Source: Registered Drug Product Database (NG) Revision Year: 2022 Publisher: Exphar s.a., Zoning Industriel de Nivelles Sud, zone II, Av. Thomas Edison 105, 1402 Thines (Belgium), Phone +32 (0)67 68 84 05, Fax +32 (0)67 68 84 19 Manufacturer: Gracure Pharmaceuticals Ltd., E-1105, RIICO Industrial Area, Phase-III, Bhiwadi, Dist. Alwar (Raj.) INDIA, Phone: +91 1493 221316, Fax: +91 1493 220659
Pharmacotherapeutic group: Other opioids; Tramadol in combination
ATC code: N02AJ13
Tramadol is an opioid analgesic that acts on the central nervous system. Tramadol is pure non selective agonists of the μ, δ, and κ opioid receptors with a higher affinity for the μ receptors. Other mechanisms which contribute to its analgesic effect are inhibition of neuronal reuptake of noradrenaline and enhancement of serotonin release. Tramadol has an antitussive effect. Unlike morphine, a broad range of analgesic doses of tramadol has no respiratory depressant effect. Similarly, the gastro-intestinal motility is not influenced. The cardiovascular effects are generally slight. The potency of tramadol is considered to be one-tenth to one-sixth that of morphine.
The precise mechanism of the analgesic properties of paracetamol remains unknown and may involve central and peripheral effects.
ANTALGEX T is positioned as a step II analgesic in the WHO pain ladder and should be used accordingly by the physician.
Tramadol hydrochloride is administered in racemic form and the [-] and [ + ] forms of tramadol and its metabolite M1, are detected in the blood. Although tramadol is rapidly absorbed after administration, its absorption is slower (and its half-life longer) than that of paracetamol. After a single oral administration of a tramadol hydrochloride/paracetamol (37.5 mg/325 mg), mean peak plasma concentrations of 64.3/55.5 ng/ml [( + )-tramadol/( - )-tramadol] and 4.2 μg/ml for paracetamol are reached after 1.8 h [( + )-tramadol/( - )-tramadol] and 0.9 h (paracetamol), respectively. The mean elimination half-lives (t1/2) are 5.1/4.7 h for racemic tramadol and 2.5 h for paracetamol.
During pharmacokinetic studies in healthy volunteers after single and repeated oral administration of tramadol/paracetamol, no clinical significant change was observed in the kinetic parameters of each active ingredient compared to the parameters of the active ingredients used alone.
Racemic tramadol is rapidly and almost completely absorbed after oral administration. The mean absolute bioavailability of a single 100 mg dose is approximately 75%. After repeated administration, the bioavailability is increased and reaches approximately 90%.
After administration of ANTALGEX T, the oral absorption of paracetamol is rapid and nearly complete and takes place mainly in the small intestine. Peak plasma concentrations of paracetamol are reached in one hour and are not modified by concomitant administration of tramadol.
The oral administration of ANTALGEX T with food has no significant effect on the peak plasma concentration or extent of absorption of either tramadol or paracetamol so that ANTALGEX T can be taken independently of meal times.
Tramadol has a high tissue affinity (Vd,β=203 ± 40 liters). It has a plasma protein binding of about 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 relative small portion (about 20%) of paracetamol is bound to plasma proteins.
Tramadol is extensively metabolized after oral administration. About 30% of the dose is excreted in urine as unchanged drug, whereas 60% of the dose is excreted as metabolites.
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. The plasma elimination half-life of M1 is 7 hours. The metabolite M1 has analgesic properties and is more potent than the parent drug. The plasma concentrations of M1 are several-fold lower than those of tramadol and the contribution to the clinical effect are unlikely to change on multiple dosing.
Paracetamol is principally metabolized in the liver through two major hepatic routes: glucuronidation and sulphation. The second 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 benzoquinone imine) 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 toxic metabolite is increased.
Tramadol and its metabolites are eliminated mainly by the kidneys. The half-life of paracetamol is approximately 2 to 3 hours in adults. It is shorter in children and slightly longer in the newborn and in cirrhotic patients. Paracetamol is mainly eliminated by dose-dependent formation of glucuro- and sulpho-conjugate derivatives. Less than 9% of paracetamol is excreted unchanged in urine.
In renal insufficiency, the half-life of both compounds is prolonged.
Conventional studies using the currently accepted standards for the evaluation of toxicity to reproduction and development are not available.
No preclinical study has been performed with the fixed combination (tramadol and paracetamol) to evaluate its carcinogenic or mutagenic effects or its effects on fertility.
No teratogenic effect that can be attributed to the medicine has been observed in the offspring of rats treated orally with the combination tramadol/paracetamol.
The combination tramadol/paracetamol has proven to be embryotoxic and foetotoxic in the rat at materno-toxic dose (50/434 mg/kg tramadol hydrochloride/paracetamol), i.e., 8.3 times the maximum therapeutic dose in human. No teratogenic effect has been observed at this dose. The toxicity to the embryo and the foetus results in a decreased foetal weight and an increase in supernumerary ribs. Lower doses, causing less severe materno-toxic effect (10/87 and 25/217 mg/kg tramadol/paracetamol) did not result in toxic effects in the embryo or the foetus.
Results of standard mutagenicity tests did not reveal a potential genotoxic risk for tramadol hydrochloride in man. Results of carcinogenicity tests do not suggest a potential risk of tramadol for human.
Animal studies with tramadol revealed, at very high doses, effects on organ development, ossification and neonatal mortality, associated with maternotoxicity. Fertility reproductive performance and development of offspring were unaffected.
Tramadol crosses the placenta. Male and female fertility was not affected.
Extensive investigations showed no evidence of a relevant genotoxic risk of paracetamol at therapeutic (i.e. non-toxic) doses.
Long-term studies in rats and mice yielded no evidence of relevant tumorigenic effects at non-hepatotoxic dosages of paracetamol.
To this day, animal studies and extensive human experience to date yield no evidence of reproductive toxicity.
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