Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2018 Publisher: Accord Healthcare Limited, Sage House, 319 Pinner road, North Harrow, Middlesex, HA1 4HF, United Kingdom
Tramadol should not be administered to patients who have previously demonstrated hypersensitivity to it, or to any of the ingredients, or in cases of acute intoxication with alcohol, hypnotics, analgesics, opioids or other psychotroic medicinal drugs.
In common with other opioid analgesics it should not be administered to patients who are receiving monoamine oxidase (MAO) inhibitors or within two weeks of their withdrawal (see section 4.5).
Tramadol should not be given to patients suffering from uncontrolled epilepsy.
Tramadol must not be used for narcotic withdrawal treatment.
At therapeutic doses, tramadol has the potential to cause withdrawal symptoms.
Tolerance, psychic and physical dependence may develop, especially after long-term use.
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.
Convulsions have been reported in patients receiving tramadol 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).
Tramadol capsule contains lactose and therefore should not be used by patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.
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>.
When a patient no longer requires therapy with tramadol, it may be advisable to taper the dose gradually to prevent symptoms of withdrawal.
Tramadol should be used with caution in opioid-dependent patients, patients with head injury, a reduced level of consciousness of uncertain origin, increased intracranial pressure, severe impairment of hepatic and renal function, disorders of the respiratory centre or 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.
Risk from concomitant use of sedative medicines such as benzodiazepines or related drugs:
Concomitant use of Tramadol and sedative medicines such as benzodiazepines or related drugs may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing with these sedative medicines should be reserved for patients for whom alternative treatment options are not possible. If a decision is made to prescribe Tramadol concomitantly with sedative medicines, the lowest effective dose should be used, and the duration of treatment should be as short as possible.
The patients should be followed closely for signs and symptoms of respiratory depression and sedation. In this respect, it is strongly recommended to inform patients and their caregivers to be aware of these symptoms (see section 4.5).
Tramadol should not be combined with monoamine oxidase (MAO) inhibitors (see section 4.3).
Patients treated with MAO inhibitors within 14 days prior to administration of the opioid pethidine have experienced life- threatening interactions affecting the central nervous system as well as the respiratory and circulatory centres. The possibility of similar interactions occurring between monoamine oxidase inhibitors and tramadol cannot be ruled out.
Concomitant administration of tramadol with other centrally acting drugs including alcohol may potentiate CNS depressant effect (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. Simultaneous or previous administration of carbamazepine (enzyme inducer) may reduce the analgesic effect and shorten the duration 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 (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:
Withdrawal of the serotonergic drugs usually brings about a rapid improvement. Treatment depends on the type and severity of the symptoms.
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.
There is a theoretical possibility that tramadol could interact with noradrenaline, 5HT or lithium due to their respective mechanisms of action, thus potentiate their anti-depressant effect. However there have been no reports of such interactions.
Caution should be exercised during concomitant treatment with tramadol and coumarin derivatives (e.g. warfarin) due to reports of increased INR 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.
Sedative medicines such as benzodiazepines or related drugs: The concomitant use of opioids with sedative medicines such as benzodiazepines or related drugs increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. The dose and duration of concomitant use should be limited (see section 4.4).
Animal studies with tramadol revealed at very high doses 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 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 should not be used during lactation or alternatively, breast-feeding should be discontinued during treatment with tramadol. Discontinuation of breast-feeding is generally not necessary following a single dose of tramadol.
Post marketing surveillance does not suggest an effect of tramadol on fertility. Animal studies did not show an effect of tramadol on fertility.
Even when taken according to instructions, Tramadol may cause drowsiness and dizziness and this effect may be potentiated by alcohol and other central nervous system (CNS) depressants or 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 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.
There have also been cases of blood dyscrasias observed with tramadol treatment, but direct causality has not been confirmed.
Rare: hypersensitivity/allergic reactions (e.g. dyspnoea, bronchospasm, wheezing, angioneurotic oedema) and anaphylaxis.
Rare: sleep disturbance, delirium, anxiety, confusion, nightmares and hallucinations, have been reported. 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.
Dependence: Prolonged administration of tramadol may lead to dependence.
Withdrawal reactions: 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).
Very common: dizziness
Common: headache and drowsiness (somnolence)
Rare: changes in appetite, paraesthesia, tremor, respiratory depression, involuntary muscle contractions, abnormal coordination. Epileptiform convulsions have been reported occurring mainly after administration of high doses of tramadol or after treatment with drugs which can lower the seizure threshold or themselves induce cerebral convulsions (e.g. anti-depressants or anti-psychotics) (see sections 4.4 and 4.5), syncope.
If the recommended doses are considerably exceeded and other centrally depressant substances are administered concomitantly (see section 4.5), respiratory depression may occur.
Not known: speech disorders
Rare: blurred vision, mydriasis
Uncommon: cardiovascular regulation (palpitations, tachycardia). These adverse reactions may occur especially on intravenous administration and in patients who are physically stressed.
Rare: bradycardia, hypertension (increase in blood pressure).
Uncommon: cardiovascular regulation (postural hypotension or cardiovascular collapse). These adverse reactions may occur especially on intravenous administration and in patients who are physically stressed.
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 and dry mouth
Uncommon: retching; gastrointestinal discomfort (a feeling of pressure in the stomach, bloating), diarrhoea
Common: sweating
Uncommon: dermal reactions (e.g. pruritus, rash, urticaria)
Rare: motorial weakness
In a few isolated cases an increase in liver enzyme values has been reported in a temporal connection with the therapeutic use of tramadol.
Rare: micturition disorders (difficulty in passing urine, dysuria and urinary retention)
Not known: hypoglycaemia
Common: fatigue
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 or search for MHRA Yellow Card in the Google Play or Apple App Store.
None known.
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