Tramadol and Paracetamol

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.

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.

In severe respiratory insufficiency, tramadol/paracetamol is not recommended.

Since tramadol/paracetamol 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.

Since tramadol/paracetamol 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/paracetamol. Discontinuation of breast-feeding is generally not necessary following a single dose of tramadol/paracetamol.

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.