COMPOSITION

Each capsule contains: Tramadol Hydrochloride Ph. Eur. 50 mg, Excipients q.s.

Source of Gelatin: Bovine.

DESCRIPTION

Domadol® is a centrally acting analgesic. The chemical name for tramadol hydrochloride is (±)cis-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl) cyclohexanol hydrochloride.

The molecular weight of tramadol hydrochloride is 299.8.

Domadol® is available as a hard gelatin capsule of size '2', with red body and black cap DOMADOL printed in white on body and cap, and containing white powder.

PHARMACODYNAMICS

Domadol® is a centrally acting synthetic opioid analgesic. Its mode of action involves at least two complementary mechanisms: binding of parent and M1 metabolite to µ-opioid receptors and weak inhibition of reuptake of norepinephrine and serotonin.

Opioid activity is due to both low affinity binding of the parent compound and higher affinity binding of the O-demethylated metabolite M1 to µ-opioid receptors. M1 is up to 6 times more potent than tramadol in producing analgesia and 200 times more potent in µ-opioid binding. Tramadol-induced analgesia is only partially antagonized by the opiate antagonist naloxone. The relative contribution of both tramadol and M1 to human analgesia is dependent upon the plasma concentrations of each compound.

Tramadol has been shown to inhibit reuptake of norepinephrine and serotonin, as have some other opioid analgesics. These mechanisms may contribute independently to the overall analgesic profile of Domadol. Analgesia in humans begins approximately within one hour after administration and reaches a peak in approximately two to three hours.

PHARMACOKINETICS

Tramadol is well absorbed orally with an absolute bioavailability of 75%. Tramadol has a volume of distribution of approximately 2.7L/kg and is only 20% bound to plasma proteins. Tramadol is extensively metabolized by a number of pathways, including CYP2D6 and CYP3A4, as well as by conjugation of parent and metabolites. One metabolite, M1, is pharmacologically active. The formation of M1 is dependent upon CYP2D6 and as such is subject to inhibition, which may affect the therapeutic response. Tramadol and its metabolites are excreted primarily in the urine with observed plasma half-lives of 6.3 and 7.4 hours for tramadol and M1, respectively. Linear pharmacokinetics have been observed following multiple doses of 50 and 100 mg to steady-state.

Absorption: Tramadol is rapidly and almost completely absorbed after oral administration. The mean peak plasma concentration of tramadol and M1 occurs at two and three hours, respectively, after administration in healthy adults. Steady-state plasma concentrations of both tramadol and M1 are achieved within two days with q.i.d. dosing. There is no evidence of self-induction.

Food Effects: Oral administration of tramadol with food does not significantly affect its rate or extent of absorption, therefore, Domadol® can be administered without regard to food.

Distribution: The binding of tramadol to human plasma proteins is approximately 20% and binding also appears to be independent of concentration up to 10 µg/mL. Saturation of plasma protein binding occurs only at concentrations outside the clinically relevant range.

Metabolism: Tramadol is extensively metabolized after oral administration. Approximately 30% of the dose is excreted in the urine as unchanged drug, whereas 60% of the dose is excreted as metabolites. The remainder is excreted either as unidentified or as unextractable metabolites. The major metabolic pathways appear to be N- and O- demethylation and glucuronidation or sulfation in the liver. One metabolite (O-desmethyltramadol, denoted M1) is pharmacologically active. Formation of M1 is dependent on CYP2D6 and as such is subject to inhibition, which may affect the therapeutic response.

Elimination: Tramadol is eliminated primarily through metabolism by the liver and the metabolites are eliminated primarily by the kidneys. The mean terminal plasma elimination half-lives of tramadol and M1 are 6.3 ± 1.4 and 7.4 ± 1.4 hours, respectively. The plasma elimination half-life of tramadol increased from approximately six hours to seven hours upon multiple dosing.

Special Populations

Renal: Impaired renal function results in a decreased rate and extent of excretion of tramadol and its active metabolite, M1. In patients with creatinine clearances of less than 30 mL/min, adjustment of the dosing regimen is recommended. The total amount of tramadol and M1 removed during a 4-hour dialysis period is less than 7% of the administered dose.

Hepatic: Metabolism of tramadol and M1 is reduced in patients with advanced cirrhosis of the liver, resulting in both a larger area under the concentration time curve for tramadol and longer tramadol and M1 elimination half-lives (13 hrs. for tramadol and 19 hrs. for M1). In cirrhotic patients, adjustment of the dosing regimen is recommended.

Geriatric: Healthy elderly subjects aged 65 to 75 years have plasma tramadol concentrations and elimination half-lives comparable to those observed in healthy subjects less than 65 years of age. In subjects over 75 years, maximum serum concentrations are elevated (208 vs. 162 ng/mL) and the elimination half-life is prolonged (7vs.6 hours) compared to subjects 65 to 75 years of age. Adjustment of the daily dose is recommended for patients older than 75 years.

INDICATIONS

Management (treatment and prevention) of moderate to severe pain

CONTRAINDICATIONS

Domadol® should not be administered to patients who have previously demonstrated hypersensitivity to it or in cases of acute intoxication with alcohol, hypnotics, centrally active analgesics, opioids or psychotropic drugs. In common with other opioid analgesics it should not be administered to patients who are receiving monoamine oxidase inhibitors (MAOI) or within two weeks of their withdrawal.

WARNINGS

At therapeutic doses, Domadol® has the potential to cause withdrawal symptoms. Rarely cases of dependence and abuse have been reported. At such doses, withdrawal symptoms have been reported at a reporting frequency of 1 in 8,000. Reports of dependence and abuse have been less frequent. Because of this potential, the clinical need for continued analgesic treatment should be reviewed regularly.

In patients with a tendency of drug abuse or dependence, treatment with Domadol® should be for short periods and under strict medical supervision. Domadol® is not suitable as a substitute in opioid-dependent patients. Although it is an opioid agonist, Domadol® cannot suppress morphine withdrawal symptoms.

PRECAUTIONS

Domadol® should be used with caution in patients with head injury, increased intracranial pressure, severe impairment of renal and hepatic function and in patients prone to convulsive disorders or in shock.

Convulsions have been reported at therapeutic doses and the risk may be increased at doses exceeding the usual upper daily dose limit. Patients with a history of epilepsy or those susceptible to seizures should only be treated with Domadol® if there are compelling reasons. The risk of convulsions may increase in patients taking Domadol® and concomitant medication that can lower the seizure threshold.

Care should be taken when treating patients with respiratory depression, or if concomitant CNS depressant drugs are being administered, as the possibility of respiratory depression cannot be excluded in these situations. At therapeutic doses, respiratory depression has infrequently been reported.

Domadol® use during potentially very light planes of general anaesthesia should be avoided. When the current practice of administering continuous, potent (volatile or intravenous) anaesthetic agents is followed, Domadol® may be used intraoperatively in the same way as other analgesic agents are routinely used.

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