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DESCRIPTION
Ultram®
(tramadol hydrochloride tablets) 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. Tramadol
hydrochloride is a white, bitter, crystalline and odorless powder. It is
readily soluble in water and ethanol and has a pKa of 9.41. The
water/n-octanol partition coefficient is 1.35 at pH 7. Ultram tablets
contain 50 mg of tramadol hydrochloride and are white in color. Inactive
ingredients in the tablet are corn starch, hydroxypropyl methylcellulose,
lactose, magnesium stearate, microcrystalline cellulose, polyethylene
glycol, polysorbate 80, sodium starch glycolate, titanium dioxide and
wax.
CLINICAL PHARMACOLOGY
Pharmacodynamics
Ultram is a centrally acting synthetic analgesic compound. Although
its mode of action is not completely understood, from animal tests, at
least two complementary mechanisms appear applicable: 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. In animal
models, M1 is up to 6 times more potent than tramadol in producing
Tramadol HCL Tablets 50 Mg Scored
NDA 20-281/S-016
Proposed Package Insert
analgesia and 200 times more potent in µ
-opioid binding. Tramadol-induced analgesia is only partially antagonized by the opiate antagonist
naloxone in several animal tests. The relative contribution of both
tramadol and M1 to human analgesia is dependent upon the plasma
concentrations of each compound (see CLINICAL PHARMACOLOGY,
Pharmacokinetics).
Tramadol has been shown to inhibit reuptake of norepinephrine and
serotonin in vitro, as have some other opioid analgesics. These
mechanisms may contribute independently to the overall analgesic
profile of Ultram. Analgesia in humans begins approximately within
one hour after administration and reaches a peak in approximately two
to three hours.
Apart from analgesia, Ultram administration may produce a
constellation of symptoms (including dizziness, somnolence, nausea,
constipation, sweating and pruritus) similar to that of an opioid.
However, tramadol causes less respiratory depression than morphine
at recommended doses (see OVERDOSAGE).
In contrast to
morphine, tramadol has not been shown to cause histamine release. At
therapeutic doses, Ultram has no effect on heart rate, left-ventricular
function or cardiac index. Orthostatic hypotension has been observed.
Pharmacokinetics
The analgesic activity of Ultram is due to both parent drug and the M1
metabolite (see CLINICAL PHARMACOLOGY, Pharmacodynamics).
Tramadol is administered as a racemate and both the [-] and [+] forms
of both tramadol and M1 are detected in the circulation. 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 in animal models. The formation of M1 is
Proposed Package Insert
dependent upon Cytochrome P-45O(2D6) and as such is subject to
both metabolic induction and inhibition which may affect the therapeutic
response (see PRECAUTIONS - Drug Interactions). 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:
Racemic tramadol is rapidly and almost completely absorbed after oral
administration. The mean absolute bioavailability of a 100 mg oral dose
is approximately 75%. The mean peak plasma concentration of
racemic tramadol and M1 occurs at two and three hours, respectively,
after administration in healthy adults. In general, both enantiomers of
tramadol and M1 follow a parallel time course in the body following
single and multiple doses although small differences ( 10%) exist in the
absolute amount of each enantiomer present.
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 (see Figure 1 and Table 1 below). |