SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

TRADOREC XL® 300 mg prolonged-release tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

One prolonged-release tablet contains 300mg tramadol hydrochloride For the full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

Prolonged-release tablet.

White to off white, plain, bevelled edge, round biconvex tablet

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Treatment of moderate to severe pain.

4.2 Posology and method of administration

Posology

The dose should be adjusted to the intensity of the pain and the sensitivity of the individual patient. The lowest effective dose for analgesia should generally be selected.

Adults and adolescents (12 years and over):

The starting dose is one 100 mg prolonged-release tablet once daily. The usual dose is one 200 mg prolonged-release tablet once daily, to be taken preferably in the evening. If this does not provide sufficient pain relief, the dosage can be increased in 100 mg dose increments to 300 mg or to a maximum of 400 mg once daily.

In general, the lowest effective analgesic dose should be chosen. A daily dose of 400mg of tramadol should not be exceeded except in special clinical cases.

Tradorec XL should not be used for a period longer than absolutely necessary. If continued pain treatment is necessary due to the nature and severity of the illness, careful regular surveillance should be carried out (including periods without treatment, if necessary) in order to determine the need for continued treatment.

Children (under 12):

Tradorec XL is not recommended for the treatment of children (under 12 years of age).

Elderly patients:

A dose adjustment is not usually necessary in patients up to 75 years of age without clinically manifest hepatic or renal insuffiency. In elderly patients over 75 years elimination may be prolonged. Therefore, if necessary the dosage interval is to be extended according to the patient’s requirements.

Renal impairment, dialysis and hepatic impairment:

In patients with renal and/or hepatic insufficiency the elimination of tramadol is delayed. In these patients prolongation of the dosage intervals should be carefully considered according to the patient’s requirements.

Tradorec XL is not recommended for patients with severe hepatic impairment or with severe renal impairment (creatinine clearance <10 ml/min, see section 4.3). Caution is advised in patients with moderate hepatic or moderate renal impairment (creatinine clearance <30 ml/min) (see section 4.5).

Method of administration

The dosage should be adjusted according to the severity of pain and the response of the individual patient.

The tablets should be swallowed whole, with a sufficient quantity of liquid and not divided or chewed. The tablets can be taken with or without food.

Alternative tablet strengths of Tradorec XL are available. Where necessary, appropriate tablet strengths should be used to achieve the required dose.

Tradorec XL should be taken once every 24 hours.

4.3 Contraindications

Known hypersensitivity to tramadol or to any of the excipients.

Acute intoxication or overdose with CNS depressants (alcohol, hypnotics, other opioid analgesics, etc.).

Patients receiving concomitant treatment with MAO inhibitors or who have been treated with MAO inhibitors during the past 2 weeks (see section 4.5). Concomitant treatment with linezolid (see section 4.5).

Severe hepatic or severe renal impairment (creatinine clearance < 10ml/min). Epilepsy not adequately controlled by treatment. (See section 4.4).

Tramadol must not be administered during breastfeeding if long-term treatment, i.e. more than 2 to 3 days, is necessary (see section 4.6).

4.4 Special warnings and precautions for use

Consumption of alcohol is not recommended during treatment with tramadol. Concomitant treatment with carbamazepine is not recommended (see section 4.5).

Warnings:

Tramadol has a low potential for dependence. However, with long-term use, tolerance and psychological and/or physical dependence may develop. At therapeutic doses, withdrawal symptoms have been reported with a frequency of 1 in 8,000 while reports of dependence and abuse have been less frequent. Because of the potential for dependence or withdrawal to occur, the clinical need for continued analgesia should be reviewed regularly. In patients with a tendency to drug abuse or dependence, tramadol should only be used for short periods under strict medical surveillance.

Tramadol is not suitable as a substitute in opioid dependent patients. Although it is an opioid agonist, tramadol cannot suppress morphine withdrawal symptoms.

Respiratory depression or patient taking CNS depressants:

Caution is recommended with administration of tramadol in patients at risk for respiratory depression or receiving medicinal products likely to produce respiratory depression.

Precautions:

Tramadol should be used with caution in patients with head trauma, increased intracranial pressure, impairment of hepatic or renal function, in patients in shock, an altered state of consciousness (with no obvious cause), respiratory centre disorders or respiratory dysfunction and in diabetic patients because of the occurrence of hypoglycaemia with tramadol.

There is an increased risk of seizures if the tramadol dose exceeds the maximum recommended daily dose (400 mg). Seizures have been reported at the therapeutic doses. Patients with controlled epilepsy or patients with a known risk of seizure should only be treated with tramadol in cases of absolute necessity. There is an increased risk of seizures in patients taking concomitant medications which lower the seizure threshold (see section 4.5).

4.5 Interaction with other medicinal products and other forms of interaction

Concomitant medication contraindicated during treatment with tramadol

Tramadol must not be used in combination with selective or nonselective MAO inhibitors. Serotonin Syndrome (diarrhoea, tachycardia, sweating, tremor, confusion and coma) may develop (see section 4.3).

Linezolid: Treatment experience with non-selective MAOI indicates a risk of development of Serotonin Syndrome: diarrhoea, tachycardia, sweating, tremor, confusion and coma.

Concomitant medication not recommended during treatment with tramadol

Mixed agonist-antagonists (buprenorphine, nalbuphine and pentazocine): Concomitant treatment with tramadol is not recommended because theoretically, this could reduce the analgesic effects of the pure agonist due to competitive blocking of receptors, resulting in the risk of occurrence of withdrawal symptoms.

Alcohol: Alcohol increases the sedative effect of opioid analgesics. The resulting drowsiness can be dangerous while driving or operating machinery. Alcoholic beverages and medicinal products containing alcohol should not be consumed during treatment with tramadol (see section 4.7).

Carbamazepine (enzyme inducer): Possibility of decreased plasma concentrations of tramadol and its pharmacologically active metabolite, resulting in reduction of the analgesic effect.

Naltrexone: Use of tramadol with naltrexone may reduce the analgesic effect. If necessary the analgesic dose can be increased.

Concomitant medication to be used with care during tramadol treatment

Other morphine derivatives (including antitussives and substitution treatments) benzodiazepines, barbiturates: Major risk of respiratory depression, can be fatal in case of overdose.

Other CNS depressants: Opioid analgesics, barbiturates, benzodiazepines, sedative antidepressants, sedative H1 antihistamines, anxiolytics other than benzodiazepines, hypnotics, neuroleptics, centrally acting antihypertensives, thalidomide, baclophene: Increased risk of central nervous system depression. The resulting impaired reaction time can make driving and operating machinery dangerous.

Tramadol can induce convulsions and increase the potential for selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, antipsychotics and other seizure threshold-lowering medicinal products (such as bupropion, mirtazapine, tetrahydrocannabinol) to cause convulsions.

Concomitant therapeutic use of tramadol and serotonergic drugs, such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), MAO inhibitors (see section 4.3), tricyclic antidepressants and mirtazapine may cause serotonin toxicity. Serotonin syndrome is likely when one of the following is observed:

•    Spontaneous clonus

•    Inducible or ocular clonus with agitation or diaphroesis

•    Tremor and hyperreflexia

•    Hypertonia and body temperature > 38°C and inducible or ocular clonus. Withdrawal of the serotonergic drugs usually brings about a rapid improvement. Treatment depends on the type and severity of the symptoms.

Venlafaxine: Risk of convulsions and/or Serotonin Syndrome.

Caution should be exercised during concomitant treatment with tramadol and coumarin derivatives (e.g. warfarin) due to reports of increased INR and ecchymoses in some patients.

4.6 Fertility, Pregnancy and lactation

Fertility:

No fertility studies have been conducted with TRADOREC XL®

Pregnancy:

Tramadol should not be used during pregnancy unless clearly necessary. In humans, there is insufficient data available to appropriately assess the safety of tramadol use in pregnant women.

As with other opioid analgesics:

-    Tramadol crosses the placental barrier.

-    Chronic use of tramadol may induce - at any dosage - a withdrawal syndrome in newborns.

-    At the end of pregnancy, high dosages, even for short-term treatment, may induce respiratory depression in the newborn.

Animal studies have not shown any teratogenic effects, but at high doses, foetotoxicity due to maternotoxicity appeared (see Section 5.3).

Breast Feeding:

Tramadol and its metabolites have been detected in human breast milk in small amounts. An infant could ingest 0.1% of the single dose given to the mother. A single administration of tramadol does not usually require breastfeeding to be interrupted. If repeated administration is needed for several days, i.e. more than 2 to 3 days, breastfeeding should be suspended. If longterm treatment after birth is necessary, breastfeeding is contraindicated (see Section 4.3).

4.7 Effects on ability to drive and use machines

Tramadol may cause dizziness and/or drowsiness and has, even when used according to the directions, an influence on the ability to drive and use machines. This effect may occur at the beginning of treatment, and may be potentiated by alcohol and concomitant use of other CNS-depressants or antihistamines. If patients are affected they should be warned not to drive or operate machinery.

This medicine can impair cognitive function and can affect a patient’s ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:

- The medicine is likely to affect your ability to drive

-    Do not drive until you know how the medicine affects you

-    It is an offence to drive while under the influence of this medicine

-    However, you would not be committing an offence (called ‘statutory defence’) if:

•    The medicine has been prescribed to treat a medical or dental problem and

•    You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and

•    It was not affecting your ability to drive safely

4.8 Undesirable effects

The most commonly reported undesirable effects, nausea and dizziness, have been observed in more than 10% of patients.

Cardiac disorders

Uncommon (>1/1,000, <1/100): effects on cardiovascular regulation (palpitations, tachycardia, orthostatic hypotension or cardiovascular collapse). These undesirable effects occur in particular after intravenous administration and in patients undergoing physical exertion. Rare (>1/10,000, <1/1,000): bradycardia, Increase in blood pressure

Nervous system disorders Very common (>1/10): dizziness.

Common (>1/100, <1/10): headaches, confusion.

Rare (>1/10,000, <1/1,000): changes in appetite, paraesthesia, tremor, respiratory depression, epileptiform seizures.

Respiratory depression may occur if the quantities administered greatly exceed the

recommended doses and in the case of concomitant administration of other CNS

depressant medicinal products. (See section 4.5).

Epileptiform seizures primarily occurred following administration of high doses of tramadol or following concomitant treatment with medicinal products that lower the seizure threshold or trigger seizures. (See sections 4.4 and 4.5).

Psychiatric disorders

Rare (>1/10,000, <1/1,000): hallucinations, confusion, sleep disturbance, nightmares.

After the administration of tramadol, in rare cases, various psychiatric adverse events may occur, the nature and severity of which vary between patients (depending on the individual reactivity and the duration of treatment). Mood disorders (usually euphoria, occasionally dysphoria), changes in activity (usually reduced activity, occasionally an increase) and, altered cognitive and sensory capacities (for example the ability to make decisions, perception problems) may be observed. Dependence may occur.

Eye disorders

Rare (>1/10,000, <1/1,000): blurred vision.

Respiratory, thoracic and mediastinal disorders

An aggravation of asthma has been reported although a causal relationship was not confirmed.

Gastrointestinal disorders Very common (>1/10): nausea.

Common (>1/100, <1/10): vomiting, constipation, dry mouth Uncommon (>1/1,000, <1/100: gastro-intestinal irritation (a feeling of gastric heaviness, flatulence).

Skin and subcutaneous tissue disorders Common (>1/100, <1/10): sweating.

Uncommon (>1/1,000, <1/100): dermal reactions (for example pruritus, rash, urticaria).

Musculoskeletal and connective tissue disorders Rare (>1/10,000, <1/1,000): muscular weakness.

Hepatobiliary disorders

In some isolated cases, an increase in hepatic enzymes was reported during the therapeutic use of tramadol.

Renal and urinary disorders

Rare (>1/10,000, <1/1,000): micturation problems (difficulty in passing urine and urinary retention).

General disorders and administration site conditions Rare (>1/10,000, <1/1,000): Allergic reactions (for example dyspnoea, bronchospasm, wheezing, Quincke’s oedema) and anaphylaxis. Withdrawal symptoms similar to those observed during withdrawal of opiates may occur, such as agitation, anxiety, nervousness, insomnia, hyperkinesias, tremor and gastro-intestinal symptoms. Other symptoms of withdrawal have also been reported, including: panic attacks, severe anxiety, hallucinations, paraesthesia, tinnitus and other CNS problems.

Metabolism and nutrition disorders

Not known (cannot be estimated from the available data): Hypoglycemia.

4.9 Overdose

Symptoms

In tramadol intoxication, in principle, the same symptoms occur as for all

other central acting analgesics (opioids). In particular, these include miosis, vomiting, cardiovascular collapse, loss of consciousness leading to coma, convulsions, respiratory depression leading to respiratory failure.

Unexpected effect of overdose: serotonin syndrome has been reported in a context of overdose or abuse with tramadol.

Treatment

General emergency measures are applicable: including maintenance of respiratory and cardiocirculatory functions.

Emptying of the stomach by means of vomiting (patient to be conscious) or by means of pumping the stomach. Gastric lavage can be considered if the ingestion of overdose is very recent. This must not delay the (repeated) administration of activated charcoal to prevent the absorption of tramadol. The antidote for respiratory depression is naloxone. There is a risk of increased convulsions with the use of naloxone. In animal tests naloxone proved to be ineffective against convulsions. In that case diazepam should be administered intravenously.

Tramadol is only minimally removed from plasma using haemodialysis or haemofiltration. Therefore treatment of acute overdose of tramadol using haemodialysis or haemofiltration alone is not a suitable way of detoxification.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Analgesics, Other opioids ATC code: N02A X02

Tramadol is a centrally acting analgesic. It is a pure non-selective p, delta and k morphine receptor agonist with a higher affinity for p receptors. Other mechanisms responsible for the product’s analgesic effects include the inhibition of the neuronal re-uptake of noradrenalin and an increase in serotonin release.

Tramadol has an antitussive effect. Unlike morphine, broad ranges of analgesic tramadol doses do not have any respiratory depressant effect. Nor is there any effect on gastro-intestinal motility. The effects on the cardiovascular system tend to be slight. Tramadol has 1/10 to 1/6 the potency of morphine.

5.2 Pharmacokinetic properties

Following oral administration of a single dose, TRADOREC XL® is almost completely absorbed (>90%).

The absolute bioavailability is approximately 70%, independent of food intake. The difference between the tramadol absorbed and the non-metabolised available tramadol is probably due to a weak first-pass effect. The first-pass effect following oral administration is a maximum of 30%.

Tramadol has a high tissue affinity (volume of distribution = 203 ± 40 litres). Approximately 20% is bound to plasma proteins.

Following single-dose administration of one 200 mg TRADOREC XL^® prolonged- release tablet, in a fasted state, a mean maximum plasma concentration (Cmax) of 241 ± 62 ng/ml is reached after a median time (tmax) of 6.0 hours.

Tramadol crosses the blood-brain barrier and the placenta. Very small quantities of the active substance and its O-demethylated derivative have been found in breast milk (0.1% and 0.02% of the administered dose respectively). The elimination half-life is approximately 6 hours, regardless of route of administration. The half life can be prolonged by a factor of approximately 1.4 in patients over 75 years of age.

In man, tramadol is extensively metabolised by N- and O-demethylation and by conjugation of the O-demethylation products with glucuronic acid. Only the O-desmethyltramadol metabolite is pharmacologically active. Considerable quantitative inter-individual differences have been observed between the other metabolites: 11 different metabolites have been identified to date in urine. Tests on animals showed that O-desmethyltramadol is more potent than the parent molecule by a factor of 2 to 4. Its half life (6 healthy volunteers) is 7.9 hours (range 5.4 to 9.6 hours), similar to that of tramadol.

The inhibition of cytochrome CYP3A4 and/or CYP2D6, the isozymes responsible for biotransformation of tramadol could modify the plasma concentration of tramadol or its active metabolite. To date, no clinically significant interactions have been observed. Tramadol and its metabolites are almost wholly excreted in urine. Cumulative urinary excretion accounts for 90% of the total radioactivity of the administered dose. The half-life may be slightly longer in the case of hepatic or renal impairment. In patients with liver cirrhosis, an elimination half-life of 13.3 ± 4.9 hours (tramadol) and 18.5 ± 9.4 hours (O-desmethyltramadol) has been observed, with one extreme case of elimination half-lives of 22.3 and 36 hours respectively. In renal insufficiency (creatinine clearance < 5 ml/min), elimination half-lives of 11 ±

3.2 and 16.9 ± 3 hours respectively have been observed, with one extreme case of 19.5 and 43.2 hours respectively. TRADOREC XL® presents a linear pharmacokinetic profile within the recommended therapeutic dosing regimen. The relationship between serum concentration and analgesic effect is dose-dependent but varies considerably between individuals. A serum concentration of 100 ng/ml to 300 ng/ml is usually effective.

5.3 Preclinical safety data

Preclinical data reveal no special risk for clinical use based on acute toxicity, repeated dose toxicity, genotoxicity, carcinogenicity and reproductive toxicity studies. Animal studies have not shown any teratogenic effects, but at high doses, foetotoxicity due to maternotoxicity appeared.

In rats, doses of tramadol greater than or equal to 50 mg/kg/day caused toxic effects in pregnant animals and an increase in neonatal mortality. Retarded growth in the form of abnormal ossification and delayed vaginal and ocular opening were observed in the progeny. There was no change in the fertility of male animals. After higher doses (> 50 mg/kg/day), females showed a reduced gestation level.

In rabbits, toxic effects were revealed in the mothers and skeletal abnormalities in the progeny above doses of 125 mg/kg. Signs indicating a mutagenic effect were found in certain in vitro tests but in vivo studies did not show any such effects. Based on findings to date, tramadol can be regarded as non mutagenic.

Studies were conducted in rats and mice on the carcinogenic potential of tramadol hydrochloride. The study in rats did not show any indication of an increased frequency of tumours linked to the active ingredient. In the study on mice, an increased frequency of hepatocellular adenomas was observed in male animals (non significant dose-dependent increase above 15 mg/kg) and an increase in pulmonary tumours in females for all dosage groups (significant but non dose-dependent increase).

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Polyvinyl acetate, povidone, sodium lauryl sulphate and silica (Kollidon SR), xanthan gum,

hydrogenated vegetable oil (Cotton seed oil), magnesium stearate, silica colloidal anhydrous,

Hydroxypropyl Distarch Phosphate - (E1442) (Contramid)

6.2 Incompatibilities

Not applicable

6.3 Shelf life

3 years

Special precautions for storage

Blisters: Do not store above 30 C.

HDPE Bottles: This medicinal product does not require any special storage conditions

6.5 Nature and contents of container

PVC/PE/PCTFE blisters with Aluminium backing foil (containing 5, 10, 15, 20, 30,

50, 60 or 100 prolonged-release tablets) or

HDPE Bottles containing 100 prolonged-release tablets

6.6 Special precautions for disposal

No special requirements.

7    MARKETING AUTHORISATION HOLDER

Endo Ventures Limited First Floor Minerva House Simmonscourt Road Ballsbridge Dublin 4 IRELAND

8    MARKETING AUTHORISATION NUMBER(S)

PL 43808/0003

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION 02/02/2010

10 DATE OF REVISION OF THE TEXT

01/11/2014