Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2020 Publisher: Grünenthal Ltd, Regus Lakeside House, 1 Furzeground Way, Stockley Park East, Uxbridge, Middlesex UB11 1BD, United Kingdom
In adults and adolescents 12 years and older. The maximum dose of 8 tablets of Tramadol hydrochloride/Paracetamol should not be exceeded. In order to avoid inadvertent overdose, patients should be advised not to exceed the recommended dose and not to use any other paracetamol (including over the counter) or tramadol hydrochloride containing products concurrently without the advice of a physician.
In severe renal insufficiency (creatinine clearance <10 ml/mm), Tramadol hydrochloride/Paracetamol is not recommended.
In patients with severe hepatic impairment Tramadol hydrochloride/Paracetamol should not be used (See Section 4.3). The hazards of paracetamol overdose are greater in patients with non-cirrhotic alcoholic liver disease. In moderate cases prolongation of dosage interval should be carefully considered.
In severe respiratory insufficiency, Tramadol hydrochloride/Paracetamol is not recommended.
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 tramadol-treated patients susceptible to seizures or taking other medications that lower the seizure threshold, especially selective serotonin re-uptake inhibitors, tricyclic antidepressants, antipsychotics, centrally acting analgesics or local anaesthesia. Epileptic patients controlled by a treatment or patients susceptible to seizures should be treated with this medicine only if there are compelling circumstances. 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 dose limit
Concomitant use of opioid agonists-antagonists (nalbuphine, buprenorphine, pentazocine) is not recommended (see 4.5 Interactions with other medicinal products and other forms of interaction).
Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the total opioid dosage.
Concomitant use of Tramadol hydrochloride/Paracetamol 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 drugs should be reserved for patients for whom alternative treatment options are not possible. If a decision is made to prescribe Tramadol hydrochloride/Paracetamol concomitantly with sedative medicines, the lowest effective dose should be used, and the duration of the concomitant 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).
Tolerance and physical and/or psychological dependence may develop, even at therapeutic doses. The clinical need for analgesic treatment should be reviewed regularly (see section 4.2). In opioid-dependent patients and patients with a history of drug abuse or dependence, treatment should only be for short period and under medical supervision. Tramadol hydrochloride/Paracetamol should be used with caution in patients with cranial trauma, in patients prone to convulsive disorder, biliary tract disorders, in a state of shock, in an altered state of consciousness for unknown reasons, with problems affecting the respiratory center or the respiratory function, or with an increased intracranial pressure.
Paracetamol in overdosage may cause hepatic toxicity in some patients.
Symptoms of withdrawal reaction, similar to those occurring during opiate withdrawal, may occur even at therapeutic doses and for short term treatment (see section 4.8). Withdrawal symptoms may be avoided by tapering it at the time of discontinuation especially after long treatment periods. Rarely, cases of dependence and abuse have been reported (see section 4.8).
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, use of tramadol during light planes of anaesthesia should be avoided.
Tramadol hydrochloride/Paracetamol tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.
Risk of serotonergic syndrome: diarrhoea, tachycardia, hyperhidrosis, trembling, confusional state, even coma.
Extrapolation from non-selective MAO inhibitors
Risk of serotonergic syndrome: diarrhoea, tachycardia, hyperhidrosis, trembling, confusional state, even coma.
Central excitation symptoms evocative of a serotonergic syndrome: diarrhoea, tachycardia, hyperhidrosis, trembling, confusional state, even coma.
In case of recent treatment with MAO inhibitors, a delay of two weeks should occur before treatment with tramadol
Concomitant use is not recommended with:
Alcohol increases the sedative effect of opioid analgesics.
The effect on alertness can make driving of vehicles and the use of machines dangerous.
Avoid intake of alcoholic drinks and of medicinal products containing alcohol.
Risk of reduced efficacy and shorter duration due to decreased plasma concentrations of tramadol.
Decrease of the analgesic effect by competitive blocking effect at the receptors, with the risk of occurrence of withdrawal syndrome.
Withdrawal of the serotonergic drugs usually brings about a rapid improvement. Treatment depends on the type and severity of the symptoms.
Increased risk of respiratory depression which can be fatal in cases of overdose.
These drugs can cause increased central depression. The effect on alertness can make driving of vehicles and the use of machines dangerous.
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 effects. The dose and duration of the concomitant use should be limited (see section 4.4).
Since this medicine is a fixed combination of active ingredients including tramadol, it should not be used during pregnancy.
Data regarding paracetamol: Epidemiological studies in human pregnancy have shown no ill effects due to paracetamol used in the recommended dosages.
Data regarding tramadol: Tramadol should not be used during pregnancy as there is inadequate evidence available to assess the safety of tramadol 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. Long-term treatment during pregnancy may lead to withdrawal symptoms in the newborn after birth, as a consequence of habituation.
Since this medicine is a fixed combination of active ingredients including tramadol, it should not be ingested during breast feeding.
Data regarding paracetamol: Paracetamol is excreted in breast milk but not in a clinically significant amount. Available published data do not contraindicate breast feeding by women using single ingredient medicinal products containing only paracetamol.
Data regarding tramadol: 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. No study on fertility was accomplished with the combination of tramadol and paracetamol.
Tramadol may cause drowsiness or dizziness, which may be enhanced by alcohol or other CNS depressants. If affected, the patient should not drive or operate machinery.
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 undesirable effects during the clinical trials performed with the paracetamol/tramadol hydrochloride combination were nausea, dizziness and somnolence, observed in more than 10% of the patients.
The frequencies are defined as follows: very common: ≥1/10, common: ≥1/100 to <1/10, uncommon: ≥1/1000 to <1/100, rare: ≥1/10 000 to <1/1000, very rare: <1/10 000, unknown: frequency cannot be estimated from the available data.
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Uncommon: palpitations, tachycardia, arrythmia
Rare: vision blurred, miosis, mydriasis
Uncommon: tinnitus
Very common: nausea
Common: vomiting, constipation, dry mouth, diarrhoea abdominal pain, dyspepsia, flatulence
Uncommon: dysphagia, melaena
Uncommon: chills, chest pain
Uncommon: transaminases increased
Unknown: hypoglycaemia
Very common: dizziness, somnolence
Common: headache trembling
Uncommon: involuntary muscular contractions, paraesthesia, amnesia
Rare: ataxia, convulsions, syncope, speech disorders
Common: confusional state, mood altered, anxiety, nervousness, euphoric mood), sleep disorders
Uncommon: depression, hallucinations, nightmares
Rare: delirium, drug dependence
very rare: abuse
Uncommon: albuminuria, micturition disorders (dysuria and urinary retention)
Uncommon: dyspnoea
Common: hyperhidrosis, pruritus
Uncommon: dermal reactions (e.g.rash, urticaria)
Uncommon: hypertension, hot flush
Although not observed during clinical trials, the occurrence of the following undesirable effects known to be related to the administration of tramadol or paracetamol cannot be excluded:
Postural hypotension, bradycardia, collapse (tramadol).
Post-marketing surveillance of tramadol has revealed rare alterations of warfarin effect, including elevation of prothrombin times.
Rare cases (≥1/10000 to <1/1000): allergic reactions with respiratory symptoms (e.g. dyspnoea, bronchospasm, wheezing, angioneurotic oedema) and anaphylaxis
Rare cases (≥1/10000 to <1/1000): changes in appetite, motor weakness, and respiratory depression
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 euphoric mood occasionally dysphoria), changes in activity (usually suppression occasionally increase) and changes in cognitive and sensorial capacity (e.g. decision behaviour perception disorders).
Worsening of asthma has been reported though a causal relationship has not been established.
Symptoms of drug withdrawal syndrome, 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 if tramadol hydrochloride is discontinued abruptly include: panic attacks, severe anxiety, hallucinations, paraesthesia, tinnitus and unusual CNS symptoms.
Adverse effects of paracetamol are rare but hypersensitivity including skin rash may occur. There have been reports of blood dyscrasias including thrombocytopenia and agranulocytosis, but these were not necessarily causally related to paracetamol.
There have been several reports that suggest that paracetamol may produce hypoprothrombinemia when administered with warfarin-like compounds. In other studies, prothrombin time did not change.
Very rare cases of serious skin reactions have been reported.
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.
Not applicable.
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