SUMMARY OF PRODUCT CHARACTERISTICS

1.    NAME OF THE MEDICINAL PRODUCT

Tramadol Hydrochloride 50 mg tablets

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 50 mg tramadol hydrochloride.

Excipient with known effect:

Each tablet contains 100.00 mg lactose monohydrate.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

A white round oral tablet with T printed on one face and a breakline on the reverse.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Management (treatment and prevention) 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 children aged 12 years and over Acute pain

An initial dose of 100mg is usually necessary. This can be followed by doses of 50 or 100 mg not more frequently than 4 hourly, and duration of therapy should be matched to clinical need.

Pain associated with chronic conditions

Use an initial dose of 50mg and then titrate dose according to pain severity. The need for continued treatment should be assessed at regular intervals as withdrawal symptoms and dependence have been reported (See Section 4.4).

A total daily oral dose of 400mg should not be exceeded except in special clinical circumstances.

Geriatric patients

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 insufficiency/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.

Paediatric population

Not recommended for children under 12 years.

Method of administration

For oral administration.

4.3    Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Tramadol should not be administered in cases of acute intoxication with alcohol, hypnotics, centrally acting analgesics, opioids or psychotropic drugs, or in patients suffering from uncontrolled epilepsy. Tramadol must not be used for narcotic withdrawal treatment. In common with other opioid analgesics it should not be administered to patients who are receiving monoamine oxidase inhibitors or within two weeks of their withdrawal.

4.4    Special warnings and precautions for use

Warnings

At therapeutic doses, tramadol has the potential to cause withdrawal symptoms. Rarely, cases of dependence and abuse have been reported.

At therapeutic doses, withdrawal symptoms have been reported at a reporting frequency of 1 in 8,000. Reports of dependence and abuse have been less frequent. Because of this potential, the clinical need for continued analgesic treatment should be reviewed regularly.

In patients with a tendency to drug abuse or dependence, treatment should be for short periods and under strict medical supervision.

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

Convulsions have been reported at therapeutic doses and the risk may be increased at doses exceeding the usual upper daily dose limit. Patients with a history of epilepsy or those susceptible to seizures should only be treated with tramadol if there are compelling reasons. The risk of convulsions may increase in patients taking tramadol and concomitant medication that can lower the seizure threshold (see section 4.5).

Precautions

Tramadol should be used with caution in patients with head injury, increased intracranial pressure, severe impairment of hepatic and renal function and in patients prone to convulsive disorders or in shock.

Care should be taken when treating patients with respiratory depression, or if concomitant CNS depressant drugs are being administered, as the possibility of respiratory depression cannot be excluded in these situations. At therapeutic doses, respiratory depression has infrequently been reported.

In one study, use of tramadol during general anaesthesia with enflurane and nitrous oxide was reported to enhance intraoperative recall. Until further information is available use of tramadol during light planes of general anaesthesia should be avoided.

Caution should be exercised in patients with a previous history of hypersensitivity to other opiates, and in patients with decreased level of consciousness of uncertain origin.

Tramadol Hydrochloride contains lactose monohydrate

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

Concomitant administration of tramadol with other centrally acting drugs including alcohol may potentiate CNS depressant effect.

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.

Simultaneous administration of carbamazepine markedly decreases serum concentrations of tramadol to an extent that a decrease in analgesic effectiveness and a shorter duration of action may occur.

Simultaneous administration with cimetidine is associated with clinically insignificant changes in serum concentrations of tramadol. Therefore no alteration of the tramadol dosage regimen is recommended for patients receiving chronic cimetidine therapy.

There is a theoretical possibility that tramadol could interact with lithium due to their respective mechanisms of action.

The simultaneous administration of Tramadol and MAOIs is contraindicated. 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. In case of concomitant administration of digoxine rare cases of toxicity signs due to digoxine have been observed such as nausea, vomiting and cardiac arrhythmias. Simultaneous administration of ritonavir can augment the concentration of Tramadol in serum which can lead to a toxicity of Tramadol (extreme sedation and respiratory depression) the dose of Tramadol must be reduced.

The combination of mixed agonists/antagonists (e.g. buprenorphine, nalbuphine, pentazocine) and tramadol is not recommended because it is theoretically possible that the analgesic effect of a pure agonist is attenuated under these circumstances.

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.

4.6 Fertility, pregnancy and lactation

Pregnancy

Animal studies (rat and rabbit, exposure to tramadol up to 7 times that expected in man) have not revealed teratogenic effects and minimal embryotoxicity (delayed ossification). Fertility, reproductive performance and development of offspring were unaffected. There is inadequate evidence available on the safety of tramadol in human pregnancy, therefore tramadol should not be used in pregnant women.

Lactation

Tramadol and its metabolites are found in small amounts in human breast milk. An infant could ingest about 0.1% of the dose given to the mother. Tramadol should not be administered during breast feeding.

4.7 Effects on ability to drive and use machines

Tramadol may cause drowsiness and this effect may be potentiated by alcohol and other CNS depressants. Ambulant patients should be warned not to drive or operate machinery if affected.

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:

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

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

o It was not affecting your ability to drive safely

4.8 Undesirable effects

The most commonly reported adverse drug reactions are nausea and dizziness, both occurring in more than 10% of patients.

In this section undesirable effects are defined as follows: 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).

Cardiovascular system disorders

Uncommon: 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, syncope, blood dyscrasias.

Metabolism and nutrition disorders Not known: hypoglycaemia

Nervous system disorders Common: headache, muzziness

Rare: changes in appetite, paraesthesia, tremor, vertigo, respiratory depression, epileptiform convulsions.

Psychiatric disorders

Rare: hallucinations, confusion, somnolence, sleep disturbance and nightmares. Psychic side-effects may occur following administration of tramadol, which 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, occasionally increase) and changes in cognitive and sensorial ability (e.g. decision behaviour, perception disorders). Dependence may occur.

Eye disorders Rare: blurred vision.

Respiratory, thoracic and mediastinal disorders

Worsening of asthma has been reported, though a casual relationship has not been established.

Gastrointestinal disorders Very common: nausea

Common: vomiting, constipation, diarrhoea, dry mouth.

Uncommon: 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)

Rare: flushing

Musculoskeletal and connective tissue disorders Rare: muscle weakness

Hepatobiliary disorders

In rare cases, increases in liver enzyme values have 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

Rare: Allergic reactions (e.g. dyspnoea, bronchospasm, wheezing, angioneurotic oedema) and anaphylaxis; symptoms of withdrawal reactions, similar to those occurring during opiate withdrawal, may occur as follows: agitation, anxiety, nervousness, insomnia, hyperkinesia, tremor and gastrointestinal symptoms.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme or the website: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Symptoms of overdosage are typical of other opioid analgesics, and include miosis, vomiting, cardiovascular collapse, sedation and coma, seizures and respiratory depression.

Supportive measures such as maintaining the patency of the airway and maintaining cardiovascular function should be instituted; naloxone should be used to reverse respiratory depression; fits can be controlled with diazepam.

Tramadol is minimally eliminated from the serum by haemodialysis or haemofiltration. Therefore treatment of acute intoxication with tramadol with haemodialysis or haemofiltration alone is not suitable for detoxification.

5. PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: other opioids; ATC Code: N02AX02.

Tramadol is a centrally acting analgesic with two mechanisms of action. It is a nonselective pure agonist at opioid receptors with a higher affinity for p receptors. It is also an inhibitor of neuronal reuptake of noradrenaline and serotonin.

5.2    Pharmacokinetic properties

Tramadol has a half-life of approximately six hours. It is eliminated metabolically and by the kidneys. The terminal half-life may therefore be increased in renal and hepatic impairment.

The half-life of the terminal elimination phase (t¹/B) was 6.0 ± 1.5 h in young volunteers. Tramadol pharmacokinetics show little age dependence in volunteers up to the age of 75 years. In volunteers aged over 75 years, tV₂B was 7.0 ± 1.6 h on oral administration.

Since tramadol is eliminated both metabolically and renally, the terminal halflife t/B may be prolonged in impaired hepatic or renal function. However, the increase in the t/B values is relatively low if at least one of these organs is functioning normally. In patients with liver cirrhosis t/B tramadol was a mean of 13.3 ±4.9 h. in patients with renal insufficiency (creatinine clearance <5 ml/min) it was 11.0 ±3.2 h.

The poor metabolisers of Tramadol may have approximately up to 10 times lower 0-desmethyltramadol levels compared with the extensive metabolisers in terms of AUC.

The inhibition of one or both P450 isoenzymes, CYP3A4 and CYP2D6 involved in the metabolism of tramadol, may affect the plasma concentration of tramadol or its active metabolite. Up to now, clinically relevant interactions have not been reported.

5.3 Preclinical safety data

Single and repeat-dose animal studies demonstrate that 10 times the expected human dose is needed before hepatotoxicity is observed. Carcinogenicity and mutagenicity tests in animals were negative.

PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Lactose monohydrate Microcrystalline cellulose Carmellose sodium Magnesium stearate

6.2    Incompatibilities

Not applicable.

6.3 Shelf life

Tramadol hydrochloride tablets have a shelf life of five years.

6.4    Special precautions for storage

°

Store below 25 C. Store in the original package in order to protect from moisture.

6.5    Nature and contents of container

Blister strips formed from 25 micrometre thick soft aluminium cover foil and 250 micrometre thick opaque PVC foil Blister packs of 10, 30, 60 and 100 tablets.

Not all pack sizes may be marketed.

6.6    Special precautions for disposal

No special requirements.

7 MARKETING AUTHORISATION HOLDER

Eurogenerics N.V.

Heizel Esplanade b 22,

1020 Brussel,

Belgie

8 MARKETING AUTHORISATION NUMBER(S)

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 12 October 1998 Date of latest renewal: 5 November 2003

10 DATE OF REVISION OF THE TEXT

01/06/2016