THERADOL 50 mg Effervescent tablets 1 Summary of product characteristics

SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

THERADOL 50 mg Effervescent tablets.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

2.1 General description

Round, biplane white or off-white tablets with bevel-edges on both sides.

2.2 Qualitative and quantitative composition

Tramadol hydrochloride 50 mg per effervescent tablet. This product also contains sodium 214 mg, lactose 75 mg and aspartame 10 mg per tablet.

For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Effervescent tablet.

4. CLINICAL PARTICULARS

4.1. Therapeutic indications

Treatment of moderate to severe acute and chronic pain, such as pain due to surgery, trauma, malignancy.

4.2. Posology and method of administration

Posology

As with all analgesic drugs, the dose of THERADOL 50 mg Effervescent tablets should be adjusted according 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 children aged 12 years and over: The usual dose is 50 to 100 mg (1 to 2 effervescent tablets), 3 to 4 times a day. In children from 12 to 14 years, it is recommended to use the lowest dose.

Geriatric patients THERADOL 50 mg Effervescent tablets 2 Summary of product characteristics

A dose adjustment is not usually necessary in patients up to 75 years without clinically manifest hepatic or renal insufficiency. 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. Tramadol is not recommended for use in patients with severe renal impairment (creatinine clearance < 10 ml/min). As tramadol is only removed very slowly by haemodialysis or haemofiltration, post-dialysis administration to maintain analgesia is not usually necessary. Tramadol is not recommended for use in patients with severe hepatic impairment.

Use in children below 12 years: Tramadol is not recommended for use in children below 12 years because its safety and efficacy have not been established.

For acute pain an initial dose of 100 mg is usually necessary. In case THERADOL 50 mg Effervescent tablets are used for acute pain, it should be stressed that its activity is somewhat delayed in comparison to that of other analgesics. For pain associated with chronic conditions an initial dose of 50 mg is advised. It is recommended, when possible in case of chronic treatment, to slowly increase tramadol dosage to its final recommended dose (with increments every 2 to 3 days) in order to reduce the incidence of adverse events.

Method of administration

The effervescent tablets should be dissolved in a glass of water prior to intake. THERADOL 50 Effervescent tablets can be taken without regard to food.

In general, a total daily dose of 400 mg (8 effervescent tablets) should not be exceeded.

The interval between the doses should be at least 4 hours. This should also be taken into account in case of any violation of the regular schedule, eg because of missing doses or delayed intervals.

Treatment periods should usually be limited and intermittent. Withdrawal symptoms may occur if tramadol is discontinued abruptly.

4.3. Contraindications

- Known hypersensitivity to the active substance or to any of the excipients or to other opioids. - Patients receiving Monoamino Oxidase Inhibitors or within two weeks of their withdrawal (see 4.5.). - Acute intoxication with alcohol, hypnotics, analgesics or any other central nervous system (CNS) acting drugs (see 4.5.). - Patients suffering from uncontrolled epilepsy. - For use in narcotic withdrawal treatment.

4.4. Special warnings and precautions for use

Relative contraindications THERADOL 50 mg Effervescent tablets 3 Summary of product characteristics

In one study the use of tramadol during general anaesthesia with enflurane and nitrous oxide was reported to enhance intraoperative recall. Until further information is available use of THERADOL 50 mg Effervescent tablets during light phases of general anaesthesia should be avoided.

Warnings

THERADOL 50 mg Effervescent tablets should be used with caution in patients with head injury or increased intra-cranial pressure, excessive bronchial secretion and in patients prone to convulsive disorders or in shock. Care should be taken when treating patients with respiratory depression, if concomitant CNS-depressing drugs are being administered (see 4.5.), or if the recommended dose of THERADOL 50 mg Effervescent tablets is abnormally high. Respiratory depression cannot be excluded in these situations. Diagnosis of, for example, acute abdominal injury can be disguised. Seizures have been observed in predisposed patients or receiving a combination of drugs known to reduce the seizure threshold, mainly anti-psychotic, anti-depressant, central analgesic or local anaesthetic drugs. Therefore, special care should be taken in these patients. In case of moderate renal (creatinine clearance <30 ml/min) or hepatic impairment, THERADOL 50 mg Effervescent tablets should be used with caution and dosage interval increased to 12 hours (see 4.2.). Tramadol has been shown to have a low potential to cause physical dependence, however, cases of abuse, dependence and withdrawal syndrome have occurred. Consequently, in patients with tendency to or history of drug abuse or dependence, treatment with tramadol is not recommended.

Precautions for use

It is recommended, when possible in case of chronic treatment, to slowly increase tramadol dosage to its final recommended dose in order to reduce the incidence of adverse events such as nausea, vomiting, dizziness and sedation (see 4.8.).

THERADOL 50 mg Effervescent tablets should be used with caution in case of concomitant administration of coumarin-derivatives (e.g. warfarin) because anticoagulation manifestations such as increase of INR and ecchymoses might occur (see 4.5.). THERADOL 50 mg Effervescent tablets should be used with caution in patients receiving treatment with another serotonergic agent, e.g. clomipramine, fluoxetine, fluvoxamine, nefazodone, paroxetine, sertraline and venlafaxine, due to the risk of seizures and serotonin syndrome (see 4.5.). In patients known to be poor metabolizers (P450 2D6) and in patients receiving inhibitors of P450 2D6, e.g. paroxetine, fluoxetine, quinidine, ritonavir and cimetidine, the analgesic effect of THERADOL 50 mg Effervescent tablets will be less intensive (see 4.5.).

This medicine contains 214 mg sodium per effervescent tablet. This should be taken into consideration by patients on a controlled sodium diet. This medicine contains aspartame which is a source of phenylalanine. This medicine may therefore be harmful for patients with phenylketonuria. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose- galactose malabsorption should not take this medicine. THERADOL 50 mg Effervescent tablets should be used with caution in patients with acute porphyria because in vitro tests have shown a risk of hepatic porphyrin accumulation which could lead to porphyric crisis.

4.5. Interaction with other medicinal products and other forms of interaction

THERADOL 50 mg Effervescent tablets 4 Summary of product characteristics

Interactions affecting the use of THERADOL 50 mg Effervescent tablets

- 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 diaphoresis • 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.

- Concomitant administration of THERADOL 50 mg Effervescent tablets with anaesthetics and other centrally acting drugs, including alcohol, may potentiate CNS depressant effects. Caution should be taken in case of concomitant use with these drugs or alcohol. - THERADOL 50 mg Effervescent tablets should be used with caution in patients receiving treatment with another serotonergic agent, e.g. clomipramine, fluoxetine, fluvoxamine, nefazodone, paroxetine, sertraline and venlafaxine, due to the risk of seizures and serotonin syndrome (see 4.4.). - Tramadol is metabolized through cytochrome P450 2D6 to an active metabolite. The analgesic effect of tramadol is less intensive in patients known to be poor metabolizers (P450 2D6) and in patients receiving inhibitors of P450 2D6, e.g. paroxetine, fluoxetine, quinidine, ritonavir and cimetidine (see 4.4.). - Simultaneous administration of carbamazepine markedly decreases serum concentrations of tramadol and its active metabolite to an extent that a decrease in analgesic effectiveness and a shorter duration of action may occur. - Simultaneous administration with agonist-antagonist opioids (buprenorphine, nalbufine, pentazocine) may reduce the analgesic effect by competitive blocking of the receptors. - The results of two studies indicate that simultaneous administration of ondansetron may reduce the analgesic effect of tramadol.

Interactions affecting the use of other medicinal products

- Concomitant administration of THERADOL 50 mg Effervescent tablets with anaesthetics and other centrally acting drugs, including alcohol, may potentiate CNS depressant effects. - Caution should be taken in case of concomitant administration of tramadol with coumarin-derivatives (e.g. warfarine) because anticoagulation manifestations such as increase of INR and ecchymoses might occur in certain patients (see 4.4.). The mechanism of this interaction is unknown. - Digoxin toxicity has occurred rarely during co-administration of digoxin and tramadol. - 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. (see 4.4.).

4.6. Fertility, pregnancy and lactation

THERADOL 50 mg Effervescent tablets 5 Summary of product characteristics

Animal studies have not revealed any embryotoxic effect, except at maternally toxic doses. There is inadequate evidence available on the safety of tramadol in human pregnancy and during delivery ; therefore THERADOL 50 mg Effervescent tablets should not be used during pregnancy and delivery.

Tramadol and its metabolites are found in small amounts in human breast milk. THERADOL 50 mg Effervescent tablets should not be used during breast-feeding.

4.7. Effects on ability to drive and use machines

Tramadol may reduce reaction time. This effect can be aggravated by alcohol or other substances depressing the CNS. THERADOL 50 mg Effervescent tablets may therefore affect the ability to drive and to use machines. Patients should be advised not to drive and not to operate machinery while taking THERADOL 50 mg Efferevescent tablets.

4.8. Undesirable effects

The most commonly reported adverse drug reaction are nausea and dizziness, both occurring in > 1/10 of patients. The following adverse drug reactions can also occur. They are ranked under headings of frequencies: very common (> 1/10) ; common (> 1/100 to < 1/10) ; uncommon (> 1/1000 to < 1/100) ; rare (> 1/10000 to < 1/1000) ; very rare (< 1/10000) ; not known (cannot be estimated from the available data).

Cardiovascular disorders: Uncommon: effects on cardiovascular regulation (palpitation, tachycardia, postural hypotension or cardiovascular collapse). These adverse effects may occur especially on intravenous administration and in patients who are physically stressed. Rare: bradycardia, increase in blood pressure. Very rare: Flushing.

Nervous system disorders: Very common: dizziness. Common: headache, somnolence. Rare: changes in appetite, paraesthesia, tremor, respiratory depression, epileptiform convulsions, involuntary muscle contractions, abnormal coordination, syncope. Not known: speech disorders.

If the recommended doses are considerabely exceeded and other centrally depressant substances are administered concomitantly (see section 4.5) respiratory depression may occur.

Epileptiform convulsions occurred mainly after administration of high doses of tramadol or after concomitant treatment with drugs, which can lower the seizure threshold or themselves induce cerebral convulsions (see section 4.4 and section 4.5).

Psychiatric disorders: Rare: hallucinations, confusion, anxiety, sleep disturbances and nightmares. Psychic side-effects may vary individually in intensity and nature (depending on personality and duration of medication). These include changes in mood (usually elation, occasionally dysphoria), changes in activity (usually suppression, THERADOL 50 mg Effervescent tablets 6 Summary of product characteristics occasionally increase) and changes in cognitive and sensorial capacity (e.g. decision behaviour, perception disorders). Dependencemay occur.

Immune system disorders: Rare: allergic reactions (e.g. dyspnoea, bronchospasm, wheezing, angioneurotic oedema, and exceptionally toxic epidermal necrolysis and Stevens-Johnson syndrome), anaphylaxis, cross reactivity with non steroidal anti-inflammatory drugs.

Eye disorders: Rare: blurred vision. Not known: mydriasis.

Respiratory, thoracic and mediastinal disorders: Rare: dyspnoea. Worsening of asthma has also been reported, though a causal relationship has not been established.

Gastrointestinal disorders: Very common: nausea. Common: vomiting, constipation, dry mouth. Uncommon: diarrhoea, retching, gastrointestinal irritation (a feeling of pressure in the stomach, bloating).

Skin and subcutaneous tissue disorders: Common: sweating. Uncommon: dermal reactions (e.g. pruritus, rash, urticaria).

Musculoskeletal and connective tissue disorders: Rare: motorial weakness.

Hepatobiliary disorders: Very rare: In a few isolated cases an increase in liver enzyme values has been reported in a temporal connection with the therapeutic use of tramadol.

Renal and urinary disorders: Rare: micturition disorders (difficulty in passing urine and urinary retention).

General disorders and administration site conditions: Common: fatigue. Rare: Symptoms of withdrawal reactions, similar to those occurring during opiate withdrawal, may occur as follows: agitation, anxiety, nervousness, insomnia, hyperkinesia, tremor and gastrointestinal symptoms. Other symptoms that have very rarely been seen with tramadol discontinuation include: panic attacks, severe anxiety, hallucinations, paraesthesias, tinnitus and unusual CNS symptoms (i.e. confusion, delusions, personalization, derealisation, paranoia).

Ear and labyrinth disorders: Very rare: Vertigo.

Metabolism and nutrition disorders: Not known: hypoglycaemia

THERADOL 50 mg Effervescent tablets 7 Summary of product characteristics

4.9. Overdose

Generally, symptoms of overdose are typical of other opioid analgesics, and include: myosis, vomiting, cardiovascular collapse, sedation and coma, convulsions and respiratory depression. One case of fulminant lethal hepatitis after overdose has been described. Massive overdose could be life threatening. The risk of fatal outcome is increased in case of concomitant use of benzodiazepines. Supportive measures such as maintaining respiratory and cardiovascular function should be instituted; naloxone should be used to reverse respiratory depression; convulsions can be controlled with diazepam. Treatment with haemodialysis or haemofiltration alone is not suitable.

5. PHARMACOLOGICAL PROPERTIES

5.1. Pharmacodynamic properties

Pharmacotherapeutic group : opioid analgesic, ATC code : NO2A XO2.

Tramadol, a centrally acting analgesic, is effective against moderate to severe acute and chronic pain. Tramadol possesses two enantiomers. The (+)-isomer is principally active as opioid with a relative high preferential affinity for the µ-opioid receptor (20 x higher affinity than the (-)-isomer). The (+)-desmethyl metabolite contributes also to the opioid effect. In vivo, the metabolite has a 6 x higher affinity for the µ-opioid receptor than tramadol. In vitro, the affinity is 170 x higher. The (-)-isomer inhibits the neuronal reuptake of noradrenaline and potentiates the analgesic effect of the (+)- isomer. The contribution of enhancement of serotonin release is of little importance, except in cases of certain interactions with cytochrome P450 2D6 inhibitors (see 4.5.)

Tramadol possesses analgesic and antitussive properties. At variance to morphine, tramadol administered at therapeutic doses has a negligible depressant effect on respiration. Its effects on gastro-intestinal motility and the cardiovascular system are minimal at therapeutic doses.

5.2. Pharmacokinetic properties

Absorption After oral administration, tramadol is rapidly and entirely absorbed. The mean absolute bioavailability is ± 72 %. Maximal serum concentrations are reached after 1 hour.

Distribution Tramadol possesses a high tissue affinity; its volume of distribution is 203 + 40 l. The rate of protein binding is 20%. Tramadol passes through the blood/brain barrier and the placenta. Elimination of tramadol or its metabolite into breast milk is limited (± 0.1%).

Biotransformation Tramadol is mainly metabolized by N- and O-demethylation and subsequently by glucuronidation of the O- demethylated metabolite. Only O-desmethyl-tramadol is pharmacologically active. O-demethylation is catalysed by cytochrome P450 2D6. This enzyme is absent in 5-10 % of the Western population, the so-called "poor-metabolizers". In these patients, plasmaconcentrations of tramadol are increased and those of O- desmethyltramadol strongly decreased.

Elimination THERADOL 50 mg Effervescent tablets 8 Summary of product characteristics

Tramadol and its metabolites are nearly completely eliminated via the kidneys (10% as unchanged drug). Elimination half-life of tramadol and its metabolites is approximately 6 hours, both in healthy volunteers as in elderly.

Renal and hepatic impairment Since tramadol is eliminated both metabolically and renally, half-life may be prolonged (doubling) in impaired hepatic or renal function. In case of simultaneous hepatic and renal insufficiency, THERADOL 50 mg Effervescent tablets should not be used.

5.3. Preclinical safety data

On the basis of the results of the mutagenicity and carcinogenicity studies no genotoxic risk for humans is expected.

6. PHARMACEUTICAL PARTICULARS

6.1. List of excipients

Anhydrous citric acid Sodium hydrogen carbonate Anhydrous sodium sulphate Lactose monohydrate Macrogol Anhydrous sodium carbonate Sodium cyclamate Povidone Aspartame Orange flavouring (containing orange oil, terpeneless orange essential oil, citric acid monohydrate, butylhydroxyanisole, dextrin, acacia) Simethicone emulsion (containing dimeticon, colloidal anhydrous silica, methylcellulose, sorbic acid)

6.2. Incompatibilities

Not applicable.

6.3. Shelf life

5 years

6.4. Special precautions for storage

Do not store above 30°C. Store in the original package. Keep the tablet container tightly closed.

6.5. Nature and contents of container THERADOL 50 mg Effervescent tablets 9 Summary of product characteristics

Polypropylene tablet container with polyethylene stopper containing silica gel as desiccant.

Packaging with 10 effervescent tablets; i.e. 1 container with 10 tablets. Packaging with 20 effervescent tablets; i.e. 1 container with 20 tablets. Packaging with 30 effervescent tablets; i.e. 2 containers with 15 tablets.

Not all pack sizes may be marketed.

6.6. Special precautions for disposal

No special requirements.

7. MARKETING AUTHORISATION HOLDER

THERABEL PHARMA N.V. Paardeweide 3g NL – 4824 EH BREDA

8. MARKETING AUTHORISATION NUMBER(S)

RVG 24573

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation : 28.06.2000 Date of last renewal : 02.11.2005

10. DATE OF REVISION OF THE TEXT

8 October 2013