Document: spc-doc_PL 11311-0084 change

• spc-doc_PL 00142-0484
• spc-doc_PL 10622-0050
• spc-doc_PL 11311-0084
• spc-doc_PL 14894-0066
• spc-doc_PL 17780-0139
• spc-doc_PL 20117-0086
• spc-doc_PL 25821-0009
• spc-doc_PL 30464-0037

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SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Tramadol Hydrochloride 50mg Capsules.

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains 50mg tramadol hydrochloride.

For the full list of excipients, see section 6.1

3    PHARMACEUTICAL FORM

Hard Capsules.

Green cap and yellow body, hard gelatine capsules containing a white odourless powder.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Tramadol Hydrochloride 50mg Capsules are indicated for:

Management (treatment and prevention) of moderate to severe pain.

4.2    Posology and method of administration Posology

As with all analgesic drugs, the dose of tramadol hydrochloride 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:

Acute pain - An initial dose of 100mg is usually necessary. This can be followed by doses of 50 or 100mg 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 - "Special Warnings and Precautions for Use").

A total oral daily 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.

It should be noted that in volunteers aged over 75 years the elimination half-life of tramadol was increased by approximately 17% following oral administration.

Renal insufficiency /renal dialysis/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.

For patients with creatinine clearance of less than 30ml/min, the dosage interval should be increased to 12 hours. Tramadol is not recommended for patients with severe renal impairment where the creatinine clearance is less than 10ml/min.

As tramadol is only removed very slowly by haemodialysis or haemofiltration, post-dialysis administration to maintain analgesia is not usually necessary.

In severe hepatic impairment the dosage interval should be increased to 12 hours. Children under 12 years:

Tramadol hydrochloride capsules are not intended for administration to children under 12 years of age.

Duration of administration

Tramadol should under no circumstances be administered for longer than absolutely necessary. If long-term pain treatment with tramadol is necessary in view of the nature and severity of the illness, then careful and regular monitoring should be carried out (if necessary with breaks in treatment) to establish whether and to what extent further treatment is necessary.

Method of administration

For oral administration.

The capsules should be swallowed whole and not chewed. They should be taken with a little water before or after meals.

4.3 Contraindications

Tramadol hydrochloride is contraindicated:

o in hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

o in cases of acute intoxication with alcohol, hypnotics, centrally acting analgesics, opioids or psychotropic drugs

o in patients who are receiving monoamine oxidase inhibitors or within two weeks of their withdrawal

o in patients with epilepsy not adequately controlled by treatment o for use in narcotic withdrawal treatment. o in patients with porphyria o during an asthmatic attack

4.4 Special warnings and precautions for use

Warnings

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.

Tramadol has a low dependence potential. On long-term use tolerance, psychic and physical dependence may develop. In patients with a tendency for 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 daily dose limit (400 mg). 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 “Interactions with other Medicaments and Other Forms of Interactions”).

Tramadol should be prescribed with special care in patients with hypotension, prostatic hypertrophy and obstructive or inflammatory bowel disease.

Precautions:

Tramadol hydrochloride should be used with caution in opioid-dependent patients, patients with head injury, increase intracranial pressure, a reduced level of consciousness of uncertain origin, disorders of the respiratory centre or function , severe impairment of hepatic and renal function and in patients prone to convulsive disorders or in shock.

In patients sensitive to opiates the product should only be used with caution.

Care should be taken when treating patients with respiratory depression, or if concomitant CNS depressant drugs being administered (see section 4.5), or if the recommended dosage is significantly exceeded (see section 4.9), as the possibility of respiratory depression cannot be excluded in these situations. At therapeutic doses respiratory depression has infrequently been reported.

In one study the use of tramadol hydrochloride 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.

4.5 Interaction with other medicinal products and other forms of interaction

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

In patients treated with MAO inhibitors in the 14 days prior to the use of the opioid pethidine, life-threatening interactions on the central nervous system, respiratory and cardiovascular function have been observed. The same interactions with MAO inhibitors cannot be ruled out during treatment with tramadol.

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

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

Tramadol can induce convulsions and increase the potential for selective seratonin reuptake inhibitors (SSRIs) , ,serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), anti-psychotics and other seizure threshold lowering medicinal products(such as bupropion, mirtazapine, tetrahydrocannabinol^ to cause convulsions (see section 4.4 - “Special Warnings and Special Precautions for Use” and 5.2 - “Pharmacokinetic Properties”).

Concomitant therapeutic use of tramadol and serotonergic drugs such as selective serotonin re-uptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), MAO inhibitors (see section 4.3),tricyclic antidepressants and mirtazapine that 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.

The other signs of serotonin syndrome may be confusion, ataxia and diarrhoea. Withdrawal of the serotoninergic medicinal products usually brings about a rapid improvement. Treatment depends on the nature and severity of the symptoms.

Simultaneous or previous administration with cimetidine (enzyme inhibitor) 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.

Simultaneous or previous administration with carbamazepine (enzyme inducer) markedly decreases serum concentrations of tramadol to an extent that a decrease in analgesic effectiveness and a shorter duration of action may occur.

The combination with mixed agonist/antagonists (e.g. buprenorphine, nalbuphine, pentazocine) and tramadol is not advisable, because the analgesic effect of a pure agonist may be theoretically reduced in such circumstances.

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

Other active substances known to inhibit CYP3A4, such as ketoconazole and erythromycin, might inhibit the metabolism of tramadol (N-demethylation) probably also the metabolism of the active O-demethylated metabolite. The clinical importance of such an interaction has not been studied (see section 4.8).

In a limited number of studies the pre- or postoperative application of the antiemetic 5-HT3 antagonist ondansetron increased the requirement of tramadol in patients with postoperative pain.

4.6 Fertility, pregnancy and lactation

Pregnancy

Animal studies (rat and rabbit, exposure to tramadol up to 7 times that expected in humans) have revealed minimal embryo-toxicity (delayed ossification, effects on organ development and neonatal mortality). Teratogenic effects were not observed. Tramadol crosses the placenta. There is inadequate evidence available on the safety of tramadol in human pregnancy, therefore tramadol should not be used in pregnant women.

Tramadol - administered before or during birth - does not affect uterine contractility.

In neonates it may induce changes in the respiratory rate which are usually not clinically relevant. Chronic use during pregnancy may lead to neonatal withdrawal symptoms.

Breast-feeding:

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 is not recommended during breast-feeding. After a single administration of tramadol it is not usually necessary to interrupt breast-feeding.

Fertility

Post marketing surveillance does not suggest an effect of tramadol on fertility. Animal studies did not show an effect of tramadol on fertility.

4.7 Effects on ability to drive and use machines

Even when taken according to instructions, Tramadol hydrochloride may cause drowsiness, somnolence and dizziness and therefore may impair the reactions of drivers and machine operators and this effect may be potentiated by other psychotropic substances, particularly 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 prescriber 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 reactions are nausea and dizziness, both occurring in more than 10 % of patients.

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 disorders:

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

Eye disorders:

Rare: blurred vision, miosis, mydriasis

Gastro-intestinal disorders:

Very common: nausea

Common: vomiting, constipation, dry mouth

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

Hepatobiliary disorders:

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

Metabolism and nutrition disorders:

Rare: changes in appetite Not known: hypoglycaemia

Musculoskeletal and connective tissue disorders:

Rare: motor weakness

Nervous system disorders:

Very common: dizziness

Common: headache, somnolence, drowsiness

Rare: paraesthesia, tremor, epileptiform, convulsion,

involuntary muscle contractions, abnormal coordination, syncope, speech disorders

If the recommended doses are considerably 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 medicinal products which can lower the seizure threshold (see sections 4.4 and 4.5).

Respiratory, thoracic and mediastinal disorders:

Rare: dyspnoea , respiratory depression

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

Unknown: worsening of existing asthma, though a causal relationship has not been established

General disorders and administration site conditions:

Common: fatigue

Psychiatric disorders:

Rare: confusion, hallucination, sleep disturbance, delirium, anxiety and nightmares,

Psychic adverse reactions may occur following administration of Tramadol which vary individually in intensity and nature (depending on personality and duration of treatment). 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 may occur

Physical dependence:

Dependence, abuse and withdrawal reactions have been reported. Typical opiate withdrawal reactions include agitation, anxiety, nervousness, insomnia, hyperkinesia, tremor & gastrointestinal symptoms (See section 4.4 - “Special Warnings and Special Precautions for Use” and 4.2 - “Posology and Method of Administration”). 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, depersonalisation, derealisation, paranoia).

Immune system disorders:

Rare: Anaphylaxis, allergic reactions (e.g. dyspnoea, bronchospasm, wheezing, angioneurotic oedema)

Skin and subcutaneous tissue disorders:

Common: Sweating (diaphoresis, hyperhidrosis)

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

Renal and urinary disorders:

Rare: micturition disorder (difficulty in passing urine, dysuria and urinary retention)

Vascular disorders:

Rare: flushing, orthostatic hypotension,

Blood and lymphatic system disorders:

Cases of blood dyscrasias have been rarely observed during treatment with tramadol but causality has not been established.

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 at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Symptoms of overdosage are typical of other opioid analgesics (centrally acting), and include miosis, vomiting, cardiovascular collapse, sedation and consciousness disorders up to coma, seizures and respiratory depression up to respiratory arrest..

Treatment-

The general emergency measures apply. Supportive measure such as maintaining the patency of the airway and maintaining cardiovascular function should be instituted.

In case of intoxication orally, gastrointestinal decontamination with activated charcoal or by gastric lavage is only recommended within 2 hours after tramadol intake. Gastrointestinal decontamination at a later time point may be useful in case of intoxication with exceptionally large quantities or prolonged-release formulation. Naloxone should be used to reverse respiratory depression. In animal experiments naloxone had no effect on convulsions, in such cases fits can be controlled with diazepam (intravenously).

Tramadol hydrochloride 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

Tramadol hydrochloride is a centrally acting opioid analgesic. It is a non-selective pure agonist at mu (p), delta and kappa opioid receptors with a higher affinity for the mu (p) receptor.

Other mechanisms which contribute to its analgesic effect are inhibitor of neuronal reuptake of noradrenaline and potentiation of serotonin release.

Tramadol has an antitussive effect. In contrast to morphine, analgesic doses of tramadol over a wide range have no respiratory depressant effect. Also gastrointestinal motility is less affected. Effects on the cardiovascular system tend to be slight. The potency of tramadol is reported to be 1/10 (one tenth) to 1/6 (one sixth) that of morphine.

5.2 Pharmacokinetic properties

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

Tramadol has a high tissue affinity (V _d,_B= 203 + 40 l). It has a plasma protein binding of about 20 %.

After administration of Zydol SR 100 mg the peak plasma concentration C_max =141 + 40 ng/ml is reached after 4.9 h. After administration of Zydol SR 200 mg C_max 260 + 62 ng/ml is reached after 4.8 hours.

Tramadol passes the blood-brain and placental barriers. Very small amounts of the substance and its O-desmethyl derivative are found in the breast-milk (0.1 % and 0.02 % respectively of the applied dose).

The half-life of the terminal elimination phase (t'A B) was 6.0 ± 1.5h in young volunteers. In patients above 75 years of age it may be prolonged by a factor of approximately 1.4. Tramadol pharmacokinetics show little age dependence in volunteers up to the age of 75 years. In volunteers aged over 75 years, t'A B was 7.0 ± 1.6h on oral administration.

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-desmethyltramadol 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 substance by the factor 2 - 4. Its half-life ti/₂,n (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 biotransformation of tramadol may affect the plasma concentration of tramadol or its active metabolite. Up to now, clinically relevant interactions have not been reported.

Since tramadol is eliminated both metabolically and renally. Cumulative urinary excretion is 90 % of the total radioactivity of the administered dose. The terminal half-life (t'A B) may be prolonged in impaired hepatic or renal function. However, the increase in the t'A B values is relatively low if at least one of these organs is functioning normally. In patients with liver cirrhosis t'A B tramadol was a mean of 13.3 ± 4.9h 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) it was 11.0 ± 3.2h and 16.9 + 3 h, in an extreme case 19.5 h and 43.2 h respectively.

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.

5.3 Preclinical safety data

On repeated oral and parenteral administration of tramadol for 6 - 26 weeks in rats and dogs and oral administration for 12 months in dogs haematological, clinico-chemical and histological investigations showed no evidence of any substance-related changes. Central nervous manifestations only occurred after high doses considerably above the therapeutic range: restlessness, salivation, convulsions, and reduced weight gain. Rats and dogs tolerated oral doses of 20 mg/kg and 10 mg/kg body weight respectively, and dogs rectal doses of 20 mg/kg body weight without any reactions.

In rats tramadol dosages from 50 mg/kg/day upwards caused toxic effects in dams and raised neonate mortality. In the offspring retardation occurred in the form of ossification disorders and delayed vaginal and eye opening. Male fertility was not affected. After higher doses (from 50 mg/kg/day upwards) females exhibited a reduced pregnancy rate. In rabbits there were toxic effects in dams from 125 mg/kg upwards and skeletal anomalies in the offspring.

In some in-vitro test systems there was evidence of mutagenic effects. In-vivo studies showed no such effects. According to knowledge gained so far, tramadol can be classified as non-mutagenic.

Studies on the tumorigenic potential of tramadol hydrochloride have been carried out in rats and mice. The study in rats showed no evidence of any substance-related increase in the incidence of tumours. In the study in mice there was an increased incidence of liver cell adenomas in male animals (a dose-dependent, non-significant increase from 15 mg/kg upwards) and an increase in pulmonary tumours in females of all dosage groups (significant, but not dose-dependent).

In single and repeat-dose toxicity studies exposure to tramadol 10 times that expected in man is required before toxicity (hepatoxicity) is observed.

Symptoms of toxicity are typical of opioids and include restlessness, ataxia, vomiting, tremor, dyspnoea, and convulsions.

Exposure to tramadol (less than that expected in man) in lifetime toxicity studies in rodents did not reveal any evidence of carcinogenic hazard, and a battery of in-vitro and in-vivo mutagenicity tests were negative.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Calcium hydrogen phosfate, dihydrate Sodium starch glycollate (type A) Magnesium stearate

Gelatin capsules consisting of: Titanium dioxide (E171)

Yellow ferric oxide (E172)

Gelatin

Indigotin (E132)

6.2. Incompatibilities

None known.

6.3 Shelf life

4 years

6.4. Special precautions for storage

Do not store above 25°C.

6.5 Nature and contents of container

Blister packs in cardboard box. 10, 28, 30, 56 or 100 capsules