Diphenoxylate Hcl and Atropine Sulfate

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Overview

What is Diphenoxylate Hcl and Atropine Sulfate?

Each tablet, for oral administration, contains:

Diphenoxylate Hydrochloride USP . . . . . . . . . . . 2.5 mg

Atropine Sulfate USP . . . . . . . . . . . . . . . . . . . . . 0.025 mg

In addition, each tablet, contains the following inactive ingredients: confectioner’s sugar, corn starch, lactose monohydrate, magnesium stearate and sodium starch glycolate.

Diphenoxylate hydrochloride, an antidiarrheal, is ethyl 1-(3-cyano-3,3-diphenylpropyl)-4-phenylisonipecotate monohydrochloride and has the following structural formula:

CHNO•HCl M.W. 489.06

Atropine sulfate, an anticholinergic, is Benzeneacetic acid,-(hydroxymethyl)-8-methyl-8-azabicyclol [3.2.1] oct-3-yl ester, -±, sulfate(2:1) (salt), monohydrate and has the following structural formula:

CHNO)•HSO•H20 M.W. 694.85

A subtherapeutic amount of atropine sulfate is present to discourage deliberate overdosage.

What does Diphenoxylate Hcl and Atropine Sulfate look like?

What are the available doses of Diphenoxylate Hcl and Atropine Sulfate?

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What should I talk to my health care provider before I take Diphenoxylate Hcl and Atropine Sulfate?

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How should I use Diphenoxylate Hcl and Atropine Sulfate?

Diphenoxylate hydrochloride and atropine sulfate tablets are effective as adjunctive therapy in the management of diarrhea

DO NOT EXCEED RECOMMENDED DOSAGE.

The recommended initial dosage is two tablets four times daily (20 mg per day). Most patients will require this dosage until initial control has been achieved, after which the dosage may be reduced to meet individual requirements. Control may often be maintained with as little as 5 mg (two tablets) daily.

Clinical improvement of acute diarrhea is usually observed within 48 hours. If clinical improvement of chronic diarrhea after treatment with a maximum daily dose of 20 mg of diphenoxylate hydrochloride is not observed within 10 days, symptoms are unlikely to be controlled by further administration.

Diphenoxylate HCl and atropine sulfate is not recommended in children under 2 years of age and should be used with special caution in young children (see WARNINGS and PRECAUTIONS). The nutritional status and degree of dehydration must be considered. In children under 13 years of age, use oral solution. Do not use tablets for this age group.

KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.

What interacts with Diphenoxylate Hcl and Atropine Sulfate?

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What are the warnings of Diphenoxylate Hcl and Atropine Sulfate?

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What are the precautions of Diphenoxylate Hcl and Atropine Sulfate?

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What are the side effects of Diphenoxylate Hcl and Atropine Sulfate?

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What should I look out for while using Diphenoxylate Hcl and Atropine Sulfate?

Diphenoxylate HCl and atropine sulfate tablets are contraindicated in patients with:

THIS IS AN INNOCUOUS DRUG AND DOSAGE RECOMMENDATIONS SHOULD BE STRICTLY ADHERED TO, ESPECIALLY IN CHILDREN. DIPHENOXYLATE HCl AND ATROPINE SULFATE 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 ). THEREFORE, KEEP THIS MEDICATION OUT OF THE REACH OF CHILDREN.

THE USE OF DIPHENOXYLATE HCl AND ATROPINE SULFATE SHOULD BE ACCOMPANIED BY APPROPRIATE FLUID AND ELECTROLYTE THERAPY, WHEN INDICATED. IF SEVERE DEHYDRATION OR ELECTROLYTE IMBALANCE IS PRESENT, THIS PRODUCT 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. DIPHENOXYLATE HCl AND ATROPINE SULFATE 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 ), and pseudomembranous enterocolitis associated with broad-spectrum antibiotics. Antipersistaltic 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 diphenoxylate HCl and atropine sulfate 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 this product with monoamine oxidase (MAO) inhibitors may, in theory, precipitate hypertensive crisis.

This product 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.

What might happen if I take too much Diphenoxylate Hcl and Atropine Sulfate?

RECOMMENDED DOSAGE SCHEDULES SHOULD BE STRICTLY FOLLOWED. THIS MEDICATION SHOULD BE KEPT IN A CHILD-RESISTANT CONTAINER AND OUT OF THE REACH OF CHILDREN, SINCE AN OVERDOSAGE MAY RESULT IN SEVERE, EVEN FATAL, RESPIRATORY DEPRESSION.

Initial signs of overdosage may include dryness of the skin and mucous membranes, mydriasis, restlessness, flushing, hyperthermia, and tachychardia followed by lethargy or coma, hypotonic reflexes, nystagmus, pinpoint pupils, and respiratory depression. Respiratory depression may be evidenced as late as 30 hours after ingestion and may recur in spite of an initial response to narcotic antagonists. TREAT ALL POSSIBLE DIPHENOXYLATE HCl AND ATROPINE SULFATE OVERDOSAGES AS SERIOUS AND MAINTAIN MEDICAL OBSERVATION FOR AT LEAST 48 HOURS, PREFERABLY UNDER CONTINUOUS HOSPITAL CARE.

In the event of overdosage, induction of vomiting, gastric lavage, establishment of a patent airway, and possibly mechanically assisted respiration are advised. and animal studies indicate that activated charcoal may significantly decrease the bioavailability of diphenoxylate. In noncomatose patients, a slurry of 100 g of activated charcoal can be administered immediately after the induction of vomiting or gastric lavage.

A pure narcotic antagonist (e.g., naloxone) should be used in the treatment of respiratory depression caused by diphenoxylate HCl and atropine sulfate. When a narcotic antagonist is administered intravenously, the onset of action is generally apparent within two minutes. It may also be administered subcutaneously or intramuscularly, providing a slightly less rapid onset of action but a more prolonged effect.

To counteract respiratory depression caused by diphenoxylate/atropine overdosage, the following dosage schedule for the narcotic antagonist naloxone hydrochloride should be followed:

An initial dose of 0.4 mg to 2 mg of naloxone hydrochloride may be administered intravenously. If the desired degree of counteraction and improvement in respiratory functions is not obtained, it may be repeated at 2 to 3 minute intervals. If no response is observed after 10 mg of naloxone hydrochloride has been administered, the diagnosis of narcotic-induced or partial narcotic-induced toxicity should be questioned. Intramuscular or subcutaneous administration may be necessary if the intravenous route is not available.

The usual initial dose in children is 0.01 mg/kg body weight given I.V. If this dose does not result in the desired degree of clinical improvement, a subsequent dose of 0.1 mg/kg body weight may be administered. If an I.V. route of administration is not available, naloxone hydrochloride may be administered I.M. or S.C. in divided doses. If necessary, naloxone hydrochloride can be diluted with sterile water for injection.

Following initial improvement of respiratory function, repeated doses of naloxone hydrochloride may be required to counteract recurrent respiratory depression. Supplemental intramuscular doses of naloxone hydrochloride may be utilized to produce a longer-lasting effect.

Since the duration of action of diphenoxylate hydrochloride, is longer than that of naloxone hydrochloride, improvement of respiration following administration may be followed by recurrent respiratory depression. Consequently, continuous observation is necessary until the effect of diphenoxylate hydrochloride on respiration has passed. This effect may persist for many hours. The period of observation should extend over at least 48 hours, preferably under continuous hospital care. Although signs of overdosage and respiratory depression may not be evident soon after ingestion of diphenoxylate hydrochloride, respiratory depression may occur from 12 to 30 hours later.

How should I store and handle Diphenoxylate Hcl and Atropine Sulfate?

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].Keep out of reach of children.Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].Keep out of reach of children.Diphenoxylate Hydrochloride and Atropine Sulfate Tablets USP are available as white, round tablets, debossed,3966 containing 2.5 mg diphenoxylate hydrochloride USP and 0.025 mg atropine sulfate USP, packaged in bottles of 100, 1000 and unit-dose boxes of 100 tablets.PHARMACIST: Dispense in a well-closed, light-resistant container as defined in the USP. Use child-resistant closure.Store at controlled room temperature 15°-30°C (59°-86°F) (See USP).MANUFACTURED BY 0172IVAX PHARMACEUTICALS, INC. 04/02MIAMI, FL 33137 B9Diphenoxylate Hydrochloride and Atropine Sulfate Tablets USP are available as white, round tablets, debossed,3966 containing 2.5 mg diphenoxylate hydrochloride USP and 0.025 mg atropine sulfate USP, packaged in bottles of 100, 1000 and unit-dose boxes of 100 tablets.PHARMACIST: Dispense in a well-closed, light-resistant container as defined in the USP. Use child-resistant closure.Store at controlled room temperature 15°-30°C (59°-86°F) (See USP).MANUFACTURED BY 0172IVAX PHARMACEUTICALS, INC. 04/02MIAMI, FL 33137 B9Diphenoxylate Hydrochloride and Atropine Sulfate Tablets USP are available as white, round tablets, debossed,3966 containing 2.5 mg diphenoxylate hydrochloride USP and 0.025 mg atropine sulfate USP, packaged in bottles of 100, 1000 and unit-dose boxes of 100 tablets.PHARMACIST: Dispense in a well-closed, light-resistant container as defined in the USP. Use child-resistant closure.Store at controlled room temperature 15°-30°C (59°-86°F) (See USP).MANUFACTURED BY 0172IVAX PHARMACEUTICALS, INC. 04/02MIAMI, FL 33137 B9Diphenoxylate Hydrochloride and Atropine Sulfate Tablets USP are available as white, round tablets, debossed,3966 containing 2.5 mg diphenoxylate hydrochloride USP and 0.025 mg atropine sulfate USP, packaged in bottles of 100, 1000 and unit-dose boxes of 100 tablets.PHARMACIST: Dispense in a well-closed, light-resistant container as defined in the USP. Use child-resistant closure.Store at controlled room temperature 15°-30°C (59°-86°F) (See USP).MANUFACTURED BY 0172IVAX PHARMACEUTICALS, INC. 04/02MIAMI, FL 33137 B9Diphenoxylate Hydrochloride and Atropine Sulfate Tablets USP are available as white, round tablets, debossed,3966 containing 2.5 mg diphenoxylate hydrochloride USP and 0.025 mg atropine sulfate USP, packaged in bottles of 100, 1000 and unit-dose boxes of 100 tablets.PHARMACIST: Dispense in a well-closed, light-resistant container as defined in the USP. Use child-resistant closure.Store at controlled room temperature 15°-30°C (59°-86°F) (See USP).MANUFACTURED BY 0172IVAX PHARMACEUTICALS, INC. 04/02MIAMI, FL 33137 B9Diphenoxylate Hydrochloride and Atropine Sulfate Tablets USP are available as white, round tablets, debossed,3966 containing 2.5 mg diphenoxylate hydrochloride USP and 0.025 mg atropine sulfate USP, packaged in bottles of 100, 1000 and unit-dose boxes of 100 tablets.PHARMACIST: Dispense in a well-closed, light-resistant container as defined in the USP. Use child-resistant closure.Store at controlled room temperature 15°-30°C (59°-86°F) (See USP).MANUFACTURED BY 0172IVAX PHARMACEUTICALS, INC. 04/02MIAMI, FL 33137 B9Diphenoxylate Hydrochloride and Atropine Sulfate Tablets USP are available as white, round tablets, debossed,3966 containing 2.5 mg diphenoxylate hydrochloride USP and 0.025 mg atropine sulfate USP, packaged in bottles of 100, 1000 and unit-dose boxes of 100 tablets.PHARMACIST: Dispense in a well-closed, light-resistant container as defined in the USP. Use child-resistant closure.Store at controlled room temperature 15°-30°C (59°-86°F) (See USP).MANUFACTURED BY 0172IVAX PHARMACEUTICALS, INC. 04/02MIAMI, FL 33137 B9

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Clinical Information

Chemical Structure

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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 sixteen-subject cross-over 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 diphenoxylate HCl and atropine sulfate oral solution) 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 the 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.

Non-Clinical Toxicology

Diphenoxylate HCl and atropine sulfate tablets are contraindicated in patients with:

THIS IS AN INNOCUOUS DRUG AND DOSAGE RECOMMENDATIONS SHOULD BE STRICTLY ADHERED TO, ESPECIALLY IN CHILDREN. DIPHENOXYLATE HCl AND ATROPINE SULFATE 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 ). THEREFORE, KEEP THIS MEDICATION OUT OF THE REACH OF CHILDREN.

THE USE OF DIPHENOXYLATE HCl AND ATROPINE SULFATE SHOULD BE ACCOMPANIED BY APPROPRIATE FLUID AND ELECTROLYTE THERAPY, WHEN INDICATED. IF SEVERE DEHYDRATION OR ELECTROLYTE IMBALANCE IS PRESENT, THIS PRODUCT 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. DIPHENOXYLATE HCl AND ATROPINE SULFATE 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 ), and pseudomembranous enterocolitis associated with broad-spectrum antibiotics. Antipersistaltic 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 diphenoxylate HCl and atropine sulfate 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 this product with monoamine oxidase (MAO) inhibitors may, in theory, precipitate hypertensive crisis.

This product 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.

In patients receiving mercaptopurine or azathioprine, the concomitant administration of 300-600 mg of allopurinol per day will require a reduction in dose to approximately one-third to one-fourth of the usual dose of mercaptopurine or azathioprine. Subsequent adjustment of doses of mercaptopurine or azathioprine should be made on the basis of therapeutic response and the appearance of toxic effects (see ).

It has been reported that allopurinol prolongs the half-life of the anticoagulant, dicumarol. The clinical basis of this drug interaction has not been established but should be noted when allopurinol is given to patients already on dicumarol therapy.

Since the excretion of oxipurinol is similar to that of urate, uricosuric agents, which increase the excretion of urate, are also likely to increase the excretion of oxipurinol and thus lower the degree of inhibition of xanthine oxidase. The concomitant administration of uricosuric agents and allopurinol has been associated with a decrease in the excretion of oxypurines (hypoxanthine and xanthine) and an increase in urinary uric acid excretion compared with that observed with allopurinol alone. Although clinical evidence to date has not demonstrated renal precipitation of oxypurines in patients either on allopurinol alone or in combination with uricosuric agents, the possibility should be kept in mind.

The reports that the concomitant use of allopurinol and thiazide diuretics may contribute to the enhancement of allopurinol toxicity in some patients have been reviewed in an attempt to establish a cause-and-effect relationship and a mechanism of causation. Review of these case reports indicates that the patients were mainly receiving thiazide diuretics for hypertension and that tests to rule out decreased renal function secondary to hypertensive nephropathy were not often performed. In those patients in whom renal insufficiency was documented, however, the recommendation to lower the dose of allopurinol was not followed. Although a causal mechanism and a cause-and-effect relationship have not been established, current evidence suggests that renal function should be monitored in patients on thiazide diuretics and allopurinol even in the absence of renal failure, and dosage levels should be even more conservatively adjusted in those patients on such combined therapy if diminished renal function is detected.

An increase in the frequency of skin rash has been reported among patients receiving ampicillin or amoxicillin concurrently with allopurinol compared to patients who are not receiving both drugs. The cause of the reported association has not been established. Enhanced bone marrow suppression by cyclophosphamide and other cytotoxic agents has been reported among patients with neoplastic disease, except leukemia, in the presence of allopurinol. However, in a well-controlled study of patients with lymphoma on combination therapy, allopurinol did not increase the marrow toxicity of patients treated with cyclophosphamide, doxorubicin, bleomycin, procarbazine and/or mechlorethamine.

Tolbutamide’s conversion to inactive metabolites has been shown to be catalyzed by xanthine oxidase from rat liver. The clinical significance, if any, of this observation is unknown.

Chlorpropamide’s plasma half-life may be prolonged by allopurinol, since allopurinol and chlorpropamide may compete for excretion in the renal tubule. The risk of hypoglycemia secondary to this mechanism may be increased if allopurinol and chlorpropamide are given concomitantly in the presence of renal insufficiency.

Rare reports indicate that cyclosporine levels may be increased during concomitant treatment with allopurinol. Monitoring of cyclosporine levels and possible adjustment of cyclosporine dosage should be considered when these drugs are co-administered.

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, diphenoxylate HCl and atropine sulfate should be used with caution since signs of atropinism may occur even with recommended doses, particularly in patients with Down’s syndrome.

At therapeutic doses, the following have been reported; they are listed in decreasing order of severity, but not of frequency:

Numbness of extremities, euphoria, depression, malaise/lethargy, confusion, sedation/drowsiness, dizziness, restlessness, headache

Anaphylaxis, angioneurotic edema, urticaria, swelling of the gums, pruritus

Toxic megacolon, paralytic ileus, pancreatitis, vomiting, nausea, anorexia, abdominal discomfort The following atropine sulfate effects are listed in decreasing order of severity, but not of frequency: hyperthermia, tachycardia, urinary retention, flushing, dryness of the skin and mucous membranes. These effects may occur, especially in children.

THIS MEDICATION SHOULD BE KEPT IN A CHILD-RESISTANT CONTAINER AND OUT OF THE REACH OF CHILDREN SINCE AN OVERDOSAGE MAY RESULT IN SEVERE RESPIRATORY DEPRESSION AND COMA, POSSIBLY LEADING TO PERMANENT BRAIN DAMAGE OR DEATH.

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Reference

This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"

While we update our database periodically, we cannot guarantee it is always updated to the latest version.

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