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Lomotil
®
Cv
(diphenoxylate hydrochloride and atropine sulfate tablets, USP)
Tablets
DESCRIPTION
Each Lomotil tablet 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.
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. 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.
INDICATIONS AND USAGE
Lomotil is indicated as adjunctive therapy in the management of diarrhea in patients 13 years of age and older.
CONTRAINDICATIONS
Lomotil is contraindicated in:
- Pediatric patients less than 6 years of age due to the risks of respiratory and central nervous system (CNS) depression (see WARNINGS ).
- Patients with diarrhea associated with pseudomembranous enterocolitis ( Clostridium difficile ) or other enterotoxin-producing bacteria due to the risk of gastrointestinal (GI) complications, including sepsis (see WARNINGS ).
- Patients with known hypersensitivity to diphenoxylate or atropine.
- Patients with obstructive jaundice.
WARNINGS
Respiratory and/or CNS Depression in Pediatric Patients Less Than 6 Years of Age Cases of severe respiratory depression and coma, leading to permanent brain damage or death have been reported in patients less than 6 years of age who received Lomotil_._ Lomotil is contraindicated in patients less than 6 years of age due to these risks (see CONTRAINDICATIONS ).
Anticholinergic and Opioid-Toxicities Toxicities associated with the atropine and diphenoxylate components of Lomotil have been reported. The initial presenting symptoms may be delayed by up to 30 hours due to prolonged gastric emptying time induced by diphenoxylate hydrochloride. Clinical presentations vary in terms of which toxicity (anticholinergic vs. opioid) will present first or predominate; non-specific findings have been reported and include symptoms such as
PRECAUTIONS
Atropinism Since a subtherapeutic dose of atropine has been added to Lomotil, consideration should be given to the development of adverse reactions associated with of atropine (see WARNINGS ).Lomotil has caused atropinism (hyperthermia, tachycardia, urinary retention, flushing, dryness of the skin and mucous membranes) particularly in pediatric patients with Down’s syndrome. Lomotil is not indicated for use in pediatric patients (see CONTRAINDICATIONS and WARNINGS ). Monitor patients for signs of atropinism.
Information for patients: Advise patients:
- Accidental ingestion of Lomotil in children, especially in those less than 6 years of age, may result in severe respiratory depression or coma. Instruct patients to take steps to store Lomotil securely and out of reach of children, and to dispose of unused Lomotil (see WARNINGS ).
- To take Lomotil at the prescribed dosage. Use of a higher than prescribed dosage may include opioid and/or anticholinergic effects (see OVERDOSAGE ). Report to a healthcare facility if they develop anticholinergic symptoms such as hyperthermia, flushing, tachycardia, tachypnea, hypotonia, lethargy, hallucinations, febrile convulsion, dry mouth, mydriasis or opioid symptoms such as progressive CNS and respiratory depression, miosis, seizures, or paralytic ileus.
- Lomotil may produce drowsiness or dizziness. Concomitant use of alcohol or other drugs that also cause CNS depression (e.g., barbiturates, benzodiazepines, opioids, buspirone, antihistamines, and muscle relaxants) may increase this effect. Inform patients not to operate motor vehicles or other dangerous machinery until they are reasonably certain that Lomotil does not affect them adversely.
- To use fluid and electrolyte therapy, if prescribed along with Lomotil, as instructed by their healthcare provider.
- Clinical improvement of diarrhea is usually observed within 48 hours. If clinical improvement is not seen within 10 days, discontinue Lomotil and contact their healthcare provider.
Drug interactions: Alcohol Alcohol may increase the CNS depressant effects of Lomotil and may cause drowsiness (see WARNINGS ). Avoid concomitant use of Lomotil with alcohol.
Other Drugs that Cause CNS Depression The concurrent use of Lomotil with other drugs that cause CNS depression (e.g., barbiturates, benzodiazepines, opioids, buspirone, antihistamines, muscle relaxants), may
potentiate the effects of Lomotil (see WARNINGS ). Either Lomotil or the other interacting drug should be chosen, depending on the importance of the drug to the patient. If CNS-acting drugs cannot be avoided, monitor patients for CNS adverse reactions.
MAO Inhibitors Diphenoxylate may interact with monoamine oxidase inhibitors (MAOIs) and precipitate a hypertensive crisis_._ Avoid use of Lomotil in patients who take MAOIs and monitor for signs and symptoms of hypertensive crisis (headache, hyperthermia, hypertension).
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: 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: The safety and effectiveness of Lomotil have been established in pediatric patients 13 years of age and older as adjunctive therapy in the management of diarrhea. The safety and effectiveness of Lomotil have not been established in pediatric patients less than 13 years of age.
Lomotil is contraindicated in pediatric patients less than 6 years of age due to the risks of severe respiratory depression and coma, possibly resulting in permanent brain damage or
hydrochloride is possible at high doses, the recommended dosage should not be exceeded.
OVERDOSAGE
Diagnosis: Overdosage can be life-threatening. Symptoms of overdosage may include opioid and/or anticholinergic effects including respiratory depression, coma, delirium, lethargy, dryness of the skin and mucous membranes, mydriasis or miosis, flushing, hyperthermia, tachycardia, hypotonia, tachypnea, toxic encephalopathy, seizures and incoherent speech. Respiratory depression has been reported up to 30 hours after ingestion and may recur despite an initial response to narcotic antagonists. Treat all possible Lomotil overdosages as serious and maintain medical observation/hospitalization until patients become asymptomatic without naloxone use.
Treatment: A pure narcotic antagonist (e.g., naloxone) should be used in the treatment of respiratory depression caused by Lomotil. Refer to the prescribing information for naloxone. Consider Lomotil toxicity even in settings of negative toxicology tests. Following initial improvement of respiratory function, repeated doses of naloxone hydrochloride may be required to counteract recurrent respiratory depression.
If over-exposure occurs, call your Poison Control Center at 1-800-222-1222 for current information on the management of poisoning or overdosage.
DOSAGE AND ADMINISTRATION
Management of Diarrhea in Patients 13 Years of Age and Older Lomotil is recommended as adjunctive therapy for the management of diarrhea in patients 13 years of age and older. Consider the nutritional status and degree of dehydration in patients prior to initiating therapy with Lomotil. The use of Lomotil should be accompanied by appropriate fluid and electrolyte therapy, when indicated. If severe dehydration or electrolyte imbalance is present, do not administer Lomotil until appropriate corrective therapy has been indicated (see WARNINGS ).
Initial and Maximum Recommended Dosage in Patients 13 Years of Age and Older The initial adult dosage is 2 Lomotil tablets four times daily (maximum total daily dose of 20 mg per day of diphenoxylate hydrochloride). Most patients will require this dosage until initial control of diarrhea has been achieved. Clinical improvement of acute diarrhea is usually observed within 48 hours.
Dosage after Initial Control of Diarrhea After initial control has been achieved, the Lomotil dosage may be reduced to meet individual requirements. Control may often be maintained with as little as two Lomotil tablets daily.
Duration of Treatment If clinical improvement of chronic diarrhea after treatment with the maximum recommended daily dosage is not observed within 10 days, discontinue Lomotil as symptoms are unlikely to be controlled by further administration.
HOW SUPPLIED
Tablets — round, white, with SEARLE debossed on one side and 61 on the other side and containing 2.5 mg of diphenoxylate hydrochloride and 0.025 mg of atropine sulfate, supplied as:
NDC Number 0025-0061-
Size bottle of 100
Store below 25°C (77°F).
This product’s label may have been updated. For current full prescribing information, please visit www.pfizer.com.
LAB-0065-2.
Revised October 2017
