Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2018 Publisher: Beacon Pharmaceuticals Limited, DCC Vital, Westminster Industrial Estate, Repton Road, Measham, DE12 7DT, England
Tramadol 50mg/ml Solution for Injection should not be given to patients who have previously demonstrated hypersensitivity towards tramadol or any of the other ingredients (see Section 6.1 for ‘list of excipients’). Tramadol 50mg/ml Solution for injection should not be given to patients suffering from acute intoxication with alcohol, hypnotics, centrally acting analgesics, opioids or psychotropic drugs.
In common with other opioid analgesics, tramadol should not be administered to patients who are receiving monoamine oxidase inhibitors or within two weeks of their withdrawal (see section 4.5 ‘Interaction with other medicinal products and other forms of interaction’).
Tramadol 50mg/ml Solution for Injection is contraindicated in patients with epilepsy not adequately controlled by treatment.
Tramadol must not be used in narcotic withdrawal treatment.
At therapeutic doses, tramadol has 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 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.
Tolerance, psychic and physical dependence may develop, especially after long-term use. When a patient no longer requires therapy with tramadol, it may be advisable to taper the dose gradually to prevent symptoms of withdrawal.
In patients with a tendency to drug abuse or dependence, treatment should be for short periods and under strict medical supervision.
Tramadol 50mg/ml Solution for Injection is not a suitable substitute in opioid dependent patients. The product does not suppress morphine withdrawal symptoms although it is an opioid agonist.
Tramadol 50mg/ml Solution for Injection 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 (see section 4.7 Effects on the ability to drive and use machines)
Tramadol is metabolised by the liver enzyme CYP2D6. If a patient has a deficiency or is completely lacking this enzyme an adequate analgesic effect may not be obtained. Estimates indicate that up to 7% of the Caucasian population may have this deficiency. However, if the patient is an ultra-rapid metaboliser there is a risk of developing side effects of opioid toxicity even at commonly prescribed doses.
General symptoms of opioid toxicity include confusion, somnolence, shallow breathing, small pupils, nausea, vomiting, constipation and lack of appetite. In severe cases this may include symptoms of circulatory and respiratory depression, which may be life threatening and very rarely fatal. Estimates of prevalence of ultra-rapid metabolisers in different populations are summarised below:
| Population | Prevalence % |
|---|---|
| African/Ethiopian | 29% |
| African American | 3.4% to 6.5% |
| Asian | 1.2% to 2% |
| Caucasian | 3.6% to 6.5% |
| Greek | 6.0% |
| Hungarian | 1.9% |
| Northern European | 1% to 2% |
There have been reports in the published literature that tramadol given post-operatively in children after tonsillectomy and/or adenoidectomy for obstructive sleep apnoea, led to rare, but life threatening adverse events. Extreme caution should be exercised when tramadol is administered to children for post-operative pain relief and should be accompanied by close monitoring for symptoms of opioid toxicity including respiratory depression.
Tramadol is not recommended for use in children in whom respiratory function might be compromised including neuromuscular disorders, severe cardiac or respiratory conditions, upper respiratory or lung infections, multiple trauma or extensive surgical procedures. These factors may worsen symptoms of opioid toxicity.
Tramadol 50mg/ml Solution for Injection should be used with 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.
Convulsions have been reported at therapeutic doses and the risk may be increased at doses exceeding the usual upper daily dose limit (400mg). 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 Medicinal Products and other Forms of Interactions’).
Care should be taken when treating patients with respiratory depression, or if concomitant CNS depressant drugs are being administered, or if the recommended dosage is significantly exceeded, 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) anaesthetic technique (with only intermittent administration of enflurane ‘as required’) tramadol was reported to enhance intra-operative recall. Hence its use during potentially very light planes of general anaesthesia should be avoided.
Two studies of tramadol administration during anaesthesia comprising continuous administration of isoflurane have shown clinically significant lightening of anaesthetic depth or intra-operative recall. Therefore providing the current practice of administering continuous, potent (volatile or intravenous) anaesthetic agent is followed, tramadol may be used intra-operatively in the same way as other analgesic agents are routinely used.
This medicinal product contains approximately 8.29mg sodium acetate trihydrate (1.4mg sodium) per 2ml dose.
Tramadol 50mg/ml Solution for Injection should not be combined with MAO inhibitors (see Section 4.3 ‘Contraindications’).
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 50mg/ml Solution for Injection.
Concomitant administration of Tramadol 50mg/ml Solution for Injection with other centrally acting drugs, including alcohol, may potentiate CNS depressant effects (see Section 4.8 ‘Undesirable Effects’).
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.
Theoretically there is a possibility that tramadol could interact with lithium. There have been no reports of this potential interaction.
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:
There have been isolated reports of interaction with coumarin anticoagulants resulting in an increased INR with major bleeding and ecchymoses in some patients and so care should be taken when commencing treatment with tramadol in patients on anticoagulants.
Pharmacokinetic studies were conducted to investigate the effects of cimetidine, quinidine and carbamazepine on the pharmacokinetics of tramadol.
Carbamazepine: The 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.
Cimetidine: With the concomitant or previous administration of cimetidine clinically relevant interactions are unlikely to occur. Therefore no alteration of the tramadol dosage regimen is recommended for patients receiving chronic cimetidine therapy.
Quinidine: A study in 12 healthy volunteers has shown that quinidine causes an approximate 25% increase in the tramadol Cmax and AUC; Tmax is unaffected. However, the increases in Cmax and AUC fall within the normal therapeutic range for tramadol, and no dosage adjustment is required.
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.
Animal studies with tramadol at very high doses have revealed effects on organ development, ossification and neonatal mortality Tramadol crosses the placenta. There is inadequate evidence available on the safety of tramadol in human pregnancy, therefore Tramadol 50mg/ml Solution for Injection 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.
Approximately 0.1% of the maternal dose of tramadol is excreted in breast milk. In the immediate post-partum period, for maternal oral daily dosage up to 400 mg, this corresponds to a mean amount of tramadol ingested by breast-fed infants of 3% of the maternal weight-adjusted dosage. For this reason tramadol 50mg/ml Solution for Injection should not be administered during breast-feeding or alternatively, breast-feeding should be discontinued during treatment with tramadol. After a single administration of tramadol however, it is not usually necessary to interrupt breast feeding.
Post marketing surveillance does not suggest an effect of tramadol on fertility. Animal studies did not show an effect of tramadol on fertility.
Tramadol 50mg/ml Solution for Injection may cause somnolence and dizziness and these effects 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:
Rapid intravenous administration may be associated with a higher incidence of adverse effects and therefore should be avoided. The most commonly reported adverse drug 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.
Uncommon: cardiovascular regulation (palpitation, tachycardia, postural hypotension or cardiovascular collapse). These adverse effects may occur especially after intravenous administration and in patients who are physically stressed.
Rare: bradycardia, increase in blood pressure.
Very common: dizziness.
Common: headache, somnolence.
Rare: changes in appetite, paraesthesia, tremor, epileptiform convulsions, involuntary muscle contractions, abnormal coordination, syncope, speech disorders.
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).
Rare: hallucinations, confusion, sleep disturbance, delirium, anxiety and nightmares. Psychic side effects may occur following administration of tramadol, which vary individually in intensity and nature (depending on personality and duration of medication). These include changes in mood (usually elation, occasionally dysphoria), changes in activity (usually suppression, occasionally increase) and changes in cognitive and sensorial ability (e.g. decision behaviour, perception disorders). Dependence may occur.
Rare: blurred vision, miosis, mydriasis
Rare: respiratory depression, dyspnoea
If the recommended doses are considerably exceeded and other centrally depressant substances are administered concomitantly (see section 4.5), respiratory depression may occur.
Worsening of asthma has been reported, though a causal relationship has not been established.
Very common: nausea
Common: vomiting, constipation, dry mouth
Uncommon: retching, gastrointestinal irritation (a feeling of pressure in the stomach, bloating), diarrhoea
Common: sweating.
Uncommon: dermal reactions (e.g. pruritus, rash, urticaria).
Rare: muscle weakness
In a few isolated cases, increases in liver enzyme values have been reported in a temporal connection with the therapeutic use of tramadol.
Rare: micturition disorders (difficulty in passing urine, dysuria and urinary retention)
Common: fatigue
Rare: allergic reactions (e.g. dyspnoea, bronchospasm, wheezing, angioneurotic oedema) and anaphylaxis.
Not known: hypoglycaemia
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 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.
Precipitation will occur if Tramadol 50mg/ml Solution for Injection is mixed in the same syringe with injections of diazepam, diclofenac sodium, indometacin, midazolam and piroxicam.
Tramadol 50mg/ml Solution for Injection must not be mixed with other medicinal products except those mentioned in section 6.6.
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