DIPHENOXYLATE HYDROCHLORIDE AND ATROPINE SULFATE

Main information

  • Trade name:
  • DIPHENOXYLATE HYDROCHLORIDE AND ATROPINE SULFATE - diphenoxylate hydrochloride and atropine sulfate tablet
  • Composition:
  • DIPHENOXYLATE HYDROCHLORIDE 2.5 mg
  • Administration route:
  • ORAL
  • Prescription type:
  • PRESCRIPTION DRUG
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • DIPHENOXYLATE HYDROCHLORIDE AND ATROPINE SULFATE - diphenoxylate hydrochloride and atropine sulfate tablet
    United States
  • Language:
  • English

Therapeutic information

  • Therapeutic indications:
  • Diphenoxylate hydrochloride and atropine sulfate tablets are effective as adjunctive therapy in the management of diarrhea. Diphenoxylate hydrochloride and atropine sulfate tablets are contraindicated in patients with - Known hypersensitivity to diphenoxylate or atropine, - Obstructive jaundice, - Diarrhea associated with pseudomembranous enterocolitis or enterotoxin-producing bacteria.
  • Product summary:
  • Diphenoxylate Hydrochloride and Atropine Sulfate Tablets, USP are available containing 2.5 mg of diphenoxylate hydrochloride, USP (Warning: May be habit forming) and 0.025 mg of atropine sulfate, USP. The tablets are white round, unscored tablets debossed with M over 15 on one side of the tablet and blank on the other side. They are available as follows: NDC 66336-0437-15 bottles of 15 tablets NDC 66336-0437-20 bottles of 20 tablets Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Protect from light. Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure. Pharmacist: Dispense with a child-resistant closure only. Manufacture: Mylan Pharmaceuticals Inc. Morgantown, WV 26505 REVISED NOVEMBER 2009 DPXAS:R12

Status

  • Source:
  • DailyMed - NLM - National Library of Medicine
  • Authorization status:
  • Abbreviated New Drug Application
  • Authorization number:
  • 66336-437-15, 66336-437-20
  • Last update:
  • 13-06-2019

Summary of Product characteristics: dosage, interactions, side effects

DIPHENOXYLATE HYDROCHLORIDE AND ATROPINE SULFATE - diphenoxylate

hydrochloride and atropine sulfate tablet

Dispensing Solutions, Inc.

----------

DESCRIPTION

Each tablet for oral administration contains:

diphenoxylate

hydrochloride, USP 2.5 mg

(Warning – May be habit forming)

atropine

sulfate, USP 0.025 mg

Diphenoxylate hydrochloride, an antidiarrheal, is ethyl 1-(3-cyano-3, 3-diphenylpropyl)-4-phenyl-

isonipecotate monohydrochloride and has the following structure:

Atropine sulfate, an anticholinergic, is endo-(±)-alpha-(hydroxymethyl) benzeneacetic acid 8-methyl-8-

azabicylo[3.2.1] oct-3-yl ester sulfate (2:1)] (salt) monohydrate and has the following structure:

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

Each tablet for oral administration contains the following inactive ingredients: colloidal silicon dioxide,

microcrystalline cellulose, pregelatinized starch and stearic acid.

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 4-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 cross-over bioavailability study, a linear relationship in the dose range of 2.5 mg to 10 mg was

found between the dose of diphenoxylate hydrochloride (given as Diphenoxylate Hydrochloride 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 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

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

management of diarrhea.

CONTRAINDICATIONS

Diphenoxylate hydrochloride and atropine sulfate tablets are 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

THIS IS NOT AN INNOCUOUS DRUG AND DOSAGE RECOMMENDATIONS SHOULD BE

STRICTLY ADHERED TO, ESPECIALLY IN CHILDREN. DIPHENOXYLATE

HYDROCHLORIDE 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 OVERDOSAGE). THEREFORE, KEEP THIS MEDICATION

OUT OF THE REACH OF CHILDREN.

THE USE OF DIPHENOXYLATE HYDROCHLORIDE 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 HYDROCHLORIDE 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 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 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.

ADVERSE REACTIONS

At therapeutic doses, the following have been reported: they are listed in decreasing order of severity,

but not of frequency:

Nervous system: Numbness of extremities, euphoria, depression, malaise/lethargy, confusion,

sedation/drowsiness, dizziness, restlessness, headache.

Allergic: anaphylaxis, angioneurotic edema, urticaria, swelling of the gums, pruritus.

Gastrointestinal system: 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.

OVERDOSAGE

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.

Diagnos is

Initial signs of overdosage may include dryness of the skin and mucous membranes, mydriasis,

restlessness, flushing, hyperthermia, and tachycardia 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 OVERDOSAGES AS SERIOUS AND MAINTAIN MEDICAL OBSERVATION

FOR AT LEAST 48 HOURS, PREFERABLY UNDER CONTINUOUS HOSPITAL CARE.

Treatment

In the event of overdose, induction of vomiting, gastric lavage, establishment of a patent airway, and

possibly mechanically assisted respiration are advised. In vitro and animal studies indicate that activated

charcoal may significantly decrease the bioavailability of diphenoxylate. In non-comatose 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 hydrochloride and atropine sulfate. When a narcotic antagonist is administered

intravenously, the onset of action is generally apparent within 2 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:

Adult Dosage: The usual initial adult dose of naloxone hydrochloride is 0.4 mg administered

intravenously. If respiratory function does not adequately improve after the initial-dose, the same IV

dose may be repeated at 2 to 3 minute intervals.

Children: The usual initial dose of naloxone hydrochloride for children is 0.01 mg/kg of body weight

administered intravenously and repeated at 2 to 3 minute intervals if necessary.

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, continued 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.

DOSAGE AND ADMINISTRATION

DO NOT EXCEED RECOMMENDED DOSAGE.

Adults

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.

Children

Diphenoxylate hydrochloride 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.

HOW SUPPLIED

Diphenoxylate Hydrochloride and Atropine Sulfate Tablets, USP are available containing 2.5 mg of

diphenoxylate hydrochloride, USP (Warning: May be habit forming) and 0.025 mg of atropine sulfate,

USP. The tablets are white round, unscored tablets debossed with M over 15 on one side of the tablet

and blank on the other side. They are available as follows:

NDC 66336-0437-15

bottles of 15 tablets

NDC 66336-0437-20

bottles of 20 tablets

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

Protect from light.

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

Pharmacist: Dispense with a child-resistant closure only.

Manufacture:

Mylan Pharmaceuticals Inc.

Morgantown, WV 26505

REVISED NOVEMBER 2009

DPXAS:R12

PRINCIPAL DISPLAY PANEL

NDC 66336-0437-XX

NDC 66336-0437-15

NDC 66336-0437-20

DIPHENOXYLATE HYDROCHLORIDE AND ATROPINE SULFATE

diphenoxylate hydrochloride and atropine sulfate tablet

Product Information

Product T ype

HUMAN

PRESCRIPTION DRUG

Ite m Code (Source )

NDC:6 6 336 -

437(NDC:0 378 -0 415)

Route of Administration

ORAL

DEA Sche dule

Dispensing Solutions, Inc.

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

DIPHENO XYLATE HYDRO CHLO RIDE (UNII: W24OD7YW48 ) (DIPHENOXYLATE -

UNII:73312P173G)

DIPHENOXYLATE

HYDROCHLORIDE

2.5 mg

ATRO PINE SULFATE (UNII: 0 3J5ZE7KA5) (ATROPINE - UNII:7C0 6 9 7DR9 I)

ATROPINE SULFATE

0 .0 25 mg

Inactive Ingredients

Ingredient Name

Stre ng th

SILICO N DIO XIDE (UNII: ETJ7Z6 XBU4)

CELLULO SE, MICRO CRYSTALLINE (UNII: OP1R32D6 1U)

STARCH, CO RN (UNII: O8 232NY3SJ)

STEARIC ACID (UNII: 4ELV7Z6 5AP)

Product Characteristics

Color

white

S core

no sco re

S hap e

ROUND

S iz e

6 mm

Flavor

Imprint Code

M;15

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:6 6 336 -437-15

15 in 1 BOTTLE

2

NDC:6 6 336 -437-20

20 in 1 BOTTLE

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 8 576 2

11/30 /20 10

Labeler -

Dispensing Solutions, Inc. (066070785)

Registrant -

PSS World Medical, Inc. (101822682)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Dispensing So lutio ns, Inc.

0 6 6 0 70 78 5

relabel, repack

Revised: 2/2012