Boxed Warnings
Limitations of use. Because of the risks associated with the use of opioids, Targin modified release tablets should only be used in patients for whom other treatment options, including non-opioid analgesics, are ineffective, not tolerated or otherwise inadequate to provide appropriate management of pain (see Section 4.4 Special Warnings and Precautions for Use).
Hazardous and harmful use. Targin modified release tablets poses risks of hazardous and harmful use which can lead to overdose and death. Assess the patient's risk of hazardous and harmful use before prescribing and monitor the patient regularly during treatment (see Section 4.4 Special Warnings and Precautions for Use).
Life threatening respiratory depression. Serious, life-threatening or fatal respiratory depression may occur with the use of Targin modified release tablets. Be aware of situations which increase the risk of respiratory depression, modify dosing in patients at risk and monitor patients closely, especially on initiation or following a dose increase (see Section 4.4 Special Warnings and Precautions for Use).
Concomitant use of benzodiazepines and other central nervous system (CNS) depressants, including alcohol. Concomitant use of opioids with benzodiazepines, gabapentinoids, antihistamines, tricyclic antidepressants, antipsychotics, cannabis or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Limit dosages and durations to the minimum required; and monitor patients for signs and symptoms of respiratory depression and sedation. Caution patients not to drink alcohol while taking Targin modified release tablets.
1 Name of Medicine
Oxycodone hydrochloride and naloxone hydrochloride.
2 Qualitative and Quantitative Composition
Targin 2.5/1.25 modified release tablets contain oxycodone hydrochloride 2.5 mg/naloxone hydrochloride 1.25 mg.
Targin 5/2.5 modified release tablets contain oxycodone hydrochloride 5 mg/naloxone hydrochloride 2.5 mg.
Targin 10/5 modified release tablets contain oxycodone hydrochloride 10 mg/naloxone hydrochloride 5 mg.
Targin 15/7.5 modified release tablets contain oxycodone hydrochloride 15 mg/naloxone hydrochloride 7.5 mg.
Targin 20/10 modified release tablets contain oxycodone hydrochloride 20 mg/naloxone hydrochloride 10 mg.
Targin 30/15 modified release tablets contain oxycodone hydrochloride 30 mg/naloxone hydrochloride 15 mg.
Targin 40/20 modified release tablets contain oxycodone hydrochloride 40 mg/naloxone hydrochloride 20 mg.
Targin 60/30 modified release tablets contain oxycodone hydrochloride 60 mg/naloxone hydrochloride 30 mg.
Targin 80/40 modified release tablets contain oxycodone hydrochloride 80 mg/naloxone hydrochloride 40 mg.
The inactive ingredients in the Targin modified release tablet core are ethylcellulose, stearyl alcohol, purified talc and magnesium stearate. Targin modified release tablets 2.5/1.25 mg, 5/2.5 mg and 15/7.5 mg also contain hyprolose. Targin modified release tablets 10/5 mg, 20/10 mg, 30/15 mg, 40/20 mg, 60/30 mg and 80/40 mg also contain povidone. The tablets are coated with polyvinyl alcohol, titanium dioxide, macrogol 3350 and purified talc.
The tablets' film coating also contains:
2.5/1.25 mg. Opadry II complete film coating system 85F220026 yellow (ARTG PI No: 108764).
5/2.5 mg. Brilliant blue FCF aluminium lake (ARTG No: 104464).
15/7.5 mg. Opadry II complete film coating system 85F275005 grey (ARTG PI No: 108768).
20/10 mg. Iron oxide red (ARTG No: 93285).
30/15 mg. Opadry II complete film coating system 85F265010 brown (ARTG PI No: 108770).
40/20 mg. Iron oxide yellow (ARTG No: 93287).
60/30 mg. Opadry II complete film coating system 85F250018 red (ARTG PI No: 110098).
80/40 mg. Opadry II complete film coating system 85F210069 brown (ARTG PI No: 110093).
Excipients with known effect. Contains sugars as lactose.
3 Pharmaceutical Form
Targin modified release tablets are available* as round or capsule shaped, unscored film-coated modified release tablets in blister pack sizes of 20, 28 and 60 modified release tablets as follows:
2.5/1.25 mg round, light yellow tablets without embossing;
5/2.5 mg capsule shaped, blue tablets, marked "OXN" on one side and "5" on the other;
10/5 mg capsule shaped, white tablets, marked "OXN" on one side and "10" on the other;
15/7.5 mg capsule shaped, grey tablets, marked "OXN" on one side and "15" on the other;
20/10 mg capsule shaped, pink tablets, marked "OXN" on one side and "20" on the other;
30/15 mg capsule shaped, brown tablets, marked "OXN" on one side and "30" on the other;
40/20 mg capsule shaped, yellow tablets, marked "OXN" on one side and "40" on the other;
60/30 mg capsule shaped, red tablets, marked with "OXN" on one side and "60" on the other;
80/40 mg capsule shaped, brown tablets, marked with "OXN" on one side and "80" on the other.
*Not all strengths and pack sizes are currently marketed in Australia.
4 Clinical Particulars
4.9 Overdose
Depending upon the history of the patient, an overdose of Targin modified release tablets may be manifested by symptoms triggered by oxycodone (opioid receptor agonist) or by naloxone (opioid receptor antagonist). However, symptoms of naloxone overdosage are unlikely (treat symptomatically in a closely-supervised environment).
Symptoms of oxycodone overdosage. Acute overdose with oxycodone can be manifested by miosis (dilated if hypoxia is severe), cold and/or clammy skin, respiratory depression (reduced respiratory rate and/or tidal volume, cyanosis), extreme somnolence progressing to stupor or coma, hypotonia, bradycardia and hypotension. Toxic leukoencephalopathy has been observed with oxycodone overdose. Coma, non-cardiogenic pulmonary oedema and circulatory failure may occur in more serious cases, and may lead to a fatal outcome.
The features of overdosage may be delayed with a controlled release product such as Targin modified release tablets.
Treatment of oxycodone overdosage. Primary attention should be given to immediate supportive therapy with the establishment of adequate respiratory exchange through the provision of a patent airway and institution of assisted or controlled ventilation. Adequate body temperature and fluid balance should be maintained.
Oxygen, intravenous fluids, vasopressors, infusions and other supportive measures 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 and fluid and electrolyte metabolism maintained.
Activated charcoal may reduce absorption of the drug if given within one to two hours after ingestion. Administration of activated charcoal should be restricted to patients who are fully conscious with an intact gag reflex or protected airway. A saline cathartic or sorbitol added to the first dose of activated charcoal may speed gastrointestinal passage of the product. In patients who are not fully conscious or have an impaired gag reflex, consideration should be given to administering activated charcoal via a nasogastric tube, once the airway is protected.
Whole bowel irrigation (e.g. 1 or 2 litres of polyethylene glycol solution orally per hour until rectal effluent is clear) may be useful for gut decontamination. Whole bowel irrigation is contraindicated in patients with bowel obstruction, perforation, ileus, haemodynamic instability or compromised, unprotected airways and should be used cautiously in debilitated patients and where the condition may be further compromised. Concurrent administration of activated charcoal and whole bowel irrigation may decrease the effectiveness of the charcoal (there may be competition for the charcoal binding site between the polyethylene glycol and the ingested drugs) but the clinical relevance is uncertain. Prolonged periods of observation (days) may be required for patients who have overdosed with long-acting preparations.
If there are signs of clinically significant respiratory or cardiovascular depression, an opioid antagonist should be considered. Naloxone hydrochloride at a dose of 0.4-2 mg intravenously is a specific antidote for respiratory depression due to overdosage or as a result of unusual sensitivity to oxycodone (please see naloxone product information for further information). Concomitant efforts at respiratory resuscitation should be carried out. Administration of naloxone should be repeated at 2-3 minute intervals, as clinically necessary. An infusion of 2 mg naloxone in 500 mL of 0.9% sodium chloride or 5% dextrose (0.004 mg/mL naloxone), run at a rate aligned to previously administered bolus doses and to the patient's response, is also a possible alternative.
The duration of action of oxycodone may exceed that of the antagonist. Consequently, the patient should remain under continued surveillance and dosing of the antagonist continued as needed to maintain adequate respiration.
In an individual physically dependent on opioids, administering opioid antagonists may precipitate a withdrawal syndrome and should be avoided if possible. Withdrawal syndrome may lead to agitation, hypertension, tachycardia and risk of vomiting with possible aspiration. The severity of withdrawal depends on the degree of dependence and the antagonist dose. If required for serious respiratory depression, the antagonist should be administered with extreme care, commencing with 10 to 20% of the usual recommended initial dose and titrating.
Toxicity. Due to the great interindividual variation in sensitivity to opioids it is difficult to determine an exact dose of any opioid that is toxic or lethal. Crushing and taking the contents of a controlled release dosage form leads to the release of oxycodone in an immediate fashion; this might result in a fatal overdose. The toxic effects and signs of overdosage may be less pronounced than expected, when pain and/or tolerance are manifest.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).
5 Pharmacological Properties
5.3 Preclinical Safety Data
Genotoxicity. The results of in vitro and in vivo studies indicate that the genotoxic risk of oxycodone to humans is minimal or absent at the systemic oxycodone concentrations that are achieved therapeutically. Oxycodone showed mutagenic activity in a mouse lymphoma assay, but was inactive in bacterial gene mutation assays. It also induced chromosomal aberrations in human lymphocytes in vitro, but not in immature erythrocytes in vivo in mice. Similar to oxycodone, naloxone induced gene mutations and chromosomal aberrations in mouse lymphoma cell lines and human lymphocytes in vitro, respectively, but did not induce chromosomal aberrations in immature erythrocytes under in vivo conditions.
Carcinogenicity. Long-term studies in animals to evaluate the carcinogenic potential of oxycodone/naloxone in combination have not been conducted.
Carcinogenicity was evaluated in a 2-year oral gavage study conducted in Sprague-Dawley rats. Oxycodone did not increase the incidence of tumours in male and female rats at doses up to 6 mg/kg/day (equivalent to 6.8 mg/day in men and 24.6 mg/day in women, based on estimated AUC values). The doses were limited by opioid-related pharmacological effects of oxycodone.
Naloxone was not carcinogenic in a 24-month dietary study in rats at doses up to 100 mg/kg/day, which is about 11-fold the naloxone dose at the maximal recommended clinical dose of Targin modified release tablets, on a body surface area basis.
6 Pharmaceutical Particulars
6.7 Physicochemical Properties
Oxycodone hydrochloride is a white, crystalline, odourless powder readily soluble in water, sparingly soluble in ethanol and nearly insoluble in ether.
Naloxone hydrochloride dihydrate is an off-white powder soluble in water.
Oxycodone hydrochloride. The chemical name is 4,5a-epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one hydrochloride. The molecular formula is C18H21NO4.HCl and molecular weight is 351.83. The pKa is 8.9 and the Partition Coefficient Log P is 0.7.
Naloxone hydrochloride. The chemical name is 17-allyl-4,5a-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride dihydrate. It is a synthetic congener of oxymorphone, with molecular formula C19H21NO4.HCl.2H2O and molecular weight 399.87. The pKa is 7.9 and the Partition Coefficient Log P is 1.5.
Chemical structure. The structural formula for oxycodone hydrochloride is:
https://stagingapi.mims.com/au/public/v2/images/fullchemgif/CSOXYHCL.gif The structural formula for naloxone hydrochloride dihydrate is:
https://stagingapi.mims.com/au/public/v2/images/fullchemgif/CSNALHCL.gif CAS number. Oxycodone hydrochloride. 124-90-3.
Naloxone hydrochloride. 51481-60-8.
7 Medicine Schedule (Poisons Standard)
S8.
Summary Table of Changes
https://stagingapi.mims.com/au/public/v2/images/fulltablegif/TARGINST.gif
