• Serotonin Syndrome is likely when one of the following is observed:

o Spontaneous clonus

o Inducible or ocular clonus with agitation or diaphoresis ,

o Tremor and hyperreflexia

o Hypertonia and body temperature > 38 °C and inducible or ocular clonus.

Withdrawal of the serotonergic drugs usually brings about a rapid improvement. Treatment depends on the type and severity of the symptoms.

• 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.

• As medically appropriate, periodic eva luation of prothrombin time should be performed when Tramadol hydrochloride/Paracetamol 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.

4.6 Fertility, pregnancy and lactation
Pregnancy

Since this medicine is a fixed combination of active ingredients including tramadol, it should not be used during pregnancy.

• Data regarding paracetamol:

Epidemiological studies in human pregnancy have shown no ill effects due to paracetamol used in the recommended dosages.

• Data regarding tramadol:

Tramadol should not be used during pregnancy as 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 this medicine is a fixed combination of active ingredients including tramadol, it should not be ingested during breast feeding.

• Data regarding paracetamol:

Paracetamol is excreted in breast milk but not in a clinically significant amount. Available published data do not contraindicate breast feeding by women using single ingredient medicinal products containing only paracetamol.

• 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 followin