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SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Tilodol SR 200 mg Prolonged-Release Tablets Invodol SR 200 mg Prolonged-Release Tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

One prolonged-release tablet contains 200 mg of tramadol hydrochloride:

16,7 mg tramadol hydrochloride, immediate release

183,3 mg tramadol hydrochloride, slow release

Excipient: 118,0 mg lactose monohydrate

For a full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Prolonged-release tablet

Tramadol 200 mg

White-green, round bilayer tablet coded TR/200 R on one side

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 above the age of 12 years:

The recommended doses are intended as a guideline. Patients should always receive the lowest dose that provides effective pain control. Chronic pain management should be preferably given on a fixed dosing schedule.

The starting dose is usually 100 mg tramadol hydrochloride as prolonged-release tablet twice daily, in the morning and in the evening. If the pain relief is not sufficient, the dose may be increased to 150 mg twice daily or 200 mg twice daily.

The dosage interval must not be less than 8 hours.

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

Tramadol hydrochloride should never be used longer than absolutely necessary for pain control. If the nature and severity of the underlying disease suggest the need for prolonged pain management, continued medical need for tramadol hydrochloride analgesia should be reviewed carefully at short, regular intervals (with breaks in treatment if necessary).

Paediatric Population

Tramadol prolonged-release tablets are not suitable for children under 12 years of age.

Older People

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.

Method of administration

The prolonged-release tablets must be swallowed whole with sufficient liquid, irrespective of mealtimes.

4.3 Contraindications

Tramadol hydrochloride must not be used in patients

•    with hypersensitivity to the active substance or to any of the excipients (see section 6.1)

•    with acute intoxication with alcohol, hypnotics, centrally acting analgesics, opioids or other psychotropic medicinal products

•    receiving monoamine oxidase inhibitors or having taken them within the last 14 days before treatment with tramadol hydrochloride (see section 4.5)

•    who are suffering from uncontrolled epilepsy

Tramadol hydrochloride must not be used as a substitute in opioid dependent

patients (see section 4.4).

4.4 Special warnings and precautions for use

Tramadol has a low dependence potential. On long-term use tolerance, psychic and physical dependence may develop.

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

Tramadol is not a suitable substitute in opioid dependent patients. The active substance does not suppress morphine withdrawal symptoms although it is an opioid agonist.

Convulsions have been reported at therapeutic doses and the risk may be increased at doses exceeding the usual upper daily dose limit (400 mg). The risk of convulsions may increase in patients taking tramadol and concomitant medication that can lower the seizure threshold (see section 4.5). Patients with a history of epilepsy or those susceptible to seizures should only be treated with tramadol if there are compelling reasons.

Particular caution must be exercised when using tramadol in any of the following cases:

•    opioid dependence

•    impaired consciousness of unknown origin, shock

•    disturbance of respiratory centre and respiratory function

•    disorders associated with elevated intracranial pressure, cephalic injury, sensitive reaction to opioids

•    renal and hepatic impairment (see section 4.2).

In patients with respiratory depression or if CNS-depressant medicinal products are administered concomitantly (see section 4.5) or if the recommended maximum daily dose is considerably exceeded (see section 4.9), treatment should be performed with caution, since the possibility of respiratory depression cannot be excluded under these circumstances.

These medicinal products contain lactose. 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

Tramadol hydrochloride must not be combined with MAO inhibitors (see section 4.3).

Patients treated with monoamine oxidase inhibitors within 14 days prior to administration of the opioid pethidine have experienced life-threatening interactions affecting the central nervous system as well as the respiratory and circulatory centers. Similar interactions with monoamine oxidase inhibitors cannot be ruled out for tramadol hydrochloride either.

Concomitant administration of tramadol hydrochloride with other centrally depressant medicinal products including alcohol may potentiate the CNS effects (see section 4.8).

If cimetidine (enzyme inhibitor) is administered concomitantly or previously, no clinically relevant interactions are to be expected according to existing pharmacokinetic results.

Other morphine derivatives (including anti-tussives, substitution treatments), benzodiazepines, barbiturates: Increased risk of respiratory depression, that may be fatal in overdosage.

Simultaneous or previous administration of carbamazepine (enzyme inducer) may reduce the analgesic effect and shorten the duration of action.

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

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 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.

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

Active substances which inhibit the enzyme CYP3A4 such as ketoconazole, ritonavir and erythromycin, may inhibit the metabolism of tramadol hydrochloride (its N-demethylation), and probably also the metabolism of its pharmacologically active O-desmethyl metabolite. The clinical consequences of the interaction has not been studied.

The analgesic effect of tramadol hydrochloride is in part mediated by inhibition of the reuptake of norepinephrine and enhancement of the release of serotonin (5-HT). In studies the pre- or post-operative application of the antiemetic 5-HT3 antagonist ondansetron increased the requirement of tramadol hydrochloride in patients with post-operative pain. Although not tested, other 5-HT3-receptor antagonists would be expected to interact similarly with tramadol hydrochloride.

4.6 Fertility, pregnancy and lactation

Pregnancy

Tramadol crosses the placenta. At very high doses, animal studies with tramadol showed effects on organ development, bone growth and mortality rate in neonates (see section 5.3). Insufficient evidence is available about the safety of tramadol during human pregnancy. Tramadol should therefore not be administered to pregnant women.

Given prior to or during birth, tramadol does not influence uterine contractility.

It can lead to changes in the respiratory rate in neonates, but these do not usually have any clinical significance. Chronic use during pregnancy can lead to withdrawal symptoms in the neonate.

Lactation

A percentage of 0.1% of the maternal dose is excreted in breast milk . Breastfeeding women should therefore not take tramadol.

In general, administration of a single dose of tramadol does not require the interruption of breast-feeding.

4.7 Effects on ability to drive and use machines

Tramadol may cause drowsiness, blurred vision and dizziness. Even when taken according to instructions, tramadol hydrochloride may impair the reactions of drivers, machine operators and workers without a safe hold. This effect may be potentiated by alcohol, at the beginning of treatment, when switching the active substance, and on concomitant use of other CNS-depressants or anti-histamines. If patients are affected they should be warned not to drive or operate machinery.

4.8 Undesirable effects

The following frequencies are used for the description of the occurrence of adverse reactions:

Very common (>1/10), Common (>1/100, <1/10), Uncommon (>1/1000, <1/100), Rare (>1/10,000, <1/1000), 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.

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

Immune system disorders

Rare: Allergic reactions (e.g. dyspnoea, bronchospasm, wheezing, angioneurotic oedema) and anaphylaxis.

Psychiatric disorders

Rare: hallucinations, confusion, anxiety, sleep disturbances and nightmares.

Psychic undesirable effects may occur following administration of tramadol hydrochloride 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 capacity (e.g. decision behaviour, perception disorders).

Dependence can develop (see section 4.4).

Nervous system disorders

Very common: dizziness

Common: headache, muzziness

Rare: changes in appetite, paraesthesiae, tremor, respiratory depression, epileptiform seizures, involuntary muscle tics, impaired coordination, syncope

Not known: speech disorders

Epileptiform convulsions occurred mainly after administration of high doses of tramadol hydrochloride or after concomitant treatment with medicinal products which can lower the seizure threshold (see sections 4.4 and 4.5).

Very rare: vertigo

Eye disorders

Rare: blurred vision

Not known: mydriasis Cardiac 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

Vascular disorders

Rare: increase in blood pressure

Very rare: flushing

Respiratory, thoracic and mediastinal disorders

Rare: dyspnoea

Worsening of asthma has also been reported, though a causal relationship has not been established. If the recommended doses are considerably exceeded and other centrally depressant substances are administered concomitantly (see section 4.5), respiratory depression may occur.

Gastrointestinal disorders

Very common: nausea

Common: constipation, dry mouth, vomiting

Uncommon: retching, gastrointestinal irritation (a feeling of pressure in the stomach, bloating), diarrhoea

Hepato-biliary disorders

Very rare: an increase in liver enzyme values has been reported in a temporal connection with the therapeutic use of tramadol hydrochloride.

Skin and subcutaneous tissue disorders

Common: sweating

Uncommon: dermal reactions (e.g. pruritus, rash, urticaria)

Musculoskeletal and connective tissue disorders

Rare: muscle weakness

Renal and urinary disorders

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

General disorders and administration site conditions

Common: fatigue

Symptoms of withdrawal reactions, similar to those occurring during opiate withdrawal, may occur as follows: agitation, anxiety, nervousness, insomnia, hyperkinesia, tremor and gastrointestinal symptoms. Further symptoms which were observed in very rare cases during withdrawal of tramadol hydrochloride involve: panic attacks, severe anxiety, hallucinations, paraesthesia, tinnitus and unusual CNS symptoms.

4.9 Overdose

Symptoms of intoxication

On principle, the symptoms of a tramadol intoxication are typical for opioid analgesics. These are miosis, vomiting, circulatory failure, hypotension, sedation, coma, epileptic seizures, respiratory depression up to respiratory failure.

Treatment of overdose

Maintenance of a patent airway, respiration and circulation according to symptoms should be a priority. Consider activated charcoal in the cases of a life-threatening overdose ingested within 1 hour.

Give naloxone as antidote in case of respiratory depression. Repeated doses of naloxone may be required.

In animal experiments, naloxone was ineffective in controlling convulsions. In case of repeated convulsions, diazepam should be used intravenously.

Tramadol is minimally eliminated from the serum by haemodialysis and haemofiltration. For this reason, haemodialysis or haemofiltration alone are not appropriate for the treatment of acute intoxication with tramadol.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: analgesics, opioids ATC code:    N02AX02

Tramadol is a centrally acting opioid analgesic. It is a non-selective pure agonist on p, 8 and k opioid receptors with a higher affinity to p receptors. Other mechanisms which contribute to its analgesic effect are inhibition of neuronal re-uptake of noradrenaline and potentiation of serotonin release.

Tramadol has antitussive activities. Unlike morphine, tramadol does not depress breathing over a wide range of analgesic doses. The effects of tramadol on the cardiovascular system are comparatively small. The potency of tramadol is 1/10-1/6 that of morphine.

5.2 Pharmacokinetic properties

About 90% of tramadol is absorbed after oral administration. The mean absolute bioavailability is approximately 70%, irrespective of concomitant intake of food. The difference between absorbed and non-metabolised available tramadol is probably due to low first-pass-effect. The first-pass-effect after oral administration is a maximum of 30%.

At the steady state on day 5, the calculated maximum plasma concentration was 487 ± 127 ng/ml and t_max 4.06 ± 1.03 h after oral administration of 200 mg prolonged-release tablets. Tramadol possesses high tissue affinity (Vd,B = 203 ± 40 l). Protein binding is limited to 20%.

Tramadol has a linear pharmacokinetic profile within the therapeutic dosage range. The relationship between serum concentrations and the analgesic effect is dose-dependent,

but varies considerably in isolated cases. A serum concentration of 100-300 ng/ml is usually effective.

Tramadol crosses both the blood-brain barrier and the placental barrier. Tramadol and its metabolite O-demethyltramadol are excreted in breast milk in very small amounts (0.1% and 0.02% of the administered dose, respectively).

In humans tramadol is mainly metabolised by means of N- and O-demethylation and conjugation of the O-demethylation products with glucuronic acid. Only O-desmethyl-tramadol is pharmacologically active. There are considerable interindividual quantitative differences between the other metabolites. So far, eleven metabolites have been found in the urine. Animal experiments have shown that O-desmethyltramadol is more potent than the parent compound by the factor 2-4. Its half-life t/ B (6 healthy volunteers) is 7.9 h (range 5.4 - 9.6 h) and is approximately that of tramadol.

The inhibition of one or both types of the 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.

Its terminal elimination half-life (t/ B) is 6 hours regardless of route, but in patients above 75 years of age it may be prolonged by a factor of 1.4.

Tramadol and its metabolites are almost completely excreted via the kidneys. Cumulative urinary excretion is 90% of the total radioactivity of the administered dose. In cases of impaired hepatic and renal function the half-life may be slightly prolonged. In patients with cirrhosis of the liver, elimination half-lives of 13.3 ± 4.9 h (tramadol) and 18.5 ± 9.4 h (O-desmethyltramadol), in an extreme case 22.3 h and 36 h respectively have been determined. In patients with renal insufficiency (creatinine clearance < 5 ml/min) the values were 11 ± 3.2 h and 16.9 ± 3 h, in an extreme case 19.5 h and 43.2 h, respectively.

5.3 Preclinical safety data

In studies of oral and parenteral administration of tramadol in rats and dogs for 6 to 26 weeks, and in dogs orally for 12 months, no haematological, clinico-chemical or histological changes associated with exposure to tramadol were observed. Only at high doses (considerably exceeding the therapeutic range) did CNS-related symptoms occur: restlessness, increased salivation, convulsions and reduced weight increase. Rats tolerated oral doses of 20 mg/kg, and dogs oral doses of 10 mg/kg and rectal doses of

20 mg/kg bodyweight, without adverse effects.

In studies on reproductive toxicity, tramadol dosages of 50 mg/kg/day and more caused maternal-toxic effects in rats and led to an increase in neonatal mortality. Retardations in the form of ossification disturbances and delayed opening of the vagina and eyes occurred in the progeny. The fertility of male rats was not impaired. Female animals showed a diminished gestation rate after receiving higher doses (from 50 mg/kg/day up). Maternal toxic-effects as well as skeletal anomalies occurred in the progeny of rabbits which received 125 mg/kg bodyweight and higher.

Evidence of mutagenic effects were seen in a few in vitro test systems. In vivo studies gave no evidence of a mutagenic effect. Based on the present knowledge, tramadol can be classified as a non-mutagenic substance.

Studies on the tumorigenic potential of tramadol hydrochloride were carried out in rats and mice. The study in rats gave no evidence of a substance-related increase in the tumor incidence. The study in mice demonstrated an increased incidence of hepatocellular adenomas in male animals (from 15 mg/kg up dose-dependent, not significantly increased) and an increase in lung tumors in female animals in all the dose groups (significantly, but not dose-dependently increased).

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Initial dose layer lactose monohydrate calcium hydrogen phosphate dihydrate maize starch

cellulose, microcrystalline sodium starch glycollate (Type A) magnesium stearate silica, colloidal anhydrous

Slow release layer lactose monohydrate hypromellose povidone K 25 magnesium stearate silica, colloidal anhydrous castor oil, hydrogenated

colouring agents green varnish (quinoline yellow, indigo carmine and aluminium hydroxide)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

5 years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

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