4.1. Therapeutic indications

Tramadol hydrochloride / Paracetamol tablets are indicated for the symptomatic treatment of moderate to severe pain.

The use of Tramadol hydrochloride/ Paracetamol should be restricted to patients whose moderate to severe pain is considered to require a combination of tramadol and paracetamol (see also Section 5.1).

4.2. Posology and method of administration

Prior to starting treatment with opioids, a discussion should be held with patients to put in place a strategy for ending treatment with Tramadol hydrochloride / Paracetamol tablets in order to minimise the risk of addiction and drug withdrawal syndrome (see section 4.4).

Posology

The use of Tramadol hydrochloride / Paracetamol should be restricted to patients whose moderate to severe pain is considered to require a combination of tramadol and paracetamol.

The dose should be adjusted to intensity of pain and the sensitivity of the individual patient. The lowest effective dose for analgesia should generally be selected. The total dose of 8 tablets (equivalent to 300 mg tramadol hydrochloride and 2600 mg paracetamol) per day should not be exceeded. The dosing interval should not be less than six hours.

Adults and adolescents (12 years and older)

An initial dose of two tablets of Tramadol hydrochloride / Paracetamol is recommended. Additional doses can be taken as needed, not exceeding 8 tablets (equivalent to 300 mg tramadol and 2600 mg paracetamol) per day.

The dosing interval should not be less than six hours.

Tramadol hydrochloride/ Paracetamol should under no circumstances be administered for longer than is strictly necessary (see also section 4.4 Special warnings and precautions for use). If repeated use or long term treatment with Tramadol hydrochloride/ Paracetamol is required as a result of the nature and severity of the illness, then careful, regular monitoring should take place (with breaks in the treatment, where possible), to assess whether continuation of the treatment is necessary.

Paediatric population

The effective and safe use of Tramadol hydrochloride / Paracetamol has not been established in children below the age of 12 years. Treatment is therefore not recommended in this population.

Elderly patients

A dose adjustment is not usually necessary in patients up to 75 years without clinically manifest hepatic or renal insufficiency. In older people over 75 years elimination may be prolonged. Therefore, if necessary the dosage interval is to be extended according to the patient's requirements.

Renal insufficiency / dialysis

In patients with renal 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.

Hepatic impairment

In patients with hepatic impairment the elimination of tramadol is delayed. In these patients, prolongation of the dosage intervals should be carefully considered according to the patient's requirements (see Section 4.4). Because of the presence of paracetamol Tramadol hydrochloride/Paracetamol should not be used in patients with severe hepatic impairment (see Section 4.3)

Method of administration

Oral use

Tablets must be swallowed whole, with a sufficient quantity of liquid. They must not be broken or chewed.

Treatment goals and discontinuation

Before initiating treatment with tramadol hydrochloride/paracetamol, a treatment strategy including treatment duration and treatment goals, and a plan for end of the treatment, should be agreed together with the patient, in accordance with pain management guidelines. During treatment, there should be frequent contact between the physician and the patient to evaluate the need for continued treatment, consider discontinuation and to adjust dosages if needed. When a patient no longer requires therapy with tramadol, it may be advisable to taper the dose gradually to prevent symptoms of withdrawal. In absence of adequate pain control, the possibility of hyperalgesia, tolerance and progression of underlying disease should be considered (see section 4.4).

4.3. Contraindications

- Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1,

- acute intoxication with alcohol, hypnotic drugs, centrally-acting analgesics, opioids or psychotropic drugs,

- Tramadol hydrochloride / Paracetamol should not be administered to patients who are receiving monoamine oxidase inhibitors or within two weeks of their withdrawal (see 4.5. Interactions with other medicinal products and other forms of interaction),

- severe hepatic impairment,

- epilepsy not controlled by treatment (see. 4.4. Special Warnings).

4.4. Special warnings and precautions for use

Warnings:

- 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 / 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).

- Cases of high anion gap metabolic acidosis (HAGMA) due to pyroglutamic acidosis have been reported in patients with severe illness such as severe renal impairment and sepsis, or in patients with malnutrition or other sources of glutathione deficiency (e.g. chronic alcoholism) who were treated with paracetamol at therapeutic dose for a prolonged period or a combination of paracetamol and flucloxacillin. If HAGMA due to pyroglutamic acidosis is suspected, prompt discontinuation of paracetamol and close monitoring, is recommended. The measurement of urinary 5-oxoproline may be useful to identify pyroglutamic acidosis as underlying cause of HAGMA in patients with multiple risk factors.

CYP2D6 metabolism

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%

Post-operative use in children

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.

Children with compromised respiratory function

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.

Sleep-related breathing disorders

Opioids can cause sleep-related breathing disorders including central sleep apnoea (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.

Adrenal insufficiency

Opioid analgesics may occasionally cause reversible adrenal insufficiency requiring monitoring and glucocorticoid replacement therapy. Symptoms of acute or chronic adrenal insufficiency may include e.g. severe abdominal pain, nausea and vomiting, low blood pressure, extreme fatigue, decreased appetite, and weight loss

Precautions for use

Risk from concomitant use of sedative medicines such as benzodiazepines or related drugs

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, psychic and physical dependence may develop, even at therapeutic doses and especially after long term use. 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 over dosage 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). When a patient no longer requires therapy with Tramadol hydrochloride / Paracetamol, it may be advisable to taper the dose gradually to prevent symptoms of withdrawal, 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.

Tolerance and opioid use disorder (abuse and dependence)

Tolerance, physical and psychological dependence, and opioid use disorder (OUD) may develop upon repeated administration of opioids such as tramadol hydrochloride/paracetamol. Repeated use of tramadol hydrochloride/paracetamol can lead to opioid use disorder (OUD). A higher dose and longer duration of opioid treatment can increase the risk of developing OUD. Abuse or intentional misuse of tramadol hydrochloride/paracetamol may result in overdose and/or death. The risk of developing OUD is increased in patients with a personal or a family history (parents or siblings) of substance use disorders (including alcohol use disorder), in current tobacco users or in patients with a personal history of other mental health disorders (e.g. major depression, anxiety and personality disorders).

Before initiating treatment with tramadol hydrochloride/paracetamol and during the treatment, treatment goals and a discontinuation plan should be agreed with the patient (see section 4.2). Before and during treatment the patient should also be informed about the risks and signs of OUD. If these signs occur, patients should be advised to contact their physician.

Patients will require monitoring for signs of drug-seeking behaviour (e.g. too early requests for refills). This includes the review of concomitant opioids and psycho-active drugs (like benzodiazepines). For patients with signs and symptoms of OUD, consultation with an addiction specialist should be considered.

Drug withdrawal syndrome

Prior to starting treatment with any opioids, a discussion should be held with patients to put in place a withdrawal strategy for ending treatment with Tramadol hydrochloride / Paracetamol tablets.

Drug withdrawal syndrome may occur upon abrupt cessation of therapy or dose reduction. When a patient no longer requires therapy, it is advisable to taper the dose gradually to minimise symptoms of withdrawal. Tapering from a high dose may take weeks to months.

The opioid drug withdrawal syndrome is characterised by some or all of the following: restlessness, lacrimation, rhinorrhoea, yawning, perspiration, chills, myalgia, mydriasis and palpitations. Other symptoms may also develop including irritability, agitation, anxiety, hyperkinesia, tremor, weakness, insomnia, anorexia, abdominal cramps, nausea, vomiting, diarrhoea, increased blood pressure, increased respiratory rate or heart rate.

If women take this drug during pregnancy, there is a risk that their newborn infants will experience neonatal withdrawal syndrome.

Hyperalgesia

Hyperalgesia may be diagnosed if the patient on long-term opioid therapy presents with increased pain.

This might be qualitatively and anatomically distinct from pain related to disease progression or to breakthrough pain resulting from development of opioid tolerance. Pain associated with hyperalgesia tends to be more diffuse than the pre-existing pain and less defined in quality. Symptoms of hyperalgesia may resolve with a reduction of opioid dose.

Serotonin syndrome

Serotonin syndrome, a potentially life-threatening condition, has been reported in patients receiving tramadol in combination with other serotonergic agents or tramadol alone (see sections 4.5, 4.8 and 4.9).

If concomitant treatment with other serotonergic agents is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose escalations.

Symptoms of serotonin syndrome may include mental status changes, autonomic instability, neuromuscular abnormalities and/or gastrointestinal symptoms.

If serotonin syndrome is suspected, a dose reduction or discontinuation of therapy should be considered depending on the severity of the symptoms. Withdrawal of the serotonergic drugs usually brings about a rapid improvement.

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

Concomitant use is contraindicated with:

- Non-selective MAO Inhibitors

Risk of serotonergic syndrome: diarrhoea, tachycardia, hyperhidrosis, trembling, confusional state even coma.

- Selective-A MAO Inhibitors

Extrapolation from non-selective MAO inhibitors

Risk of serotonergic syndrome: diarrhoea, tachycardia, hyperhidrosis, trembling, confusional state, even coma.

- Selective-B MAO Inhibitors

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

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.

- Carbamazepine and other enzyme inducers

Risk of reduced efficacy and shorter duration due to decreased plasma concentrations of tramadol.

- Opioid agonists-antagonists (buprenorphine, nalbuphine, pentazocine)

Decrease of the analgesic effect by competitive blocking effect at the receptors, with the risk of occurrence of withdrawal syndrome.

Concomitant use which needs to be taken into consideration:

- Tramadol can induce convulsions and increase the potential for selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, antipsychotics and 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 re-uptake inhibitors (SSRIs) serotonin-norepinephrine reuptake inhibitors (SNRIs), MAO inhibitors (see section 4.3), tricyclic antidepressants and mirtazapine may cause serotonin syndrome, a potentially life-threatening condition (see sections 4.4 and 4.8).

- Other opioid derivatives (including antitussive drugs and substitutive treatments)

- Caution should be taken when paracetamol is used concomitantly with flucloxacillin as concurrent intake has been associated with high anion gap metabolic acidosis due to pyroglutamic acidosis, especially in patients with risks factors (see section 4.4)

Increased risk of respiratory depression which can be fatal in cases of overdose.

- Other central nervous system depressants, such as other opioid derivatives (including antitussive drugs and substitutive treatments), other anxiolytics, hypnotics, sedative antidepressants, sedative antihistamines, neuroleptics, centrally acting antihypertensive drugs, thalidomide and baclofen.

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 tramadol hydrochloride/paracetamol with gabapentinoids (gabapentin and pregabalin) may result in respiratory depression, hypotension, profound sedation, coma or death.

- Sedating medicinal products such as benzodiazepines or related substances:

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).

- As medically appropriate, periodic evaluation of prothrombin time should be performed when Tramadol hydrochloride/Paracetamol and warfarin like compounds are administered concurrently due to reports of increased INR.

- 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.

4.6. Fertility, pregnancy and lactation

Pregnancy

Since this medicine is a fixed combination of active ingredients including tramadol, it should not be used during pregnancy.

- Data regarding paracetamol:

Studies in animals are insufficient to conclude on reproductive toxicity. A large amount of data on pregnant women indicate neither malformative, nor feto/neonatal toxicity. Epidemiological studies on neurodevelopment in children exposed to paracetamol in utero show inconclusive results.

- Data regarding tramadol:

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 neonate as a consequence of habituation.

If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

Administration during labor may depress respiration in the neonate and an antidote for the child should be readily available.

Breast-feeding

Since this medicine is a fixed combination of active ingredients including tramadol, it should not be used during lactation or alternatively, breast-feeding should be discontinued during treatment with tramadol hydrochloride/paracetamol. Discontinuation of breast-feeding is generally not necessary following a single dose of tramadol hydrochloride/paracetamol.

- 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.

Administration to nursing women is not recommended as Tramadol hydrochloride / Paracetamol may be secreted in breast milk and may cause respiratory depression in the infant.

Fertility

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.

4.7. Effects on ability to drive and use machines

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 medicine is likely to affect your ability to drive

- Do not drive until you know how the medicine affects you

- It is an offence to drive while under the influence of this medicine

- However, you would not be committing an offence (called 'statutory defence') if:

•

The medicine has been prescribed to treat a medical or dental problem and

•

You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and

•

It was not affecting your ability to drive safely

4.8. Undesirable effects

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.

Cardiac disorders:

- Uncommon: palpitation, tachycardia, arrhythmia.

Eye disorders:

- Rare: vision blurred, miosis, mydriasis

Ear and labyrinth disorders:

- Uncommon: tinnitus

Gastro-intestinal disorders:

- Very common: nausea

- Common: vomiting, constipation, dry mouth, diarrhoea abdominal pain, dyspepsia, flatulence

- Uncommon: dysphagia, melaena

General disorders and administration site conditions:

- Uncommon: chills, chest pain, drug withdrawal syndrome

Investigations:

- Uncommon: transaminases increased

Metabolism and nutrition disorders:

- Unknown: hypoglycaemia, High anion gap metabolic acidosis

Nervous system disorders:

- Very common: dizziness, somnolence

- Common: headache trembling

- Uncommon: involuntary muscular contractions, paraesthesia, amnesia

- Rare: ataxia, convulsions, syncope, speech disorders.

Psychiatric disorders:

- Common: confusional state, mood altered, anxiety, nervousness, euphoric mood, sleep disorders

- Uncommon: depression, hallucinations, nightmares

- Rare: delirium, Drug dependence

Post marketing surveillance

very rare: abuse.

Renal and urinary disorders:

- Uncommon: albuminuria, micturition disorders (dysuria and urinary retention)

Respiratory, thoracic and mediastinal disorders:

- Uncommon: dyspnoea

Skin and subcutaneous tissue disorders:

- Common: hyperhidrosis, pruritus

- Uncommon: dermal reactions (e.g.rash, urticaria).

Vascular disorders:

- 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:

Drug dependence

Repeated use of tramadol hydrochloride/paracetamol can lead to drug dependence, even at therapeutic doses. The risk of drug dependence may vary depending on a patient's individual risk factors, dosage, and duration of opioid treatment (see section 4.4).

Description of selected adverse reactions

High anion gap metabolic acidosis

Cases of high anion gap metabolic acidosis due to pyroglutamic acidosis have been observed in patients with risk factors using paracetamol (see section 4.4). Pyroglutamic acidosis may occur as a consequence of low glutathione levels in these patients.

Tramadol

- 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.

- Nervous system disorders: Not known: Serotonin syndrome.

- 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.

- Respiratory, thoracic and mediastinal disorders: frequency not known: hiccups.

Paracetamol

- 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.

- Metabolism and nutrition disorders: cases of pyroglutamic acidosis (PGA) were reported with frequency not known. When paracetamol is used alone or with concomitant treatment of flucloxacillin, especially in patients with risk factors and prolonged treatment (see sections 4.4 and 4.5).

Reporting of suspected adverse reactions

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 Yellow Card Scheme at:www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Tramadol hydrochloride / Paracetamol is a fixed combination of active ingredients. In case of overdose, the symptoms may include the signs and symptoms of toxicity of tramadol or paracetamol or of both these active ingredients.

Symptoms of overdose from tramadol:

In principle, on intoxication with tramadol, symptoms similar to those of other centrally acting analgesics (opioids) are to be expected. These include in particular, miosis, vomiting, cardiovascular collapse, consciousness disorders up to coma, convulsions and respiratory depression up to respiratory arrest.

Serotonin syndrome has also been reported.

Patients should be informed of the signs and symptoms of overdose and to ensure that family and friends are also aware of these signs and to seek immediate medical help if they occur.

Symptoms of overdose from paracetamol:

An overdose is of particular concern in young children. Symptoms of paracetamol overdosage in the first 24 hours are pallor, nausea, vomiting, anorexia and abdominal pain. Liver damage may become apparent 12 to 48 hours after ingestion. Abnormalities of glucose metabolism and metabolic acidosis may occur. In severe poisoning, hepatic failure may progress to encephalophathy, coma and death. Acute renal failure with acute tubular necrosis may develop even in the absence of severe liver damage. Cardiac arrhythmias and pancreatitis have been reported.

Liver damage is possible in adults who have taken 7.5-10 g or more of paracetamol. It is considered that excess quantities of a toxic metabolite (usually adequately detoxified by glutathione when normal doses of paracetamol are ingested), become irreversibly bound to liver tissue.

Emergency treatment:

- Transfer immediately to a specialised unit.

- Maintain respiratory and circulatory functions

- Prior to starting treatment, a blood sample should be taken as soon as possible after overdose in order to measure the plasma concentration of paracetamol and tramadol and in order to perform hepatic tests.

- Perform hepatic tests at the start (of overdose) and repeat every 24 hours. An increase in hepatic enzymes (ASAT, ALAT) is usually observed, which normalizes after one or two weeks.

- Empty the stomach by causing the patient to vomit (when the patient is conscious) by irritation or gastric lavage.

- 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; fits can be controlled with diazepam.

- Tramadol is minimally eliminated from the serum by haemodialysis or haemofiltration. Therefore, treatment of acute intoxication with Tramadol hydrochloride/ Paracetamol with haemodialysis or haemofiltration alone is not suitable for detoxification.

Immediate treatment is essential in the management of paracetamol overdose. Despite a lack of significant early symptoms, patients should be referred to hospital urgently for immediate medical attention and any adult or adolescent who had ingested around 7.5 g or more of paracetamol in the preceding 4 hours or any child who has ingested ≥150 mg/kg of paracetamol in the preceding 4 hours should undergo gastric lavage. Paracetamol concentrations in blood should be measured later than 4 hours after overdose in order to be able to assess the risk of developing liver damage (via the paracetamol overdose nomogram). Administration of oral methionine or intravenous N-acetylcysteine (NAC) which may have a beneficial effect up to at least 48 hours after the overdose, may be required. Administration of intravenous NAC is most beneficial when initiated within 8 hours of overdose ingestion. However, NAC should still be given if the time to presentation is greater than 8 hours after overdose and continued for a full course of therapy. NAC treatment should be started immediately when massive overdose is suspected. General supportive measures must be available.

Irrespective of the reported quantity of paracetamol ingested, the antidote for paracetamol, NAC, should be administered orally or intravenously, as quickly as possible, if possible, within 8 hours following the overdose.