Tramadol and Dexketoprofen

The initial total daily dosage should be reduced to 150 mg of hydrochloride and 50 mg of dexketoprofen in patients with mildly impaired renal function (creatinine clearance 60-89 ml/min).

Patients with mild to moderate hepatic impairment should start therapy at reduced number of doses (total daily dose 150 mg of tramadol and 50 mg of dexketoprofen) and be closely monitored.

No cases of pregnancy occurred during the tramadol/dexketoprofen clinical development. The safety profile of tramadol/dexketoprofen during pregnancy has not been established in the clinical studies included in this section. Data reported for dexketoprofen and tramadol as single agents should be taken into account.

Dexketoprofen

Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the embryo/foetal development. Data from epidemiological studies raise concern about an increased risk of miscarriage and of cardiac malformation and gastroschisis after use of a prostaglandin synthesis inhibitor in early pregnancy. The absolute risk for cardiovascular malformation was increased from less than 1%, up to approximately 1.5%. The risk is believed to increase with dose and duration of therapy. In animals, administration of a prostaglandin synthesis inhibitor has been shown to result in increased pre- and post-implantation loss and embryo-foetal lethality. In addition, increased incidences of various malformations including cardiovascular, have been reported in animals given a prostaglandin synthesis inhibitor during the organogenetic period. Nevertheless, animal studies with dexketoprofen haven't shown reproductive toxicity. From the 20th week of pregnancy onward, dexketoprofen use may cause oligohydramnios resulting from foetal renal dysfunction. This may occur shortly after treatment initiation and is usually reversible upon discontinuation. In addition, there have been reports of ductus arteriosus constriction following treatment in the second trimester, most of which resolved after treatment cessation.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose the foetus to:

• cardiopulmonary toxicity (premature constriction/closure of the ductus arteriosus and pulmonary hypertension);
• renal dysfunction (see above);

At the end of pregnancy, the mother and the neonate may be exposed to:

• possible prolongation of bleeding time, an anti-platelet effect which may occur even at very low doses;
• inhibition of uterine contractions resulting in delayed or prolonged labour.

Tramadol

Animal studies with tramadol revealed at very high doses effects on organ development, ossification and neonatal mortality. Teratogenic effects were not observed. Tramadol crosses the placenta. There is inadequate evidence available on the safety of tramadol in human pregnancy.

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. Chronic use during pregnancy may lead to neonatal withdrawal symptoms.

Considering the above tramadol/dexketoprofen is contraindicated in pregnancy.

No controlled trials have been conducted to study the excretion of tramadol/dexketoprofen in human milk. Data reported for dexketoprofen and tramadol as single agents should be taken into account.

Dexketoprofen

It is not known whether dexketoprofen is excreted in human milk.

Tramadol

Tramadol and its metabolites are found in small amounts in human breast milk.

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.Considering the above tramadol/dexketoprofen is contraindicated during breastfeeding.

Fertility

As with other NSAIDs, the use of dexketoprofen may impair female fertility and is not recommended in women attempting to conceive. In women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of dexketoprofen should be considered.

The effects known for the single components apply to the fixed combination.

Dexketoprofen

Dexketoprofen has minor or moderate influence on the ability to drive and use machines, due to possible occurrence of dizziness or somnolence.

Tramadol

Even when taken according to instructions, tramadol may cause effects such as somnolence and dizziness and therefore may impair the reactions of drivers and machine operators.

This applies particularly in conjunction with other psychotropic substances and alcohol.

The adverse events at least possibly related reported in the clinical trials performed with tramadol/dexketoprofen and the adverse reactions reported in dexketoprofen and tramadol oral formulations SmPCs are tabulated below, classified by system organ class.

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, Not known: cannot be estimated from the available data.

Dexketoprofen-tramadol

In clinical studies the most commonly observed adverse reactions were vomiting, nausea and dizziness (2.9%, 2.7% and 1.1% of patients, respectively).

Dexketoprofen

Gastrointestinal: The most commonly-observed adverse events are gastrointestinal in nature. Peptic ulcers, perforation or gastrointestinal bleeding, sometimes fatal, particularly in the elderly, may occur. Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn's disease have been reported following administration. Less frequently, gastritis has been observed. Oedema, hypertension and cardiac failure have been reported in association with NSAIDs treatment.

As with other NSAIDs the following undesirable effects may appear: aseptic meningitis, which might predominantly occur in patients with systemic lupus erythematosus or mixed connective tissue disease; haematological reactions (purpura, aplastic and haemolytic anaemia, and rarely agranulocytosis and medullar hypoplasia).

Bullous reactions including Stevens Johnson Syndrome and Toxic Epidermal Necrolysis (very rare).

Clinical trial and epidemiological data suggest that use of some NSAIDs (particularly at high doses and in long term treatment) may be associated with a small increase in the risk of arterial thrombotic events (for example myocardial infarction or stroke).

Tramadol

The most commonly reported adverse reactions due to tramadol are nausea and dizziness, both occurring in more than 10% of patients.

If the recommended doses are considerably exceeded and other centrally depressant substances are administered concomitantly respiratory depression may occur.

Worsening of asthma has been reported, though a causal relationship has not been established.

Epileptiform convulsions occurred mainly after administration of high doses of tramadol or after concomitant treatment with drugs, which can lower the seizure threshold or themselves induce cerebral convulsions.

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 with tramadol discontinuation include: panic attacks, severe anxiety, hallucinations, paraesthesias, tinnitus, and unusual CNS symptoms (i.e. confusion, delusions, depersonalisation, derealisation, paranoia).