
As for younger adults the dosage should be adjusted to the intensity of the pain 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 Targinact 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 Targinact to patients with renal impairment (see section 4.4).
Method of administration
Targinact is 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. Targinact must be swallowed whole, and not broken or chewed.
Duration of use
Targinact should not be administered for longer than absolutely necessary. If long-term pain treatment is necessary in view the nature and severity of the illness, careful and regular monitoring is required to establish whether and to what extent further treatment is necessary. When the patient no longer requires opioid therapy, it may be advisable to taper the dose gradually (see section 4.4).
4.3 Contraindications
• Hypersensitivity to the active substances or to any of the excipients,
• Any situation where opioids are contraindicated,
• Severe respiratory depression with hypoxia and/or hypercapnoea,
• Severe chronic obstructive pulmonary disease,
• Cor pulmonale,
• Severe bronchial asthma,
• Non-opioid induced paralytic ileus,
• Moderate to severe hepatic impairment.
4.4 Special Warnings And Precautions For Use
The major risk from opioids 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, 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, or patients taking MAO inhibitors.
Caution must also be exercised when administering Targinact to patients with mild hepatic or renal impairment. A careful medical monitoring is particularly necessary for patients with severe renal impairment.
Diarrhoea may be considered as a possible effect of naloxone.
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, including Targinact. Targinact should be used with particular care in patients with a history of alcohol and drug abuse. Oxycodone alone has an abuse profile similar to other strong agonist opioids.
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).
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 Targinact in this population is not recommended.
Targinact is 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 postoperative treatment with Targinact depends on a careful risk-benefit assessment for each individual patient.
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.
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.
This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take Targinact.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
No interaction studies have been performed in adults.
Substances having a CNS-depressant effect (e.g. other opioids, sedatives, hypnotics, anti-depressants, sleeping aids, phenothiazines, neuroleptics, anti-histamines and anti-emetics) may enhance the CNS-depressant effect (e.g. respiratory depression) of Targinact.
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.
In vitro metabolism studies indicate that no clinically relevant interactions are to be expected between oxycodone and naloxone. At therapeutic concentrations, Targinact is not expected to cause clinically relevant interactions with other concomitantly administered active substances metabolised over the CYP isomers CYP1A2, CYP2A6, CYP2C9/19, CYP2D6, CYP2E1 and CYP3A4. 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.
4.6 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 Targinact 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.
Targinact should only be used during pregnancy if the benefit outweighs the possible risks to the unborn child or neonate.
Lactation
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 use of Targinact 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 Targinact by the breast-feeding mother.
Breast-feeding should be discontinued during treatment with Targinact.
4.7 Effects On Ability To Drive And Use Machines
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 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.
4.8 Undesirable Effects
The following frequencies are the basis for assessing undesirable effects:
Very common (
Common (
Uncommon (
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.
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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.
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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, skeletal muscle flaccidity, bradycardia as well as hypotension. 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.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Oxycodone combinations
ATC code: N02AA55
Oxycodone and naloxone have an affinity for kappa, mu and delta opiate receptors in the brain, spinal cord and peripheral organs (e.g. intestine). Oxycodone acts as opioid-receptor agonist at these receptors and affects pain relief by binding to the endogenous opioid receptors in the CNS. By contrast, naloxone is a pure antagonist acting on all types of opioid receptors.
Because of the pronounced first-pass metabolism, the bioavailability of naloxone upon oral administration is < 3%, therefore a clinically relevant systemic effect is unlikely. Due to the local competitive antagonism of the opioid receptor mediated oxycodone effect by naloxone in the gut, naloxone reduces the bowel function disorders that are typical for opioid treatment.
In a 12 weeks parallel group double-blinded study in 322 patients with opioid-induced constipation, patients who were treated with oxycodone hydrochloride - naloxone hydrochloride had on average one extra complete spontaneous (without laxatives) bowel movement in the last week of treatment, compared to patients who continued using similar doses of oxycodone hydrochloride prolonged release tablets (p<0.0001). The use of laxatives in the first four weeks was significantly lower in the oxycodone-naloxone group compared to the oxycodone monotherapy group (31% versus 55%, respectively, p<0.0001). Similar results were shown in a study with 265 non-cancer patients comparing daily doses of oxycodone hydrochloride/naloxone hydrochloride of 60 mg/30 mg to up to 80 mg/40 mg with oxycodone hydrochloride monotherapy in the same dose range.
Opioids can influence the hypothalamic-pituitary-adrenal or gonadal axes. Among the changes observed are an increase of prolactin in the serum and a reduced level of cortisol and testosterone in the plasma. Clinical symptoms may occur because of these hormone changes.
Preclinical studies show differing effects of natural opioids on components of the immune system. The clinical significance of these findings is not known. It is not known whether oxycodone, a semi-synthetic opioid, has similar effects on the immune system to natural opioids.
5.2 Pharmacokinetic Properties
Oxycodone hydrochloride
Absorption
Oxycodone has a high absolute bioavailability of up to 87% following oral administration.
Distribution
Following absorption, oxycodone is distributed throughout the entire body. Approximately 45% is bound to plasma protein.
Oxycodone crosses the placenta and may be detected in breast milk.
Metabolism
Oxycodone is metabolized in the gut and the liver to noroxycodone and oxymorphone and to various glucuronide conjugates. Noroxycodone, oxymorphone and noroxymorphone are produced via the cytochrome P450 system. In vitro studies suggest that therapeutic doses of cimetidine are not likely to significantly influence the production of noroxycodone. Quinidine reduces the production of oxymorphone in man without substantially influencing the pharmacodynamics of oxycodone. The contribution of the metabolites to overall pharmacodynamic effect is insignificant.
Elimination
Oxycodone and its metabolites are excreted in both urine and faeces.
Naloxone hydrochloride
Absorption
Following oral administration, naloxone has a very low systemic availability of <3%.
Distribution
Naloxone passes into the placenta. It is not known, whether naloxone also passes into breast milk.
Metabolism and Elimination
After parenteral administration, the plasma half-life is approximately one hour. The duration of action depends upon the dose and route of administration, intramuscular injection producing a more prolonged effect than intravenous doses. It is metabolised in the liver and excreted in the urine. The principal metabolites are naloxone glucuronide, 6β-Naloxol and its glucuronide.
Oxycodone hydrochloride/ naloxone hydrochloride combination (Targinact)
The pharmacokinetic characteristics of oxycodone from Targinact is equivalent to those of prolonged-release oxycodone hydrochloride tablets administered together with prolonged-release naloxone hydrochloride tablets.
All dosage strengths of Targinact are interchangeable.
After the oral administration of Targinact in maximum dose to healthy subjects, the plasma concentrations of naloxone are so low that it is not feasible to carry out a pharmacokinetic analysis. To conduct a pharmacokinetic analysis naloxone-3-glucuronide as surrogate marker is used, since its plasma concentration is high enough to measure.
Overall, following ingestion of a high-fat breakfast, the bioavailability and peak plasma concentration (Cmax) of oxycodone were increased by an average of 16% and 30% respectively compared to administration in the fasting state. This was evaluated as clinically not relevant, therefore Targinact prolonged-release tablets may be taken with or without food (see section 4.2).
In vitro drug metabolism studies have indicated that the occurrence of clinically relevant interactions involving Targinact is unlikely.
Elderly patients
Oxycodone:
For AUC of oxycodone, on average there was an increase to 118% (90% C.I.: 103, 135), for elderly compared with younger volunteers. For Cmax of oxycodone, on average there was an increase to 114% (90% C.I.: 102, 127). For Cmin of oxycodone, on average there was an increase to 128% (90% C.I.: 107, 152).
Naloxone:
For AUC of naloxone, on average there was an increase to 182% (90% C.I.: 123, 270), for elderly compared with younger volunteers. For Cmax of naloxone, on average there was an increase to 173% (90% C.I.: 107, 280). For Cmin of naloxone, on average there was an increase to 317% (90% C.I.: 142, 708).
Naloxone-3-glucuronide:
For AUC of naloxone-3-glucuronide, on average there was an increase to 128% (90% C.I.: 113, 147), for elderly compared with younger volunteers. For Cmax of naloxone-3-glucuronide, on average there was an increase to 127% (90% C.I.: 112, 144). For Cmin of naloxone-3-glucuronide, on average there was an increase to 125% (90% C.I.: 105, 148).
Patients with impaired hepatic function
Oxycodone:
For AUCINF of oxycodone, on average there was an increase to 143% (90% C.I.: 111, 184), 319% (90% C.I.: 248, 411) and 310% (90% C.I.: 241, 398) for mild, moderate and severe hepatically impaired subjects, respectively, compared with healthy volunteers. For Cmax of oxycodone, on average there was an increase to 120% (90% C.I.: 99, 144), 201% (90% C.I.: 166, 242) and 191% (90% C.I.: 158, 231) for mild, moderate and severe hepatically impaired subjects, respectively, compared with healthy volunteers. For t1/2Z of oxycodone, on average there was an increase to 108% (90% C.I.: 70, 146), 176% (90% C.I.: 138, 215) and 183% (90% C.I.: 145, 221) for mild, moderate and severe hepatically impaired subjects, respectively, compared with healthy volunteers.
Naloxone:
For AUCt of naloxone, on average there was an increase to 411% (90% C.I.: 152, 1112), 11518% (90% C.I.: 4259, 31149) and 10666% (90% C.I.: 3944, 28847) for mild, moderate and severe hepatically impaired subjects, respectively, compared with healthy volunteers. For Cmax of naloxone, on average there was an increase to 193% (90% C.I.: 115, 324), 5292% (90% C.I: 3148, 8896) and 5252% (90% C.I.: 3124, 8830) for mild, moderate and severe hepatically impaired subjects, respectively, compared with healthy volunteers. Due to insufficient amount of data available t1/2Z and the corresponding AUCINF of naloxone were not calculated. The bioavailability comparisons for naloxone were therefore based on AUCt values.
Naloxone-3-glucuronide:
For AUCINF of naloxone-3-glucuronide, on average there was an increase to 157% (90% C.I.: 89, 279), 128% (90% C.I.: 72, 227) and 125% (90% C.I.
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