Label: DIPHENOXYLATE HYDROCHLORIDE AND ATROPINE SULFATE tablet
43353-083-70, view more43353-083-80, 43353-083-90
- Packager: Aphena Pharma Solutions - Tennessee, LLC
- This is a repackaged label.
- Source NDC Code(s): 59762-1061
- Category: HUMAN PRESCRIPTION DRUG LABEL
- DEA Schedule: CV
- Marketing Status: New Drug Application Authorized Generic
Drug Label Information
Updated June 10, 2016
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Each diphenoxylate hydrochloride and atropine sulfate 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 diphenoxylate hydrochloride tablets include acacia, corn starch, magnesium stearate, sorbitol, sucrose, and talc.
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 diphenoxylate hydrochloride 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
DIPHENOXYLATE HYDROCHLORIDE IS NOT AN INNOCUOUS DRUG AND DOSAGE RECOMMENDATIONS SHOULD BE STRICTLY ADHERED TO, ESPECIALLY IN CHILDREN. DIPHENOXYLATE HYDROCHLORIDE 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 SHOULD BE ACCOMPANIED BY APPROPRIATE FLUID AND ELECTROLYTE THERAPY, WHEN INDICATED. IF SEVERE DEHYDRATION OR ELECTROLYTE IMBALANCE IS PRESENT, DIPHENOXYLATE HYDROCHLORIDE 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 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 diphenoxylate hydrochloride 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 diphenoxylate hydrochloride with monoamine oxidase (MAO) inhibitors may, in theory, precipitate hypertensive crisis.
Diphenoxylate hydrochloride 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.
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 hydrochloride 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 DIPHENOXYLATE HYDROCHLORIDE 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. Diphenoxylate hydrochloride 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 diphenoxylate hydrochloride should be explained to the patient. The physician should also provide the patient with other information in this labeling, as appropriate.
Known drug interactions include barbiturates, tranquilizers, and alcohol. Diphenoxylate hydrochloride 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 diphenoxylate hydrochloride in humans is unknown.
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. Diphenoxylate hydrochloride should be used during pregnancy only if the anticipated benefit justifies the potential risk to the fetus.
Caution should be exercised when diphenoxylate hydrochloride 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.
Diphenoxylate hydrochloride may be used as an adjunct to the treatment of diarrhea but should be accompanied by appropriate fluid and electrolyte therapy, if needed. DIPHENOXYLATE HYDROCHLORIDE IS NOT RECOMMENDED FOR CHILDREN UNDER 2 YEARS OF AGE. Diphenoxylate hydrochloride 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.
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.
DRUG ABUSE AND DEPENDENCE
Diphenoxylate hydrochloride is classified as a Schedule V controlled substance by federal regulation. Diphenoxylate hydrochloride is chemically related to the narcotic analgesic meperidine.
Drug abuse and dependence
In doses used for the treatment of diarrhea, whether acute or chronic, diphenoxylate has not produced addiction.
Diphenoxylate hydrochloride is devoid of morphine-like subjective effects at therapeutic doses. At high doses it exhibits codeine-like subjective effects. The dose which produces antidiarrheal action is widely separated from the dose which causes central nervous system effects. The insolubility of diphenoxylate hydrochloride in commonly available aqueous media precludes intravenous self-administration. A dose of 100 to 300 mg/day, which is equivalent to 40 to 120 tablets, administered to humans for 40 to 70 days, produced opiate withdrawal symptoms. Since addiction to diphenoxylate hydrochloride is possible at high doses, the recommended dosage should not be exceeded.
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 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 despite an initial response to narcotic antagonists. TREAT ALL POSSIBLE DIPHENOXYLATE HYDROCHLORIDE OVERDOSAGES AS SERIOUS AND MAINTAIN MEDICAL OBSERVATION FOR AT LEAST 48 HOURS, PREFERABLY UNDER CONTINUOUS HOSPITAL CARE.
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 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 hydrochloride. 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 hydrochloride 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.
DOSAGE AND ADMINISTRATION
DO NOT EXCEED RECOMMENDED DOSAGE.
The recommended initial dosage is two diphenoxylate hydrochloride tablets four times daily . 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 hydrochloride 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. Do not use diphenoxylate hydrochloride tablets for children under 13 years of age .
KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.
- HOW SUPPLIED
- SPL UNCLASSIFIED SECTION
Please reference the How Supplied section listed above for a description of individual tablets. This drug product has been received by Aphena Pharma - TN in a manufacturer or distributor packaged configuration and repackaged in full compliance with all applicable cGMP regulations. The package configurations available from Aphena are listed below:
Count 2.5/0.025mg 30 43353-083-30 60 43353-083-53 90 43353-083-60 120 43353-083-70 180 43353-083-80 240 43353-083-90
Store between 20°-25°C (68°-77°F). See USP Controlled Room Temperature. Dispense in a tight light-resistant container as defined by USP. Keep this and all drugs out of the reach of children.
Cookeville, TN 38506
- PRINCIPAL DISPLAY PANEL
INGREDIENTS AND APPEARANCE
DIPHENOXYLATE HYDROCHLORIDE AND ATROPINE SULFATE
diphenoxylate hydrochloride and atropine sulfate tablet
Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:43353-083(NDC:59762-1061) Route of Administration ORAL DEA Schedule CV Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength DIPHENOXYLATE HYDROCHLORIDE (UNII: W24OD7YW48) (DIPHENOXYLATE - UNII:73312P173G) DIPHENOXYLATE HYDROCHLORIDE 2.5 mg ATROPINE SULFATE (UNII: 03J5ZE7KA5) (ATROPINE - UNII:7C0697DR9I) ATROPINE SULFATE 0.025 mg Inactive Ingredients Ingredient Name Strength ACACIA (UNII: 5C5403N26O) STARCH, CORN (UNII: O8232NY3SJ) MAGNESIUM STEARATE (UNII: 70097M6I30) SORBITOL (UNII: 506T60A25R) SUCROSE (UNII: C151H8M554) TALC (UNII: 7SEV7J4R1U) Product Characteristics Color WHITE Score no score Shape ROUND Size 6mm Flavor Imprint Code SEARLE;61 Contains Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:43353-083-30 30 in 1 BOTTLE; Type 0: Not a Combination Product 07/13/2015 2 NDC:43353-083-53 60 in 1 BOTTLE; Type 0: Not a Combination Product 07/14/2015 3 NDC:43353-083-60 90 in 1 BOTTLE; Type 0: Not a Combination Product 07/13/2015 4 NDC:43353-083-70 120 in 1 BOTTLE; Type 0: Not a Combination Product 07/13/2015 5 NDC:43353-083-80 180 in 1 BOTTLE; Type 0: Not a Combination Product 08/15/2015 6 NDC:43353-083-90 240 in 1 BOTTLE; Type 0: Not a Combination Product 07/27/2015 Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA AUTHORIZED GENERIC NDA012462 02/27/2013 Labeler - Aphena Pharma Solutions - Tennessee, LLC (128385585) Establishment Name Address ID/FEI Business Operations Aphena Pharma Solutions - Tennessee, LLC 128385585 REPACK(43353-083)