Tramadol hydrochloride 50mg Capsules.

Each capsule contains 50mg tramadol hydrochloride.

Hard Capsule.

Tramadol capsules are white capsules imprinted with “T 50” on the top.

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

As with all analgesic drugs, the dose of Tramadol hydrochloride should be adjusted according to the severity of pain and the clinical response of the individual patient.

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 related to clinical need.

Pain associated with chronic conditions: Use an initial dose of 50mg and then titrate dose according to severity of pain. The need for continued treatment should be assessed at regular intervals as withdrawal symptoms and dependence have been reported (see section 'Special Warnings and Precautions for Use'). A total daily dose of 400mg should not be exceeded except in special clinical circumstances.

Elderly:

The usual doses may be used although it should be noted that in volunteers over 75 years old, the elimination half-life of tramadol was increased by 17% following oral administration.

Renal Impairment/ renal dialysis:

The elimination of tramadol may be prolonged. The usual initial dosage should be used. For patients with creatinine clearance <30 ml/min, the dosage interval should be increased to 12 hours. Tramadol is not recommended for patients with severe renal impairment (creatinine clearance <10 ml/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 old:

Not recommended.

Tramadol hydrochloride should not be administered to patients who have previously demonstrated hypersensitivity to it or in cases of acute intoxication with alcohol, hypnotics, centrally active analgesics, opioids or psychotropic drugs. In common with other opioid analgesics it should not be administered to patients who are receiving monoamine oxidase inhibitors or within two weeks of their withdrawal.

Warnings:

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

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

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

Precautions:

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

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

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

In one study using a nitrous oxide/opioid (Tramadol hydrochloride) anaesthetic technique (with only intermittent administration of enflurane 'as required') Tramadol hydrochloride was reported to enhance intra-operative recall. Hence its use during potentially very light planes of general anaesthesia should be avoided.

Two recent studies of Tramadol hydrochloride administration during anaesthesia comprising continuous administration of isoflurane did not show clinically significant lightening of anaesthetic depth or intra-operative recall. Therefore providing the current practice of administering continuous, potent (volatile or intravenous) anaesthetic agents is followed, Tramadol hydrochloride may be used intra-operatively in the same way as other analgesic agents are routinely used.

Concomitant administration of Tramadol hydrochloride with other centrally acting drugs including alcohol may potentiate CNS depressant effects.

Tramadol may increase the potential for both selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) to cause convulsions (see section 'Special Warnings and Precautions for Use' and 'Pharmacokinetic Properties'). There is a theoretical possibility that tramadol could interact with lithium. There have been no reports of this potential interaction.

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

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

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

Pregnancy:

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

Lactation:

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

Tramadol hydrochloride may cause drowsiness and this effect may be potentiated by alcohol and other CNS depressants. It may also cause blurred vision. Ambulant patients should be warned not to drive or operate machinery if affected by either or both of these side effects.

Gastrointestinal system:

Nausea, vomiting and occasionally dry mouth. Both diarrhoea and constipation have been reported. In controlled trials the incidence of constipation is lower than that of comparator agents.

Central nervous system and psychiatric:

Tiredness, fatigue, drowsiness, somnolence, dizziness, headache, confusion, hallucinations and rarely respiratory depression. Dependence, dysphoria and convulsions have been reported occasionally (see 'Interactions with other Medicaments and other forms of Interaction').

Physical dependence:

Dependence, abuse and withdrawal symptoms have been reported. Typical opiate withdrawal reactions include agitation, anxiety, nervousness, insomnia, hyperkinesia, tremor and gastrointestinal symptoms (see 'Special Warnings and Precautions for Use' and 'Posology and Method of Administration').

Allergic/anaphylactic reaction:

Dyspnoea, wheezing, bronchospasm and worsening of existing asthma.

Other adverse events:

Diaphoresis, urticaria and pruritus have been reported. Skin rashes, blurred vision, difficulty passing urine or urine retention, tachycardia, orthostatic hypotension, increase in blood pressure, bradycardia, flushing, syncope and anaphylaxis have been rarely reported. Cases of blood dyscrasias have been rarely observed during treatment with tramadol, but causality has not been established.

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

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

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

Tramadol hydrochloride is a centrally acting analgesic. It is a non selective pure agonist at mu, delta and kappa opioid receptors with a higher affinity for the mu receptor. Other mechanisms which may contribute to its analgesic effect are inhibition of neuronal reuptake of noradrenaline and enhancement of serotonin release.

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 linear pharmacokinetic profile within the therapeutic dosage range. The half life of the terminal elimination phase (t½β) was 6.0±1.5 h in young volunteers. Tramadol pharmacokinetics show little age dependence in volunteers up to the age of 75 years. In volunteers aged over 75 years, t½β was 7.0±1.6 h after oral administration.

Since tramadol is eliminated both metabolically and renally, the terminal half-life t½β may be prolonged in impaired hepatic or renal function. However, the increase in the t½β values is relatively low if at least one of these organs is functioning normally. In patients with liver cirrhosis t½β tramadol was a mean of 13.3±4.9 h; in patients with renal insufficiency (creatinine clearance 5 ml/min) it was 11.0±3.2 h.

In single and repeat-dose toxicity studies (rodents and dogs) exposure to 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.

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 and in vivo mutagenicity tests were negative.

Tramadol capsules contain microcrystalline cellulose, povidone K30, α-lactose monohydrate, magnesium stearate and sodium starch glycollate (type A). The capsule shell contains gelatine and titanium dioxide (E171). The black ink contains shellac, industrial methylated spirit 74 OP, soya lecithin, antifoam DC 1510, n-butyl alcohol and black iron oxide (E172).

None known.

36 months.

Do not store above 25°C. Store in the original package.

PVC/foil blister packs of 30 or 100 capsules.

None.

PLIVA Pharma Ltd

Vision House

Bedford Road

Petersfield

Hampshire

GU32 3QB

PL 10622/0050

31 January 2000

16 June 2003