ANTALGEX T Capsule Ref.[115641] Active ingredients: Paracetamol Tramadol

Warnings

• In adults and adolescents over 12 years, the maximum dose of 8 capsules of ANTALGEX T should not be exceeded. In order to avoid accidental overdose, patients should be advised not to exceed the recommended dose and not to use any other paracetamol (including over the counter medicines) or tramadol hydrochloride containing products concurrently without the advice of a physician.
• In severe renal insufficiency (creatinine clearance <10 ml/min), ANTALGEX T is not recommended.
• In patients with severe hepatic impairment ANTALGEX T 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, ANTALGEX T is not recommended.
• Tramadol is not suitable as a substitute in opioid-dependent treatment patients. Although it is an opioid receptor 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 anaesthesics. Epileptic patients controlled by a treatment or patients susceptible to seizures should be treated with ANTALGEX T 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 maximum dose limit.
• Concomitant administration of opioids agonists-antagonists (nalbuphine, buprenorphine, pentazocine) is not recommended (see section 4.5 Interactions with other medicinal products and other forms of interactions).

Sleep-related breathing disorders

Opioids can cause sleeping-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioids use increase the risk of CSA in a dose-dependent manner. In patients who present CSA, consider decreasing the total opioids dosage.

Serotonin syndrome

Serotonin syndrome, potentially life-threatening syndrome, has been reported in patients treated with tramadol in association with other serotonin agents or by tramadol alone (see sections 4.5, 4.8 and 4.9)

If a concomitant treatment with others serotonin medicines is justified on the clinical plan, it is advice to monitor closely the patient, especially a the installation of the treatment and dose incrementation.

Symptoms of serotonin syndrome can include modification of the mental state, autonomous instability, neuromuscular anomalies and/or gastrointestinal symptoms.

In case of suspicion of serotonin syndrome, dose reduction or discontinuation of the treatment should be considered depending on the severity of the symptoms. Withdrawal of the serotonin medicines generally bring 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 the 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 opioids toxicity event even at commonly prescribed doses.

General symptoms of opioids toxicity include confusion, drowsiness, shallow breathing, constricted 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 fatal in very rarely cases.

Prevalence estimates of ultra-rapid metabolisers in different populations are summarised below:

Post-operative use in children

Literature report cases of tramadol given post-operatively in children after tonsillectomy and/or adenoidectomy for obstructive sleep apnea, 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 gland insufficiency

Opioid analgesics can occasionally cause reversible adrenal gland insufficiency needing a monitoring and a glucocorticoid substitute treatment. Symptoms of acute or long term adrenal gland insufficiency can include, for example, severe abdominal pain, nausea, vomiting, hypotension, extreme fatigue, decrease of appetite and weight loss.

Precautions for use

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

Concomitant use of ANTALGEX T 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 no other alternative treatment options exists. If a decision is made to prescribe ANTALGEX T 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).

Besides tolerance, psychic and physical dependence may develop, even at therapeutic doses and especially after long-term use. The clinical need for an analgesic treatment should be regularly reassessed (see section 4.2). In patients with opioid dependence and with history of drug abuse or dependence, the treatment should be administered only for a short duration and under medical supervision. ANTALGEX T should be used with caution in patients with cranial trauma, in patients with predispositions to seizure disorders, in patients with biliary tract dysfunctions, in state of shock, consciousness alteration from unknown origin, respiratory centre or respiratory function disorders or with an increased intracranial pressure.

Paracetamol overdosage may cause hepatic toxicity in some patients.

Withdrawal symptoms similar to those occurring during opiates withdrawal might occur even at therapeutically doses or for short duration (see section 4.8). When a patient no longer requires treatment with ANTALGEX T, it may be advisable to reduce the dose gradually to prevent symptoms of withdrawal, especially after long treatment periods. Rare 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 anaesthesia should be avoided.

Concomitant use is contraindicated with

• Non-selective MAO Inhibitors

Risk of serotoninergic syndrome: diarrhoea, tachycardia, hyperhidrosis, trembling, confusion, even coma.

• Selective-A MAO Inhibitors

Extrapolation from non-selective MAO inhibitors Risk of serotoninergic syndrome: diarrhoea, tachycardia, hyperhidrosis, trembling, confusion, even coma.

• Selective-B MAO Inhibitors

Central excitation symptoms evocative of a serotoninergic syndrome: diarrhoea, tachycardia, hyperhidrosis, trembling, confusion, even coma.

In case of recent treatment with MAO inhibitors, a delay of two weeks should be respected before starting 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 medicinal products containing alcohol.

• Carbamazepine and other enzyme inducers

Risk of decreased efficiency and action duration because of the decreased plasma concentration 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 cause convulsions and increase the convulsing potential of selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, antipsychotics and other medicines that lower the seizure threshold (as bupropion, mirtazapine, tetrahydrocannabinol).
• The concomitant therapeutic use of tramadol and serotoninergic medicines as serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), MAO inhibitors (see section 4.3), tricyclic antidepressants and mirtazapine, might cause a serotoninergic syndrome, potentially life-threatening syndrome (see sections 4.4 and 4.8).
• Other opioids derivatives (including antitussives and substitutive treatments) Increased risk of respiratory depression which can be fatal in cases of overdose.
• Other central nervous system depressants such as other opioids analgesics (including antitussives and substitutive treatments), other anxiolytics, hypnotics, sedative

Pregnancy

Since ANTALGEX T is a fixed combination of active substances including tramadol, it should not be administered 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 foeto/neonatal toxicity. Epidemiological studies on neurodevelopment in children exposed to paracetamol in utero show inconclusive results.

Data regarding tramadol

There is not enough pertinent data available to evaluate the safe use 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 however 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

ANTALGEX T being a fixed combination of active ingredients containing tramadol, this medicine should not be used during breast-feeding or alternatively, breast-feeding should be discontinued during treatment with ANTALGEX T. Discontinuation of breast-feeding is generally not necessary following a single dose of ANTALGEX T.

Data on paracetamol

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

Data on tramadol

About 0.1% of the dose of tramadol administered to the mother is excreted in breast milk. During the immediate post-partum period, for a daily oral dose up to 400 mg administered to the mother, corresponds in the nursed infant to 3% of the maternal weight-adjusted dose. Therefore, tramadol should not be used during breast-feeding, or breast-feeding should be interrupted in case of tramadol treatment. Discontinuation of breast-feeding is generally not required in case of a single administration of tramadol.

Fertility

Post marketing surveillance does not suggest any effect of tramadol on fertility. Animal studies did not demonstrate an effect of tramadol on fertility. No study on fertility was conducted with a 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 nor operate machinery.

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

The frequencies are defined as follows: Very common ≥1/10, Common ≥1/100, <1/10, Uncommon ≥1/1,000, <1/100, Rare ≥/10,000, <1/1,000, Very rare <1/10,000, Undetermined frequency which cannot be estimated based on the available data.

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

Cardiovascular disorders

Uncommon: palpitations, tachycardia, arrhythmia.

Eye disorders

Rare: blurred vision, miosis, mydriasis.

Ear and labyrinth disorders

Uncommon: tinnitus.

Gastrointestinal disorders

Very common: nausea.

Common: vomiting, constipation, dry mouth, diarrhoea, abdominal pain, dyspepsia, gas.

Uncommon: dysphagia, melaena.

General disorders and administration site conditions

Rare: chills, chest pain.

Investigations

Uncommon: transaminases increased

Metabolism and nutrition disorders

Undetermined frequency: hypoglycaemia.

Nervous system disorders

Very common: dizziness, drowsiness.

Common: headache, trembling.

Uncommon: involuntary muscular contractions, paraesthesia, amnesia.

Rare: ataxia, convulsions, syncope, speech disorders.

Psychiatric disorders

Common: confusion state, mood altered (anxiety, nervousness, euphoria), 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: skin reactions (i.e. rash, hives).

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 of warfarin effect, including elevation of prothrombin times.
• Rare cases (≥1/10.000 to <1/1.000): allergic reactions with respiratory symptoms (e.g. dyspnoea, bronchospasm, wheezing, angioneurotic oedema) and anaphylaxis.
• Rare cases (≥1/10.000 to <1/1.000): 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 capacities (e.g. decision behaviour, perception disorders).
• Nervous system affection: unknown frequency: Serotonin syndrome.
• Worsening of asthma has been reported though a causal relationship has not been established.
• Symptoms of drug withdrawal syndrome, similar to those occurring during opioids 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 attacks, hallucinations, paraesthesia, tinnitus and unusual CNS symptoms.
• Respiratory, thoracic and mediastinal disorders: undetermined: hiccup.

Paracetamol

• Despite the fact that the undesirable effects are rare, hypersensitivity including skin rash may occur. Cases of blood dyscrasias have been reported, including thrombocytopenia and agranulocytosis, but the causality relation with paracetamol has not been established in all cases.
• Several reports suggest that paracetamol could induce a hypoprothrombinaemia in case of concomitant administration with warfarin-like compounds. In other studies, the prothrombin time has not been modified.
• Severe skin reactions have been reported in very rare cases.

Not applicable.