MEDOTRAMOL Film-coated tablet Ref.[50520] Active ingredients: Paracetamol Tramadol Tramadol and Paracetamol

Warnings

• In adults and adolescents 12 years and older: the maximum dose of 8 tablets of Medotramol 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), Medotramol is not recommended.
• In patients with severe hepatic impairment Medotramol 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, Medotramol 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 Medotramol 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 section 4.5).

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.

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.

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:

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.

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 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 Medotramol 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).

Caution is advised if paracetamol is administered concomitantly with flucloxacillin due to increased risk of high anion gap metabolic acidosis (HAGMA), particularly in patients with severe renal impairment, sepsis, malnutrition and other sources of glutathione deficiency (e.g. chronic alcoholism), as well as those using maximum daily doses of paracetamol. Close monitoring, including measurement of urinary 5-oxoproline, is recommended.

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. Medotramol 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 taper 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.

Concomitant use is contraindicated with:

• Non-selective MAO Inhibitors: Risk of serotoninergic syndrome (diarrhoea, tachycardia, hyperhidrosis, trembling, confusional state, even coma), a potentially life-threatening condition (see sections 4.4 and 4.8).
• Selective-A MAO Inhibitors: Extrapolation from non-selective MAO inhibitors. Risk of serotoninergic syndrome, a potentially life-threatening condition (see sections 4.4 and 4.8).
• Selective-B MAO Inhibitors: Central excitation symptoms evocative of a serotoninergic syndrome (diarrhoea, tachycardia, hyperhidrosis, trembling, confusional state, even coma), a potentially life-threatening condition (see sections 4.4 and 4.8).

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 reuptake 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), benzodiazepines and barbiturates: 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), barbiturates, benzodiazepines, 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.

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

Pregnancy

Since Medotramol 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. If clinically needed, paracetamol can be used during pregnancy however, it should be used at the lowest effective dose for the shortest possible time and at the lowest possible frequency.

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 newborn after birth, as a consequence of habituation.

Breast-feeding

Since Medotramol 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 Medotramol. Discontinuation of breast-feeding is generally not necessary following a single dose of Medotramol.

Data regarding paracetamol

Paracetamol is excreted in breast milk but not in a clinically significant amount.

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.

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.

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.

The most commonly reported undesirable effects during the clinical trials performed with the paracetamol/tramadol combination were nausea, dizziness and somnolence, observed in more than 10 % of the patients.

The following terms and frequencies are applied: Very common (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1,000 to <1/100), Rare (≥1/10,000 to <1/1,000), Very rare (<1/10,000) and not known (cannot be estimated from the available clinical trial data).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Psychiatric disorders

Common: confusion, mood changes (anxiety, nervousness, euphoria), sleep disorders

Uncommon: depression, hallucinations, nightmares, amnesia

Rare: delirium, drug dependence.

Nervous system disorders

Very common: dizziness, somnolence

Common: headache, trembling

Uncommon: involuntary muscular contractions, paraesthesia, tinnitus

Rare: ataxia, convulsions, syncope, speech disorders.

Cardiac disorders

Uncommon: hypertension, palpitations, 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

Investigations

Uncommon: transaminases increased

Metabolism and nutrition disorders

Unknown: hypoglycaemia

Post marketing surveillance

Psychiatric disorders

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: sweating, 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:

Tramadol

• Postural hypotension, bradycardia, collapse (tramadol).
• Post-marketing surveillance of tramadol has revealed rare alterations ofwarfarin effect, including elevation of prothrombin times.
• Rare cases: allergic reactions with respiratory symptoms (e.g. dyspnoea, bronchospasm, wheezing, angioneurotic oedema) and anaphylaxis
• Rare cases: 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 elation 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 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 if tramadol hydrochloride is discontinued abruptly include: panic attacks, severe anxiety, hallucinations, paraesthesia, tinnitus and unusual CNS symptoms.
• Respiratory, thoracic and mediastinal disorders (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 to Pharmaceutical Services, Ministry of Health, CY-1475 Nicosia, Tel: +357 22608607, Fax: +357 22608669, website: www.moh.gov.cy/phs.

Not applicable.