Document: spc-doc_PL 00289-1603 change

• spc-doc_PL 00289-1603
• spc-doc_PL 17907-0110
• spc-doc_PL 20395-0065

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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Tramadol 50mg Capsules

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains tramadol hydrochloride 50mg.

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Capsule, hard

Green/pale yellow hard gelatine capsules imprinted ‘9T150’ on the cap and body.

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.

Unless otherwise prescribed, tramadol should be administered as follows: Adults and children aged 12 years and over

Acute Pain - An initial dose of 100 mg 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 50 mg 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 daily oral dose of 400 mg should not be exceeded except in special clinical circumstances

The capsules are to be taken whole, not divided or chewed, with sufficient liquid, independent of meals.

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.

Elderly 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. The usual initial dosage should be used. For patients with creatinine clearance <30ml/min, the dosage interval should be increased to 12 hours. Tramadol is not recommended for patients with severe renal impairment (creatinine clearance <10ml/min). As tramadol is only removed very slowly by haemodialysis or haemofiltration, post-dialysis administration to maintain analgesia is not usually necessary.

Hepatic impairment

The elimination of tramadol may be prolonged. The usual initial dosage should be used but in severe hepatic impairment the dosage interval should be increased to 12 hours

Children under 12 years

Tramadol capsules are not suitable for children below the age of 12 years

Route of administration

Oral

4.3 Contraindications

Tramadol is contraindicated

in hypersensitivity to tramadol or any of the excipients (see section 6.1),

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

•    In common with other opioid analgesics it should not be administered

•    In patients who are receiving MAO inhibitors or who have taken them within the last 14 days (see section 4.5).

•    in patients with epilepsy not adequately controlled by treatment,

•    for use in narcotic withdrawal treatment.

4.4 Special warnings and precautions for use

Warnings

At therapeutic doses, Tramadol Hydrochloride capsules 50 mg have 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.

Convulsions have been reported in patients receiving tramadol at the recomended dose level. The risk may be increased when doses of tramadol exceed the recommended upper daily dose limit (400 mg)..

In addition, tramadol may increase the seizure risk in patients taking other medicinal products that lowers the seizure threshold (see section 4.5). Patients with epilepsy or those susceptible to seizures should be only treated with tramadol if there are compelling circumstances.

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 with tramadol should only be carried out for short periods 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.

Precautions

Tramadol should be used with particular caution in opioid-dependent patients, patients with head injury, a reduced level of consciousness of uncertain origin, disorders of the respiratory centre or function, increased intracranial pressure, 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 are 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 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.

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 with other centrally depressant medicinal products including alcohol may potentiate CNS depressant effects (see section 4.8)..

Cimetidine

The results of pharmacokinetic studies have so far shown that on the concomitant or previous administration of cimetidine (enzyme inhibitor) clinically relevant interactions are unlikely to occur. Therefore no alteration of the tramadol dosage regimen is recommended for patients receiving chronic cimetidine therapy.

Carbarmazepine

Simultaneous administration of 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.

Quinidine

A study in 12 healthy volunteers has shown that quinidine causes an approximate 25% increase in the tramadol C_max and AUC; T_max is unaffected. However, the increase in C_max and AUC fall within the normal therapeutic range for tramadol, and no dosage adjustment is required.

Pharmacokinetic studies were conducted to investigate the effects of cimetidine, quinidine and carbamazepine on the pharmacokinetics of tramadol.

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.

Tramadol can induce convulsions and increase the potential for selective serotonin re-uptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs) , tricyclic anti-depressants (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 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 serotoninergic drugs usually brings about a rapid improvement. Treatment depends on the nature and severity of the symptoms.

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-demethyl-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.

There is a theoretical possibility that tramadol could interact with lithium and 5HT and noradrenaline potentiating anti depressants due to their respective mechanisms of action. There have been no reports of this potential interaction.

4.6 Fertility, pregnancy and lactation Pregnancy

Animal studies with tramadol revealed at very high doses effects on organ development, ossification 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.

Lactation

Tramadol and its metabolites are found in small amounts in human breast milk. An infant could ingest 0.1% of the dose given to the mother. During lactation about 0.1 % of the maternal dose is secreted into the milk. Tramadol is not recommended during breast-feeding. After a single administration of tramadol it is not usually necessary to interrupt breast-feeding

4.7 Effects on ability to drive and use machines

Even when taken according to instructions, tramadol may cause effects such as somnolence, drowsiness and dizziness and therefore may impair the reactions of drivers and machine operators. This applies particularly in conjunction with alcohol and other psychotropic substances.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:

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

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

•    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.

The frequencies are defined as follows:

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

Immune system disorders

rare: allergic reactions (e.g. dyspnoea, bronchospasm, wheezing, angioneurotic oedema) and anaphylaxis

Cardiac disorders

uncommon: palpitation, tachycardia

rare: bradycardia

These adverse reactions may occur especially on intravenous administration and in patients who are physically stressed.

Vascular disorders

uncommon: postural hypotension, cardiovascular collapse rare: increase in blood pressure

These adverse reactions may occur especially on intravenous administration and in patients who are physically stressed.

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 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).

Psychiatric disorders:

rare: hallucinations, confusion, sleep disturbance, 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.

Metabolism and nutrition disorders :

not known: hypoglycaemia

Eye disorders: rare: blurred vision not known: mydriasis

Respiratory, thoracic and mediastinal disorders:

rare: dyspnoea

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

Gastrointestinal disorders:

very common: nausea

common: vomiting, constipation, dry mouth.

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

Both diarrhoea and constipation have been reported. In controlled trials the incidence of constipation is lower than that of comparator agents.

Skin and subcutaneous disorders:

common: sweating

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

Musculoskeletal and connective tissue disorders: rare: motorial weakness

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.

Renal and urinary disorders:

rare: micturition disorders (difficulty in passing urine, dysuria 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 (see section 4.4 Special Warnings and Special Precautions in use and section 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, personalisation, derealisation, paranoia).

Physical dependence:

Not known: abuse and withdrawal reactions have been reported.

Other adverse effects:

Not known: Diaphoresis have been reported.

The following have been rarely reported: flushing.

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

In principle, on intoxication with tramadol symptoms similar to those of other centrally acting analgesics (opioids) are to be expected. These include in particular miosis, vomiting, cardiovascular collapse, sedation, consciousness disorders up to coma, convulsions and respiratory depression up to respiratory arrest.

Treatment

The general emergency measures apply. Supportive measures such as maintaining the patency of the airway and maintaining cardiovascular function should be instituted. Keep open the respiratory tract (aspiration!), maintain respiration and circulation depending on the symptoms. The antidote for respiratory depression is naloxone. In animal experiments naloxone had no effect on convulsions. In such cases diazepam should be given intravenously. Fits can be controlled with diazepam.

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.

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 N 02 AX 02

Tramadol is a centrally acting opioid analgesic. It is a non-selective pure agonist at p, 8 and k opioid receptors with a higher affinity for the p receptor. Other mechanisms which contribute to its analgesic effect are inhibition of neuronal reuptake of noradrenaline and enhancement 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 tramadol 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 %.

After oral administration, tramadol is almost completely absorbed. Mean absolute bioavailability is approximately 70% following a single dose and increases to approximately 90% at steady state. Plasma protein binding of tramadol is approximately 20%. When C14 labelled tramadol was administered to humans, approximately 90% was excreted via the kidneys with the remaining 10% appearing in the faeces.

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

Following a single oral dose administration of tramadol 100 mg as capsules or tablets to young healthy volunteers, plasma concentrations were detectable within approximately 15 to 45 minutes within a mean C_max of 280 to 208 mcg/L and T_max of 1.6 to 2h.

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).

Elimination half-life t1/2,B is approximately 6 h, irrespective of the mode of administration. In patients above 75 years of age it may be prolonged by a factor of approximately 1.4.

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 t1/2,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 biotransformation of tramadol may affect the plasma concentration of tramadol or its active metabolite. Up to now, clinically relevant interactions have not been reported.

Tramadol is metabolised by the cytochrome P450 isoenzyme CYP2D6. It undergoes biotransformation to a number of metabolites mainly by means of N- and

O-demethylation. O-desmethyl tramadol appears to be the most pharmacologically active metabolite, showing analgesic activity in rodents. As humans excrete a higher percentage of unchanged tramadol than animals it is believed that the contribution made by this metabolite to analgesic activity is likely to be less in humans than animals. In humans the plasma concentration of this metabolite is about 25% that of unchanged tramadol.

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.

Since tramadol is eliminated both metabolically and renally, the terminal half-life t'A B may be prolonged in impaired hepatic or renal function. In patients with liver cirrhosis t'A B tramadol was a mean of 13.3 + 4.9h; in patients with renal insufficiency (creatinine clearance < 5 ml/min) it was 11.0 + 3.2h.

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

In single and repeat-dose toxicity studies (rodents and dogs) exposure in tramadol 10 times that expected in man is required before toxicity (hepatotoxicity) is observed. Symptoms of toxicity are typical of opioids and include restlessness, ataxia, vomiting, tremor, dyspnoea and convulsions.

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.

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

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 dosedependent, 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)

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Microcrystalline Cellulose Ph. Eur,

Sodium starch glycolate Ph. Eur,

Magnesium stearate Ph. Eur,

Colloidal anhydrous silica Ph. Eur,

Capsule Shell contains:

Gelatin Ph. Eur,

Indigo Carmine (E132),

Iron Oxide Yellow (E172)

Titanium Dioxide (E171).

Printing ink contains:

Shellac

Iron Oxide (E172)

Propylene Glycol (E1520)

6.2    Incompatibilities

None known.

6.3    Shelf life

2 years

6.4    Special precautions for storage

Store in a dry place below 30°C.

6.5 Nature and contents of container

PVC/Aluminium blister packs of 10, 20, 30 and 100 capsules or Polypropylene/Aluminium blister packs of 10, 20 and 100 capsules.