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Mundipharma Pharmaceuticals Limited - Formerly Napp Laboratories

Millbank House, Arkle Road, Sandyford, Dublin 18, Ireland
Telephone: +353 1 206 3800
Fax: +353 1 294 5104
Medical Information e-mail: info@mundipharma.ie


Summary of Product Characteristics last updated on medicines.ie: 07/06/2013
SPC Targin 5/2.5mg, 10mg/5mg, 20mg/10mg and 40/20mg prolonged release tablets



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1. NAME OF THE MEDICINAL PRODUCT

Targin 5 mg/2.5 mg, 10 mg/5 mg, 20 mg/10 mg, 40 mg/20 mg prolonged-release tablets


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2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Targin 5 mg/2.5 mg

Each prolonged-release tablet contains 5 mg of oxycodone hydrochloride equivalent to 4.5 mg oxycodone, 2.73 mg of naloxone hydrochloride dihydrate equivalent to 2.5 mg naloxone hydrochloride and 2.25 mg naloxone.

Excipient with known effect:

Each prolonged-release tablet contains 68.17 mg lactose anhydrous

Targin 10 mg/5 mg

Each prolonged-release tablet contains 10 mg of oxycodone hydrochloride equivalent to 9.0 mg oxycodone, 5.45 mg of naloxone hydrochloride dihydrate equivalent to 5.0 mg naloxone hydrochloride and 4.5 mg naloxone.

Excipient with known effect:

Each prolonged-release tablet contains 61.04 mg lactose anhydrous

Targin 20 mg/10 mg

Each prolonged-release tablet contains 20 mg of oxycodone hydrochloride equivalent to 18.0 mg oxycodone, 10.9 mg of naloxone hydrochloride dihydrate equivalent to 10.0 mg naloxone hydrochloride and 9 mg naloxone.

Excipient with known effect:

Each prolonged-release tablet contains 51.78 mg lactose anhydrous

Targin 40 mg/20 mg

Each prolonged-release tablet contains 40 mg of oxycodone hydrochloride equivalent to 36.0 mg oxycodone, 21.8 mg of naloxone hydrochloride dihydrate equivalent to 20.0 mg naloxone hydrochloride and 18 mg naloxone.

Excipient with known effect:

Each prolonged-release tablet contains 103.55 mg lactose anhydrous

For the full list of excipients, see section 6.1.


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3. PHARMACEUTICAL FORM

Prolonged-release tablet

Targin 5 mg/2.5 mg

Oblong, blue film-coated tablets marked “OXN” on one side and “5” on the other side.

Targin 10 mg /5 mg

Oblong, white film-coated tablets marked “OXN” on one side and “10” on the other side.

Targin 20 mg/10 mg

Oblong, pink film-coated tablets marked “OXN” on one side and “20” on the other side.

Targin 40 mg/20 mg

Oblong, yellow film-coated tablets marked “OXN” on one side and “40” on the other side.


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4. CLINICAL PARTICULARS

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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.


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4.2 Posology and method of administration

Targin is for oral use.

Posology

The analgesic efficacy of Targin 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, Targin should be administered as follows:

Adults

The usual starting dose for an opioid naive 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 Targin depending on their previous opioid experience.

Targin 5 mg/2.5 mg is intended for dose titration when initiating opioid therapy and individual dose adjustment.

The maximum daily dose of Targin is 80 mg oxycodone hydrochloride and 40 mg naloxone hydrochloride. For patients requiring higher doses of Targin, administration of supplemental prolonged-release oxycodone hydrochloride 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 Targin with a subsequent switch to another opioid a worsening of the bowel function can be expected.

Some patients taking Targin according to a regular time schedule require immediate-release analgesics as “rescue” medication for breakthrough pain. Targin 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 Targin 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 hydrochoride 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.

Targin 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.

Paediatric population

The safety and efficacy of Targin in children aged below 18 years has not been established. No data are available.

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 Targin to patients with mild hepatic impairment (see section 4.4). In patients with moderate and severe hepatic impairment Targin 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 Targin to patients with renal impairment (see section 4.4).

Method of administration

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 or chewed.

Duration of use

Targin should not be administered for longer than absolutely necessary. If long-term pain 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 (see section 4.4).


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4.3 Contraindications

• Hypersensitivity to the active substances or to any of the excipients listed in section 6.1,

• Any situation where opioids are contraindicated,

• Severe respiratory depression with hypoxia and/or hypercapnia,

• Severe chronic obstructive pulmonary disease,

• Cor pulmonale,

• Severe bronchial asthma,

• Non-opioid induced paralytic ileus,

• Moderate to severe hepatic impairment.


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4.4 Special warnings and precautions for use

The major risk of opioid excess is respiratory depression. Caution must be exercised when administering Targin 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 Targin 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 Targin 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 of Targin may lead to physical dependence. Withdrawal symptoms may occur upon the abrupt cessation of therapy. If therapy with Targin 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 Targin. Targin 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 Targin may increase the undesirable effects of Targin. Concomitant use should be avoided.

Studies have not been performed on the safety and efficacy of Targin 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 Targin 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 Targin by drug addicts is strongly discouraged. If abused parenterally, intranasally or orally by individuals dependent on opioid agonists, such as heroin, morphine, or methadone, Targin 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).

Targin 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 Targin may produce positive results in doping controls. The use of Targin 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 Targin.


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4.5 Interaction with other medicinal products and other forms of interaction

Substances having a CNS-depressant effect (e.g. other opioids, sedatives, hypnotics, antidepressants, phenothiazines, neuroleptics, antihistamines and antiemetics) may enhance the CNS-depressant effect (e.g. respiratory depression) of Targin.

Alcohol may enhance the pharmacodynamic effects of Targin; 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.


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4.6 Fertility, pregnancy and lactation

Pregnancy

There are no data from the use of Targin 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 Targin 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. Targin should only be used during pregnancy if the benefit outweighs the possible risks to the unborn child or neonate.

Breastfeeding

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 Targin 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 Targin by the breast-feeding mother. Breastfeeding should be discontinued during treatment with Targin.

Fertility

There are no data with respect to fertility.


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4.7 Effects on ability to drive and use machines

Targin may impair the ability to drive and use machines. This is particularly likely at the beginning of treatment with Targin, after dose increase or product rotation and if Targin 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.


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4.8 Undesirable effects

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.

System organ class

MedDRA

Common

Uncommon

Rare

Very rare

Not known

Immune system disorders

 

Hypersensitivity

   

Metabolism and nutritional disorders

Decreased appetite up to loss of appetite

    

Psychiatric disorders

Insomnia

Restlessness

Abnormal thinking

Anxiety

Confusion

Depression

Nervousness

  

Euphoric mood

Hallucination

Nightmares

Nervous system disorders

Dizziness

Headache

Somnolence

Convulsions1

Disturbance in attention

Speech disorder

Syncope

Tremor

  

Paraesthesia

Sedation

Eye disorder

 

Visual impairment

   

Ear and labyrinth disorder

Vertigo

    

Cardiac disorders

 

Angina pectoris2

Palpitations

Tachycardia

  

Vascular disorders

Hot flush

Decrease in blood pressure

Increase in blood pressure

   

Respiratory, thoracic and mediastinal disorders

 

Dyspnoea

Rhinorrhoe

Cough

Yawning

 

Respiratory depression

Gastrointestinal disorders

Abdominal pain

Constipation

Diarrhoea

Dry mouth

Dyspepsia

Vomiting

Nausea

Flatulence

Abdominal distention

Tooth disorder

 

Eructation

Hepatobiliary disorders

 

Hepatic enzymes increased

Biliary colic

   

Reproductive system and breast disorders

    

Erectile dysfunction

Skin and subcutaneous tissue disorder

Pruritus

Skin reactions

Hyperhidrosis

    

Musculoskeletal and connective tissue disorder

 

Muscle spasms

Muscle twitching, Myalgia

   

Renal and urinary disorders

 

Micturition urgency

  

Urinary retention

General disorders and application site conditions

Asthenic conditions

Drug withdrawal syndrome

Chest pain

Chills

Malaise

Pain

Peripheral oedema

Weight decrease

Weight increase

  

Injury, poisoning, and procedural complications

 

Injury from accidents

   

1 particularly in persons with epileptic disorder or predisposition to convulsions

2 particular in patients with history of coronary artery disease

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.

System organ class

MedDRA

Common

Uncommon

Rare

Very rare

Not known

Infections and infestations

  

Herpes simplex

  

Immune system disorders

    

Anaphylactic responses

Metabolism and nutritional disorders

 

Dehydration

Increased appetite

  

Psychiatric disorders

Altered mood and personality changes

Decreased activity

Psychomotor hyperactivity

Agitation

Perception disturbances (e.g. derealisation)

Reduced libido

Drug dependence

   

Nervous system disorders

 

Concentration impaired

Migraine

Dysgeusia

Hypertonia

Involuntary muscle contractions

Hypoaesthesia

Abnormal co-ordination

   

Ear and labyrinth disorders

 

Hearing impaired

   

Vascular disorders

 

Vasodilation

   

Respiratory, thoracic and mediastinal disorders

 

Dysphonia

   

Gastrointestinal disorders

Hiccups

Dysphagia

Ileus

Mouth ulceration

Stomatitis

Melaena

Gingival bleeding

  

Hepatobiliary disorders

    

Cholestasis

Skin and subcutaneous tissue disorders

 

Dry skin

Urticaria

  

Renal and urinary disorders

Dysuria

    

Reproductive system and breast disorders

    

Amenorrhoea

General disorders and administration site conditions

 

Oedema

Thirst

Drug tolerance

   


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4.9 Overdose

Symptoms of intoxication

Depending on the history of the patient, an overdose of Targin 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 measure (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.


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5. PHARMACOLOGICAL PROPERTIES

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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.


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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.

Biotransformation

Oxycodone is metabolised 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. 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.

Biotransformation and elimination

After parentral 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 (Targin)

The pharmacokinetic characteristics of oxycodone from Targin is equivalent to those of prolonged-release oxycodone hydrochloride tablets administered together with prolonged-release naloxone hydrochloride tablets.

All dosage strengths of Targin are interchangeable.

After the oral administration of Targin 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 Targin 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 Targin is unlikely.

Elderly patients

Oxycodone

For AUCτ 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 AUCτ 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 AUCτ 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.: 71, 222) for mild, moderate and severe hepatically impaired subjects, respectively, compared with healthy volunteers. For Cmax of naloxone-3-glucuronide, on average there was an increase to 141% (90% C.I.: 100, 197), 118% (90% C.I.: 84, 166) and a decrease to 98% (90% C.I.: 70, 137) for mild, moderate and severe hepatically impaired subjects, respectively, compared with healthy volunteers. For t1/2Z of naloxone-3-glucuronide, on average there was an increase to 117% (90% C.I.: 72, 161), a decrease to 77% (90% C.I.: 32, 121) and a decrease to 94% (90% C.I.: 49, 139) for mild, moderate and severe hepatically impaired subjects, respectively, compared with healthy volunteers.

Patients with impaired renal function

Oxycodone

For AUCINF of oxycodone, on average there was an increase to 153% (90% C.I.: 130, 182), 166% (90% C.I.: 140, 196) and 224% (90% C.I.: 190, 266) for mild, moderate and severe renally impaired subjects, respectively, compared with healthy volunteers. For Cmax of oxycodone, on average there was an increase to 110% (90% C.I.: 94, 129), 135% (90% C.I.: 115, 159) and 167% (90% C.I.: 142, 196) for mild, moderate and severe renally impaired subjects, respectively, compared with healthy volunteers. For t1/2Z of oxycodone, on average there was an increase to 149%, 123% and 142% for mild, moderate and severe renally impaired subjects, respectively, compared with healthy volunteers.

Naloxone

For AUCt of naloxone, on average there was an increase to 2850% (90% C.I.: 369, 22042), 3910% (90% C.I.: 506, 30243) and 7612% (90% C.I.: 984, 58871) for mild, moderate and severe renally impaired subjects, respectively, compared with healthy volunteers. For Cmax of naloxone, on average there was an increase to 1076% (90% C.l.: 154, 7502), 858% (90% C.I.: 123, 5981) and 1675% (90% C.I.: 240, 11676) for mild, moderate and severe renally 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. The ratios may have been influenced by the inability to fully characterize the naloxone plasma profiles for the healthy subjects.

Naloxone-3-glucuronide

For AUCINF of naloxone-3-glucuronide, on average there was an increase to 220% (90% C.I.: 148, 327), 370% (90% C.I.: 249, 550) and 525% (90% C.I.: 354, 781) for mild, moderate and severe renally impaired subjects, respectively, compared with healthy subjects. For Cmax of naloxone-3-glucuronide, on average there was an increase to 148% (90% C.I.: 110, 197), 202% (90% C.I.: 151, 271) and 239% (90% C.I.: 179, 320) for mild, moderate and severe renally impaired subjects, respectively, compared with healthy subjects. For t1/2Z of naloxone-3-glucuronide, on average there was no significant change between the renally impaired subjects and the healthy subjects.

Abuse

To avoid damage to the prolonged-release properties of the tablets, Targin must not be broken, crushed or chewed, as this leads to a rapid release of the active substances. In addition, naloxone has a slower elimination rate when administered intranasally. Both properties mean that abuse of Targin will not have the effect intended. In oxycodone-dependent rats, the intravenous administration of oxycodone hydrochloride / naloxone hydrochloride at a ratio of 2:1 resulted in withdrawal symptoms.


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5.3 Preclinical safety data

There are no data from studies on reproductive toxicity of the combination of oxycodone and naloxone. Studies with the single components showed that oyxcodone had no effect on fertility and early embryonic development in male and female rats in doses of up to 8 mg/kg body weight and induced no malformations in rats in doses of up to 8 mg/kg and in rabbits in doses of 125 mg/kg bodyweight. However, in rabbits, when individual foetuses were used in statistical evaluation, a dose related increase in developmental variations was observed (increased incidences of 27 presacral vertebrae, extra pairs of ribs). When these parameters were statistically evaluated using litters, only the incidence of 27 presacral vertebrae was increased and only in the 125 mg/kg group, a dose level that produced severe pharmacotoxic effects in the pregnant animals. In a study on pre- and postnatal development in rats F1 body weights were lower at 6 mg/kg/d when compared to body weights of the control group at doses which reduced maternal weight and food intake (NOAEL 2 mg/kg body weight). There were neither effects on physical, reflexological, and sensory developmental parameters nor on behavioural and reproductive indices. The standard oral reproduction toxicity studies with naloxone show that at high oral doses naloxone was not teratogenic and/or embryo/foetotoxic, and does not affect perinatal/postnatal development. At very high doses (800 mg/kg/day) naloxone produced increased pup deaths in the immediate post-partum period at dosages that produced significant toxicity in maternal rats (e.g. body weight loss, convulsions). However, in surviving pups, no effects on development or behaviour were observed.

Long-term carcinogenicity studies with oxycodone/naloxone in combination or oxycodone as a single entity have not been performed. For naloxone, a 24-months oral carcinogenicity study was performed in rats with naloxone doses up to 100 mg/kg/day. The results indicate that naloxone is not carcinogenic under these conditions.

Oxycodone and naloxone as single entities show a clastogenic potential in in vitro assays. No similar effects were observed, however, under in vivo conditions, even at toxic doses. The results indicate that the mutagenic risk of Targin to humans at therapeutic concentrations may be ruled out with adequate certainty.


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6. PHARMACEUTICAL PARTICULARS

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6.1 List of excipient(s)

Targin 5 mg/2.5 mg

Tablet core:

Ethylcellulose,

Stearyl alcohol,

Lactose monohydrate,

Talc,

Magnesium stearate,

Hydroxylpropylcellulose

Targin 10 mg/5 mg, 20 mg/10 mg, 40 mg/20 mg

Tablet core:

Ethylcellulose,

Stearyl alcohol,

Lactose monohydrate,

Talc,

Magnesium stearate,

Povidone K30

Targin 5 mg/2.5 mg

Tablet coat:

Poly(vinylalcohol),

Titanium dioxide (E171),

Macrogol 3350,

Talc

Brilliant Blue FCF aluminium lake (E133)

Targin 10 mg/5 mg

Tablet coat:

Poly(vinylalcohol),

Titanium dioxide (E171),

Macrogol 3350,

Talc

Targin 20 mg/10 mg

Tablet coat:

Poly(vinylalcohol),

Titanium dioxide (E171),

Macrogol 3350,

Talc

Iron oxide red (E172)

Targin 40 mg/20 mg

Tablet coat:

Poly(vinylalcohol),

Titanium dioxide (E171),

Macrogol 3350,

Talc

Iron oxide yellow (E172)


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6.2 Incompatibilities

Not applicable.


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6.3 Shelf life

Polyvinylchloride/aluminium foil blisters: 3 years


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6.4 Special precautions for storage

Do not store above 25°C.

Targin 5 mg/2.5 mg

Store in the origional package in order to protect from light.


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6.5 Nature and contents of container

Polyvinylchloride/aluminium foil blisters

56 prolonged-release tablets


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6.6 Special precautions for disposal and other handling

Any unused product or waste material should be disposed of in accordance with local requirements.


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7. MARKETING AUTHORISATION HOLDER

Mundipharma Pharmaceuticals Limited

Millbank House

Arkle Road

Sandyford

Dublin 18

Ireland


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8. MARKETING AUTHORISATION NUMBER(S)

PA 1688/10/1 - 4


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9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Targin 10 mg/5 mg and 20 mg/10 mg

Date of first authorisation: 06th March 2009

Date of latest renewal: 31st May 2011

Targin 5 mg/2.5 mg and 40 mg/20 mg

Date of first authorisation: 25th September 2009


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10. DATE OF REVISION OF THE TEXT

April 2013



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