DESCRIPTION
Each Lomotil tablet and each 5 ml of Lomotil liquid for oral use
contains:
diphenoxylate hydrochloride 2.5 mg
atropine sulfate................. 0.025 mg
Diphenoxylate hydrochloride, an antidiarrheal, is ethyl
1-(3-cyano-3,3-diphenylpropyl)-4-phenylisonipecotate monohydrochloride and has
the following structural formula:
Atropine sulfate, an anticholinergic, is endo-(±)-α-(hydroxymethyl)
benzeneacetic acid 8-methyl-8-azabicyclo[3.2.1] oct-3-yl ester sulfate (2:1)
(salt) monohydrate and has the following structural formula:A subtherapeutic amount of atropine sulfate is present to discourage
deliberate overdosage.
Inactive ingredients of Lomotil tablets include acacia, corn starch,
magnesium stearate, sorbitol, sucrose, and talc. Inactive ingredients of Lomotil
liquid include cherry flavor, citric acid, ethyl alcohol 15%, glycerin, sodium phosphate, sorbitol, and water.
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CLINICAL PHARMACOLOGY
Diphenoxylate is rapidly and extensively metabolized in man by
ester hydrolysis to diphenoxylic acid (difenoxine), which is biologically active
and the major metabolite in the blood. After a 5-mg oral dose of carbon-14
labeled diphenoxylate hydrochloride in ethanolic solution was given to three
healthy volunteers, an average of 14% of the drug plus its metabolites was
excreted in the urine and 49% in the feces over a four-day period. Urinary
excretion of the unmetabolized drug constituted less than 1% of the dose, and
diphenoxylic acid plus its glucuronide conjugate constituted about 6% of the
dose. In a 16-subject crossover bioavailability study, a linear relationship in
the dose range of 2.5 to 10 mg was found between the dose of diphenoxylate
hydrochloride (given as Lomotil liquid) and the peak plasma concentration, the
area under the plasma concentration-time curve, and the amount of diphenoxylic
acid excreted in the urine. In the same study the bioavailability of the tablet
compared with an equal dose of the liquid was approximately 90%. The average
peak plasma concentration of diphenoxylic acid following ingestion of four
2.5-mg tablets was 163 ng/ml at about 2 hours, and the elimination half-life of
diphenoxylic acid was approximately 12 to 14 hours.
In dogs, diphenoxylate hydrochloride has a direct effect on circular smooth
muscle of the bowel that conceivably results in segmentation and prolongation of
gastrointestinal transit time. The clinical antidiarrheal action of
diphenoxylate hydrochloride may thus be a consequence of enhanced segmentation
that allows increased contact of the intraluminal contents with the intestinal
mucosa.
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