Each capsule contains: Tramadol Hydrochloride Ph. Eur. 50 mg, Excipients q.s.
Source of Gelatin: Bovine.
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.
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.
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.
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.
Management (treatment and prevention) of moderate to severe pain
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.
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.
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.