TRADOREC XL^® 100 mg prolonged-release tablets

TRADOREC XL^® 200 mg prolonged-release tablets

TRADOREC XL^® 300 mg prolonged-release tablets

One prolonged-release tablet contains 100mg, 200mg or 300mg tramadol hydrochloride

For a full list of excipients, see section 6.1

Prolonged-release tablet.

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

Treatment of moderate to severe pain.

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 as follows:

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:

Dose adjustment in elderly patients (up to 75 years of age) without clinically relevant hepatic or renal impairment is normally not necessary. In patients over 75 years, the elimination half-life of tramadol may be prolonged. Use in these patients is not recommended.

Renal impairment, dialysis and hepatic impairment:

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).

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).

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.

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).

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.

Selective serotonin re-uptake inhibitors (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) and anti-depressants: Risk of convulsions and/or serotonin syndrome.

Medicinal products that reduce seizure threshold, notably tricyclic antidepressants (imipramines), selective serotonin re-uptake inhibitors (SSRIs), neuroleptic antidepressants (phenothiazine, butyrophenone), mefloquine, bupropion: Increased risk of convulsions.

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.

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).

Lactation:

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 long-term treatment after birth is necessary, breastfeeding is contraindicated (see Section 4.3).

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.

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.

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.

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.

Pharmacotherapeutic group: Analgesics, Other opioids

ATC code: N02A X02

Tramadol is a centrally acting analgesic. It is a pure non-selective µ, delta and k morphine receptor agonist with a higher affinity for µ 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.

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.

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).

Polyvinyl acetate, povidone, sodium laury sulphate and silica (Kollidon SR),

xanthan gum,

hydrogenated vegetable oil (Cotton seed oil),

magnesium stearate,

silica colloidal anhydrous,

Hydroxypropyl Distarch Phosphate – (E1442) (Contramid)

Not applicable

3 years

Blisters: Do not store above 30°C.

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

TRADOREC XL 100 mg and 200mg:

PVC/PVDC blisters with Aluminium backing foil (containing 5, 10, 15, 20, 30, 50, 60 or 100 prolonged-release tablets) or

PVC/PE/PCTFE blisters with Aluminium backing foil (containing 5, 10, 15, 30, 60 or 100 prolonged-release tablets) or

HDPE Bottles containing 100 prolonged-release tablets

TRADOREC XL 300 mg:

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

Not all pack sizes may be marketed.

No special requirements.

LABOPHARM Europe Limited

5, The Seapoint Building

44 Clontarf Road Dublin 3,

IRELAND

TRADOREC XL^® 100 mg: PL 23232/0007

TRADOREC XL^® 200 mg: PL 23232/0008

TRADOREC XL^® 300 mg: PL 23232/0009

19 February 2010

26 February 2010

POM

SPC.TRA.10.UK.3257.REN