PRODUCT SUMMARY

1. NAME OF THE MEDICINAL PRODUCT

Tramadol Hydrochloride Injection 50mg/ml

2. Qualitative and quantitative composition

Tramadol hydrochloride 50mg/ml

3. Pharmaceutical Form

Sterile Solution for Injection. The solution is slightly hypertonic.

CLINICAL PARTICULARS

4.1    Therapeutic indications

The management (treatment and prevention) of moderate to severe pain

4.2    Posology and method of administration

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 children aged 12 years and over:

Tramadol injection may be administered intramuscularly, by slow intravenous injection, or diluted for administration by infusion or patient controlled analgesia.

The usual dose is 50 or 100mg 4-6 hourly by the intravenous or intramuscular route. Dosage should be adjusted according to pain severity and response. Intravenous injections must be given slowly over 2-3 minutes.

For post operative pain administer an initial bolus of 100mg. During the 60 minutes following the initial bolus, further doses of 50mg may be given every 10-20 minutes, up to a total dose of 250mg including the initial bolus. Subsequent doses should be 50mg or 100mg 4-6 hourly up to a total daily dose of 600mg.

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

Children under 12 years:

Not recommended.

Renal insufficiencv/dialvsis 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.

4.3 Contra-indications

Tramadol should not be administered to patients who have already shown hypersensitivity to it. Tramadol must not be administered if the patient is acutely intoxicated with hypnotics, alcohol, centrally acting analgesics, opiods of psychotropic drugs. Like other opioid analgesics, Tramadol should not be administered to patients who are receiving monoamine oxidase inhibitors (MAOI's) or within two weeks of their withdrawal.

4.4    Special Warnings and Precautions for Use

Warnings

•    At therapeutic doses tramadol has potential to cause withdrawal symptoms.

•    Rarely cases of dependence and abuse have been reported.

•    Therapeutic dose withdrawal symptoms have been reported at a 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 to drug abuse or dependence, treatment should be for short periods and under strict medical supervision.

•    Tramadol Hydrochloride Injection is not a suitable substitute in opioid dependent patients. The product 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 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 section 4.5 Interactions with other Medicaments and other forms of interaction below).

NB The upper daily dose limit approved for tramadol injection is 600mg

Precautions

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

•    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 hydrochloride injection during light planes of anaesthesia should be avoided.

•    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.

4.5 Interaction with other medicinal products and other forms of interaction

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

Simultaneous administration with cimetidine is associated with clinically insignificant changes in serum concentrations of tramadol. Alteration of the Tramadol dosage regimen is not recommended for patients receiving chronic cimetidine therapy.

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.

Administration of Tramadol together with carbamazepine will markedly decrease serum concentrations of Tramadol to an extent that a decrease in analgesic effectiveness and a shorter duration of action may occur.

It is theoretically possible that Tramadol could interact with lithium due to their respective mechanisms of actions.

4.6 Pregnancy and Lactation

Pregnancy

Animal studies (rat and rabbit, exposure to Tramadol up to 7 times that expected in man) have revealed no teratogenic effect and minimal embryotoxicity (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 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 about 0.1% of the dose given to the mother. Tramadol should not be administered during 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 must be warned not to drive or operate machinery if affected.

4.8 Undesirable Effects

Gastrointestinal system: Nausea, vomiting, constipation and occasionally dry mouth

Central nervous system and psychiatric: Tiredness, fatigue, drowsiness, somnolence, dizziness, headache, confusion, hallucinations and, infrequently, respiratory depression. Dysphoria has been rarely reported. Convulsions have been rarely reported (see Interactions).

Physical dependence: Dependence, abuse and withdrawal reactions have been reported. Typical opiate withdrawal reactions include agitation, anxiety, nervousness, insomnia, hyperkinesia, tremor and gastro-intestinal symptoms (see section 4.4 Special Warnings and Precautions and section 4.2 Posology and Methods of Administration).

Other adverse events: Diaphoresis, pruritis, urticaria, dyspnoea, wheezing, bronchospasm and a worsening of existing asthma. Skin rashes, 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.

4.9 Overdose

Symptoms of overdosage 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 cardiovascular function should be instituted; Naloxone should be used to reverse respiratory depression.

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.

PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Tramado is a centrally acting analgesic and is a non-selective pure agonist at mu, delta and kappa opioid receptors - highest affinity occurring at the mu receptors. Tramadol also inhibits neuronal uptake of noradrenaline and enhances serotonin release.

Tramadol also has an antitussive action but has no effect on gastrointestinal motility. At the recommended dosages, the effects of tramadol given parenterally on the respiratory and cardiovascular systems appear to be clinically insignificant.

5.2    Pharmacokinetic properties

The absolute bioavailability of intramuscularly administered Tramadol is

100%.

Volumes of distribution of Tramadol following oral and intravenous administration to young healthy volunteers were 306 and 203 L respectively, indicating a high tissue affinity.

In healthy volunteers, a serum concentration of 100ng/ml following an intravenous dose of 100mg was reached after 0.68±0.17 hours, and maintained for 9.0±2.2 hours.

The elimination half-life is about 6 hours, independent of the route of administration. Where hepatic or renal function is depressed, a slight prolongation of the half-life is expected. In more severe cases of impairment (e.g. liver cirrhosis, creatinine clearance <5ml/min) a 2-3 fold prolongation of the elimination time would be expected. In patients over 75 years of age, the elimination half life can be prolonged by a factor of 1.4.

5.3 Preclinical safety data

This product has been available for many years and its side effects and clinical profile are well understood, therefore no further data is provided.

PHARMACEUTICAL PARTICULARS

6.1. List of excipients

Sodium acetate Water for injections.

6.2    Incompatibilities

Tramadol Injection is incompatible with injection solutions of diclofenac, indomethacin, phenylbutazone, diazepam, flunitrazepam, midazolam, piroxicam and glycerol trinitrate.

6.3    Shelf Life

36 months

6.4    Special Precautions for Storage

Do not store above 25°C. Keep container in outer carton.

6.5    Nature and Content of Container

2ml clear Type I clear glass ampoule containing tramadol hydrochloride 50mg/ml.

Instructions for use/handling

Use once and discard any remaining solution in an appropriate manner.

ADMINISTRATIVE DATA

7.    MARKETING AUTHORISATION HOLDER

Aurum Pharmaceuticals Ltd

Bampton Road

Harold Hill

Romford

Essex

RM3 8UG

United Kingdom

8.    Marketing Authorisation Number

12064/0066

9.    Date of First Authorisation/Renewal of Authorisation

2 August 2000

10 DATE OF REVISION OF THE TEXT

15/11/2012