TRAMACET

Posology The use of Tramacet should be restricted to patients whose moderate to severe pain is considered to require a combination of tramadol hydrochloride 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 effervescent tablets of Tramacet (equivalent to 75 mg tramadol hydrochloride and 650 mg paracetamol) is recommended. Additional doses can be taken as needed, not exceeding 8 effervescent tablets (equivalent to 300 mg tramadol hydrochloride and 2600 mg paracetamol) per day.

The dosing interval should not be less than six hours. 4). If repeated use or long term treatment with Tramacet 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 Tramacet has not been established in children below the age of 12 years. Treatment is therefore not recommended in this population. Older people A dose adjustment is not usually necessary in patients up to 75 years without clinically manifest hepatic or renal insufficiency.

In elderly patients 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. 4). 3). Method of administration Oral use Effervescent tablets should be taken dissolved in a glass of drinking water.

Treatment goals and discontinuation Before initiating treatment with Tramacet, 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.

4).

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: arrhythmia, tachycardia, palpitations. Eye disorders: • Rare: vision blurred, miosis, mydriasis Ear and labyrinth disorders: • Uncommon: tinnitus Gastrointestinal 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. Nervous system disorders: • Very common: somnolence, dizziness • Common: headache, trembling • Uncommon: muscular contractions involuntary, paraesthesia, amnesia • Rare: convulsions, ataxia, 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 disorder (dysuria and urinary retention). rash, urticaria). Vascular disorders: • Uncommon: hypertension, hot flush Drug dependence Repeated use of Tramacet can lead to drug dependence, even at therapeutic doses.

4). Although not observed during clinical trials, the occurrence of the following undesirable effects known to be related to the administration of tramadol hydrochloride or paracetamol cannot be excluded: Tramadol hydrochloride • Postural hypotension, bradycardia, collapse.

• Post-marketing surveillance of tramadol hydrochloride has revealed rare alterations of warfarin effect, including elevation of prothrombin times. 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 hydrochloride which vary individually in intensity and nature (depending on personality and duration of medication).

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: not known (cannot be estimated from the available data): high anion gap metabolic acidosis. 4). Pyroglutamic acidosis may occur as a consequence of low glutathione levels in these patients. 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. uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Warnings: - In adults and adolescents 12 years and older. The maximum dose of 8 tablets of Tramacet 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), Tramacet is not recommended. 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, Tramacet is not recommended. - Tramadol hydrochloride is not suitable as a substitute in opioid-dependent patients. Although it is an opioid agonist, tramadol hydrochloride cannot suppress morphine withdrawal symptoms.

- Convulsions have been reported in tramadol hydrochloride-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 Tramacet only if there are compelling circumstances. Convulsions have been reported in patients receiving tramadol hydrochloride at the recommended dose levels.

The risk may be increased when doses of tramadol hydrochloride exceed the recommended upper dose limit. 5). Sleep-related breathing disorders 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. 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.

9% 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. Adrenal insufficiency Opioid analgesics may occasionally cause reversible adrenal insufficiency requiring monitoring and glucocorticoid replacement therapy. 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 Tramacet 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 Tramacet concomitantly with sedative medicines, the lowest effective dose should be used, and the duration of the concomitant treatment should be as short as possible.

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