TAMOLTRA Film coated tablet Ref.[115184] Active ingredients: Paracetamol Tramadol

Absorption

After oral administration tramadol is well absorbed, and peak activity is reached within 2 to 3 hours. Bioavailability can increase to up to 90% with multiple dosing. Peak plasma concentration of paracetamol after oral administration is within 1 hour. The absorption of paracetamol is not affected by the co-administration of tramadol.

The oral administration of tramadol/paracetamol with food has no significant effect on the peak plasma concentration or extent of absorption of either tramadol or paracetamol, so that tramadol/paracetamol can be taken independently of mealtimes.

Distribution

Tramadol has a high tissue affinity (V_d,β = 203 ± 40 L). It has a plasma protein binding is 20%.

Paracetamol appears to be widely distributed throughout most body tissues except fat. Its apparent volume of distribution is about 0.9 L/kg. A relatively small portion (~20%) of paracetamol is bound to plasma proteins.

Biotransformation

Tramadol and paracetamol are both extensively metabolised in the liver. Tramadol undergoes extensive hepatic metabolism by a number of pathways including CYP2D6 and CYP3A4, as well as conjugation (see section 4.5).

Tramadol is metabolised through O-demethylation (catalysed by the enzyme CYP2D6) to the metabolite M1, and through N-demethylation (catalysed by CYP3A) to the metabolite M2. M1 is further metabolised through N-demethylation and by conjugation with glucuronic acid. Plasma elimination half-lives of tramadol and the O-demethylated metabolite are about 6 and 7 hours respectively. The metabolite M1 has analgesic properties and is more potent than the parent medicine. The plasma concentrations of M1 are several-fold lower than those of tramadol and the contribution to the clinical effect is unlikely to change on multiple dosing.

Paracetamol is principally metabolised by the liver through two major hepatic routes: glucuronidation and sulphation. The latter route can be rapidly saturated at doses above the therapeutic doses. A small fraction (less than 4%) is metabolized by cytochrome P 450 to an active intermediate (the N-acetyl benzoquinoneimine) which, under normal conditions of use, is rapidly detoxified by reduced glutathione and excreted in urine after conjugation to cysteine and mercapturic acid. However, during massive overdose, the quantity of this metabolite is increased.

Elimination

Approximately 30% of tramadol is excreted unchanged in the urine. Tramadol and its metabolites are eliminated primarily by the kidneys. The plasma elimination half-lives of tramadol and its M1 metabolite are approximately 6 and 7 hours respectively.

Paracetamol is eliminated from the body primarily by formation of glucuronide and sulphate conjugates in a dose-dependent manner. The half-life of paracetamol is about 2-3 hours in adults. Less than 9% of paracetamol is excreted unchanged in the urine. Paracetamol is eliminated from the body primarily by formation of glucuronide and sulphate conjugates in a dose-dependent manner. The half-life of paracetamol is about 2-3 hours in adults. Less than 9% of paracetamol is excreted unchanged in the urine.

In renal insufficiency, the half-life of both compounds is prolonged.