Lomotil

LOMOTIL — diphenoxylate hydrochloride and atropine sulfate tablet
Physicians Total Care, Inc.

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:

image of chemical structure for diphenoxylate hcl
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:
image of chemical structure for atropine sulfate
(click image for full-size original)

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.

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.

Lomotil Indications and Usage

Lomotil is effective as adjunctive therapy in the management of diarrhea.

CONTRAINDICATIONS

Lomotil is contraindicated in patients with

  1. Known hypersensitivity to diphenoxylate or atropine.
  2. Obstructive jaundice.
  3. Diarrhea associated with pseudomembranous enterocolitis or enterotoxin-producing bacteria.

WARNINGS

LOMOTIL IS NOT AN INNOCUOUS DRUG AND DOSAGE RECOMMENDATIONS SHOULD BE STRICTLY ADHERED TO, ESPECIALLY IN CHILDREN. LOMOTIL IS NOT RECOMMENDED FOR CHILDREN UNDER 2 YEARS OF AGE. OVERDOSAGE MAY RESULT IN SEVERE RESPIRATORY DEPRESSION AND COMA, POSSIBLY LEADING TO PERMANENT BRAIN DAMAGE OR DEATH (SEE OVERDOSAGE). THEREFORE, KEEP THIS MEDICATION OUT OF THE REACH OF CHILDREN.

THE USE OF LOMOTIL SHOULD BE ACCOMPANIED BY APPROPRIATE FLUID AND ELECTROLYTE THERAPY, WHEN INDICATED. IF SEVERE DEHYDRATION OR ELECTROLYTE IMBALANCE IS PRESENT, LOMOTIL SHOULD BE WITHHELD UNTIL APPROPRIATE CORRECTIVE THERAPY HAS BEEN INITIATED. DRUG-INDUCED INHIBITION OF PERISTALSIS MAY RESULT IN FLUID RETENTION IN THE INTESTINE, WHICH MAY FURTHER AGGRAVATE DEHYDRATION AND ELECTROLYTE IMBALANCE.

LOMOTIL SHOULD BE USED WITH SPECIAL CAUTION IN YOUNG CHILDREN BECAUSE THIS AGE GROUP MAY BE PREDISPOSED TO DELAYED DIPHENOXYLATE TOXICITY AND BECAUSE OF THE GREATER VARIABILITY OF RESPONSE IN THIS AGE GROUP.

Antiperistaltic agents may prolong and/or worsen diarrhea associated with organisms that penetrate the intestinal mucosa (toxigenic E. coli, Salmonella, Shigella), and pseudomembranous enterocolitis associated with broad-spectrum antibiotics. Antiperistaltic agents should not be used in these conditions.

In some patients with acute ulcerative colitis, agents that inhibit intestinal motility or prolong intestinal transit time have been reported to induce toxic megacolon. Consequently, patients with acute ulcerative colitis should be carefully observed and Lomotil therapy should be discontinued promptly if abdominal distention occurs or if other untoward symptoms develop.

Since the chemical structure of diphenoxylate hydrochloride is similar to that of meperidine hydrochloride, the concurrent use of Lomotil with monoamine oxidase (MAO) inhibitors may, in theory, precipitate hypertensive crisis.

Lomotil should be used with extreme caution in patients with advanced hepatorenal disease and in all patients with abnormal liver function since hepatic coma may be precipitated.

Diphenoxylate hydrochloride may potentiate the action of barbiturates, tranquilizers, and alcohol. Therefore, the patient should be closely observed when any of these are used concomitantly.

PRECAUTIONS

General

Since a subtherapeutic dose of atropine has been added to the diphenoxylate hydrochloride, consideration should be given to the precautions relating to the use of atropine. In children, Lomotil should be used with caution since signs of atropinism may occur even with recommended doses, particularly in patients with Down’s syndrome.

Information For Patients

INFORM THE PATIENT (PARENT OR GUARDIAN) NOT TO EXCEED THE RECOMMENDED DOSAGE AND TO KEEP LOMOTIL OUT OF THE REACH OF CHILDREN AND IN A CHILD-RESISTANT CONTAINER. INFORM THE PATIENT OF THE CONSEQUENCES OF OVERDOSAGE, INCLUDING SEVERE RESPIRATORY DEPRESSION AND COMA, POSSIBLY LEADING TO PERMANENT BRAIN DAMAGE OR DEATH. Lomotil may produce drowsiness or dizziness. The patient should be cautioned regarding activities requiring mental alertness, such as driving or operating dangerous machinery. Potentiation of the action of alcohol, barbiturates, and tranquilizers with concomitant use of Lomotil should be explained to the patient. The physician should also provide the patient with other information in this labeling, as appropriate.

Drug Interactions

Known drug interactions include barbiturates, tranquilizers, and alcohol. Lomotil may interact with MAO inhibitors (see Warnings).

In studies with male rats, diphenoxylate hydrochloride was found to inhibit the hepatic microsomal enzyme system at a dose of 2 mg/kg/day. Therefore, diphenoxylate has the potential to prolong the biological half-lives of drugs for which the rate of elimination is dependent on the microsomal drug metabolizing enzyme system.

Carcinogenesis, Mutagenesis, Impairment Of Fertility

No long-term study in animals has been performed to evaluate carcinogenic potential. Diphenoxylate hydrochloride was administered to male and female rats in their diets to provide dose levels of 4 and 20 mg/kg/day throughout a three-litter reproduction study. At 50 times the human dose (20 mg/kg/day), female weight gain was reduced and there was a marked effect on fertility as only 4 of 27 females became pregnant in three test breedings. The relevance of this finding to usage of Lomotil in humans is unknown.

Pregnancy

Pregnancy Category C. Diphenoxylate hydrochloride has been shown to have an effect on fertility in rats when given in doses 50 times the human dose (see above discussion). Other findings in this study include a decrease in maternal weight gain of 30% at 20 mg/kg/day and of 10% at 4 mg/kg/day. At 10 times the human dose (4 mg/kg/day), average litter size was slightly reduced.

Teratology studies were conducted in rats, rabbits, and mice with diphenoxylate hydrochloride at oral doses of 0.4 to 20 mg/kg/day. Due to experimental design and small numbers of litters, embryotoxic, fetotoxic, or teratogenic effects cannot be adequately assessed. However, examination of the available fetuses did not reveal any indication of teratogenicity.

There are no adequate and well-controlled studies in pregnant women. Lomotil should be used during pregnancy only if the anticipated benefit justifies the potential risk to the fetus.

Nursing Mothers

Caution should be exercised when Lomotil is administered to a nursing woman, since the physicochemical characteristics of the major metabolite, diphenoxylic acid, are such that it may be excreted in breast milk and since it is known that atropine is excreted in breast milk.

Pediatric Use

Lomotil may be used as an adjunct to the treatment of diarrhea but should be accompanied by appropriate fluid and electrolyte therapy, if needed. LOMOTIL IS NOT RECOMMENDED FOR CHILDREN UNDER 2 YEARS OF AGE. Lomotil should be used with special caution in young children because of the greater variability of response in this age group. See Warnings and Dosage and Administration. In case of accidental ingestion by children, see Overdosage for recommended treatment.

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