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  • Targin
    / Rafa


    Active Ingredient *
    Oxycodone HCl 5, 10, 20, 30, 40 mg
    Naloxone HCl 2.5, 5, 10, 15, 20 mg

    Status in Israel
    RX

    Presentation and Status in Health Basket

    Presentation Basket Yarpa Pharmasoft

    Prolonged-Release Tablets

    20 X 5/2.5 mg

    partial basket chart 20606 20681

    Prolonged-Release Tablets

    20 X 10/5 mg

    partial basket chart 89485 20638

    Prolonged-Release Tablets

    20 X 20/10 mg

    partial basket chart 89486 20639

    Prolonged-Release Tablets

    20 X 30/15 mg

    partial basket chart 38275

    Prolonged-Release Tablets

    20 X 40/20 mg

    partial basket chart 20609 20682

    Related information


    Dosage

    Adults: The usual starting dose for an opioid naïve patient is 10 mg of oxycodone hydrochloride/naloxone hydrochloride at 12 hourly intervals (Targin 10).
    Lower strength (Targin 5) is available to facilitate dose titration when initiating opioid therapy and for individual dose adjustment.
    Patients already receiving opioids may be started on higher doses of Targin, depending on their previous opioid experience.
    The maximum daily dose of this drug is 80 mg oxycodone hydrochloride and 40 mg naloxone hydrochloride. For patients requiring higher doses of it, administration of supplemental prolonged-release oxycodone hydrochloride at the same time intervals should be considered. In the case of supplemental oxycodone dosing, the beneficial effect of naloxone on bowel function may be impaired.
    After complete discontinuation of therapy with this drug with a subsequent switch to another opioid a worsening of the bowel function can be expected. Some patients taking it according to a regular time schedule require immediate release analgesics as “rescue” medication for breakthrough pain. It 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 it requires upward adjustment. This adjustment should be made every 1-2 days in steps of twice daily Targin 5, or where demand Targin 10 until a stable dose is reached. The aim is to establish a patientspecific 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. This drug 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 40mg/20mg oxycodone hydrochloride/naloxone hydrochloride are usually sufficient, but higher doses may be needed.
    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. The clinical relevance of a relative high naloxone exposure in hepatic impaired patients is yet not known. Caution must be exercised when administering this drug  to patients with mild hepatic impairment. In patients with moderate and severe hepatic impairment this drug is contraindicated.
    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. 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 this drug to patients with renal impairment.
    Paediatric population: The safety and efficacy of Targin in children aged below 18 years has not been established. No data are available.
    Method of administration: Oral use. Targin 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. Targin must be swallowed whole, and not broken, chewed or crushed.
    Duration of use: Targin should not be administered for longer than absolutely necessary. If long-term treatment is necessary in view of 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.


    Indications

    Moderate to severe pain in adults who require around the clock opioid analgesia for several days or more. The opioid antagonist naloxone is added to counteract opioid-induced constipation by blocking the action of oxycodone at opioid receptors locally in the gut.


    Contra-Indications

    Hypersensitivity to the active substances or to any of the excipients, 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.


    Special Precautions

    WARNING: RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS
    – Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death.
    – Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.
    – Limit dosages and durations to the minimum required.
    – Follow patients for signs and symptoms of respiratory depression and sedation.

    The major risk of opioid excess is respiratory depression. Caution must be exercised when administering this drug to elderly or infirm patients, patients with opioid-induced paralytic ileus, patients presenting severely impaired pulmonary function, patients with 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, or patients taking MAO inhibitors.
    Caution must also be exercised when administering to patients with mild hepatic or renal impairment. A careful medical monitoring is particularly necessary for patient with severe renal impairment.
    Diarrhoea may be considered as a possible effect of naloxone.
    In patients under long-term opioid treatment, the switch can initially provoke withdrawal symptoms. Such patients may require specific attention.
    Targin 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 may lead to physical dependence. Withdrawal symptoms may occur upon the abrupt cessation of therapy. If therapy with this drug it 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 opiod analgesics, including this drug. 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 it, 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.
    Concomitant use of alcohol and it may increase the undesirable effects of it; concomitant use should be avoided.
    Studies have not been performed on the safety and efficacy 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 in this population is not recommended.
    Targin 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 post-operative treatment with Targin depends on a careful risk-benefit assessment for each individual patient.
    Any abuse of this drug by drug addicts is strongly discouraged.
    If abused parenterally, intranasally or orally by individuals dependent on opioid agonists, such as heroin, morphine, or methadone, It is expected to produce marked withdrawal symptoms – because of the opioid receptor antagonist characteristics of naloxone – or to intensify withdrawal symptoms already present.
    It is 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 may produce positive results in doping controls.The use 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 it.
    See prescribing information for full details.


    Side Effects

    Common undesirable effects: Decreased appetite up to loss of appetite, Insomnia, Dizziness, Headache, Somnolence, Vertigo, Hot flush,  Abdominal pain, Constipation, Diarrhoea, Dry mouth, Dyspepsia, Vomiting, Nausea, Flatulence, Pruritus, Skin reactions, Hyperhidrosis, Asthenia,
    Fatigue, Altered mood and personality changes, Decreased activity, Psychomotor hyperactivity, Hiccups, Dysuria.
    See prescribing information for full details.


    Drug interactions

    Substances having a CNS-depressant effect (e.g. other opioids, sedatives and  hypnotics such as benzodiazepines, anti-depressants, phenothiazines, neuroleptics, anti-histamines and anti-emetics) may enhance the CNS-depressant effect (e.g. respiratory depression) of it.
    Concomitant administration of oxycodone with anticholinergics or medications with anticholinergic activity (e.g. tricyclic antidepressants, antihistamines, antipsychotics, muscle relaxants, anti-Parkinson drugs) may result in increased anticholinergic adverse effects.
    Alcohol may enhance the pharmacodynamic effects of it; 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. Targin 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 Targin 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 pain 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.


    Pregnancy and Lactation

    Pregnancy: There are no data from the use 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 this drug is relatively low. Both oxycodone and naloxone pass into the placenta. Animal studies have not been performed with oxycodone and naloxone in combination. Animal studies with oxycodone or naloxone administered as single drugs have not reveald any teratogenic or embryotoxic effects. ong-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. This drug 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 it systemic naloxone levels are very low. A risk to suckling child cannot be excluded in particular following intake of multiple doses of this drug by the breast-feeding mother. Breast-feeding should be discontinued during treatment with it.


    Overdose

    Symptoms of intoxication: Depending on the history of the patient, an overdose  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.


    Manufacturer
    Rafa Laboratories Ltd.
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