This information is intended for use by health professionals

1. Name of the medicinal product

Tramadol Hydrochloride 50mg Capsules

2. Qualitative and quantitative composition

Each capsule contains 50mg tramadol hydrochloride. Each capsule also contains the excipient lactose monohydrate. For a full list of excipients, see section 6.1.

3. Pharmaceutical form

Capsule, hard.

Appearance: Green and yellow, hard gelatin capsule printed with 'TRA 50'.

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.

Unless otherwise prescribed, Tramadol Hydrochloride Capsules should be administered as follows:

Adults and adolescents 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).

The lowest analgesically effective dose should generally be selected. Daily doses of 400 mg active substance should not be exceeded, except in special clinical circumstances.

Tramadol Hydrochloride Capsules should under no circumstances be administered for longer than absolutely necessary. If long-term pain treatment with Tramadol Hydrochloride Capsules 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.

Children under 12 years

Tramadol Hydrochloride Capsules are not suitable for children below the age of 12 years.

Geriatric patients

The usual dosages may be used although it should be noted that in volunteers aged over 75 years the elimination half-life of tramadol was increased by 17% following oral administration. 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 extended according to the patient's requirements,

Renal insufficiency/dialysis

The elimination of tramadol may be prolonged. 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).

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.

As tramadol is only removed very slowly by haemodialysis or haemofiltration, post-dialysis administration to maintain analgesia is not usually necessary. In these patients the dosage intervals should be carefully considered according to the patients requirements.

Method of administration

For oral administration.

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

4.3 Contraindications

Tramadol is contraindicated:

- in hypersensitivity to tramadol or any of the excipients listed in section 6.1,

- in acute intoxication with alcohol, hypnotics, analgesics, opioids, or psychotropic medicinal products,

- in patients with epilepsy not adequately controlled by treatment,

- for use in narcotic withdrawal treatment

- in patients who are receiving MAO inhibitors or who have taken them within the last 14 days (see section 4.5),

- in pregnancy and breast- feeding ( see section 4.6)

4.4 Special warnings and precautions for use

Tramadol may only be used with particular caution in opioid-dependent patients, patients with head injury, convulsive disorders, shock, a reduced level of consciousness of uncertain origin, disorders of the respiratory center or function, increased intracranial pressure, severe impairment of hepatic and renal function.

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.

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

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

Slow metaboliser status for CYP3A4 and/or CYP2D6 may present a risk for tramadol toxicity (see section 5.2 Pharmacokinetic properties).

Convulsions have been reported in patients receiving tramadol at the recommended dose levels. 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.

Dizziness may increase the risk of falling with associated risk of fracture, particularly in the elderly.

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

At therapeutic doses withdrawal symptoms have been reported at a reporting frequency of 1 in 8,000. Reports of abuse and dependence 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.

Tramadol may mask the signs of perforated peptic ulcers.

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 the CNS effects (see section 4.8).

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.

Simultaneous or previous administration of carbamazepine (enzyme inducer) may reduce the analgesic effect and shorten the duration of action. There is a theoretical possibility that tramadol could interact with lithium due to their respective mechanisms of action.

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 reuptake inhibitors, tricyclic anti-depressants, anti-psychotics and other seizure threshold lowering medicinal products to cause convulsions.

In isolated cases there have been reports of serotonin syndrome in a temporal connection with the therapeutic use of tramadol in combination with other serotoninergic medicinal products such as selective serotonin re-uptake inhibitors (SSRIs) or with MAO inhibitors. Signs of serotonin syndrome may be for example confusion, agitation, fever, sweating, ataxia, hyperreflexia, myoclonus and diarrhoea.

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 medicinal products 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-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 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.

Breast-feeding

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

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 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.

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

Cardiovascular disorders:

Uncommon: cardiovascular regulation (palpitation, tachycardia, postural hypotension or cardiovascular collapse). These adverse reactions may occur especially on intravenous administration and in patients who are physically stressed.

Rare: bradycardia, increase in blood pressure

Vascular disorders

Uncommon: orthostatic hypotension and flushing

Rare: increase in blood pressure

Nervous system disorders:

Very common: dizziness

Common: headache, somnolence, drowsiness

Rare: changes in appetite, fatigue paraesthesia, tremor, respiratory depression, epileptiform convulsions, involuntary muscle contractions, abnormal coordination, syncope.

Not known: speech disorders have been reports rarely.

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, changes in appetite, dysphoria 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 incognitive and sensorial capacity (e.g. decision behaviour, perception disorders).

Dependence may occur; abuse and withdrawal reactions have been reported.

Eye disorders:

Rare: blurred vision

Not known: mydriasis

Ear and labyrinth disorders

Very rarely (>0.1%): Tinnitus has been reported

Respiratory 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

Skin and subcutaneous disorders:

Common: sweating (sweating profusely)

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

Rare: angioedema

Musculoskeletal disorders:

Rare: motorial weakness, muscle 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)

Metabolism and nutrition disorders:

Not known: hypoglycaemia

Blood and lymphatic system disorders

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

Immune system disorders

Rare: allergic reactions including dyspnoea, wheezing, bronchospasm and worsening of existing asthma and anaphylaxis have been reported. Urticaria, pruritus and skin rashes have also been reported.

General disorders:

Common: fatigue

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.

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).

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, and cardiovascular collapse, consciousness disorders sedation up to coma, convulsions / seizures and respiratory depression up to respiratory arrest.

Treatment

The general emergency measures apply. 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. Fits can be controlled with diazepam. In such cases diazepam should be given intravenously.

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, effective for moderate to severe acute and chronic pains. Tramadol consists of two enantiomers. The (+)-isomer is predominantly active as an opiate with a higher affinity for the µ-opiate receptor (20, times higher affinity than the (-)-isomer). The (+)-desmethyl metabolite will certainly contribute to its action as an opiate as well. The metabolite has a six times stronger affinity for the µ-receptor in vivo than tramadol. In vitro this affinity is 170 times stronger. The (-)-isomer acts as an inhibitor of the re-uptake of noradrenaline and potentiates the analgesic action of the (+)-isomer. The contribution of the stimulation of the serotonin release is considered low. Tramadol has an analgesic and antitussive effect. It is a non-selective pure agonist at μ, δ, and κ opioid receptors with a higher affinity for the μ 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 rapidly 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,ß = 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 Cmax of 280 to 208 mcg/L and Tmax 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, ß 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. Tramadol and its metabolites are almost completely excreted renally, of which approximately 10% as unchanged drug. There are considerable inter-individual 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, ß (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 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.

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.

Since tramadol is eliminated both metabolically and renally, the half- life of the terminal elimination phase may be prolonged in impaired hepatic and renal function. In those cases the half- life of the terminal elimination phase is twice as long. . In patients with both renal and hepatic impairment, the use of tramadol should be avoided.

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, clinic-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)

6. Pharmaceutical particulars
6.1 List of excipients

Microcrystalline cellulose, povidone, lactose monohydrate, sodium starch glycollate, magnesium stearate.

Capsule shell: Titanium dioxide (E171), indigotine (E132), yellow iron oxide (E172), erythrosin (E127), gelatin.

Printing ink: Shellac, propylene glycol and black iron oxide (E172).

6.2 Incompatibilities

None known.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

Store below 25°C in a dry place

6.5 Nature and contents of container

Blister strips composed of transparent PVC/PVDC (250 µ m/60 g/m2) and 20 µ m hard temper aluminium foil, contained in a carton.

Pack sizes: 30, 50, 100, 250 and 500 capsules.

Not all pack sizes may be marketed

6.6 Special precautions for disposal and other handling

No special requirements

Any unused product or waste material should be disposed of in accordance with local requirements.

7. Marketing authorisation holder

ATHLONE PHARMACEUTICALS LIMITED

BALLYMURRAY

ROSCOMMON

COUNTY ROSCOMMON

IRELAND

8. Marketing authorisation number(s)

PL 30464/0037

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 07/07/1998

Date of latest renewal: 21/12/2004

10. Date of revision of the text

January 2016