DIPHENOXYLATE HYDROCHLORIDE AND ATROPINE SULFATE tablet

1. No Title 1572555380
2. Diphenoxylate Hydrochloride And Atropine Sulfate
3. Principal Display Panel - 2.5 Mg/0.025 Mg Tablet Bottle Label
4. Description
5. Principal Display Panel - 2.5 Mg/0.025 Mg
6. Storage
7. Diphenoxylate Hydrochloride And Atropine Sulfate
8. Package/label Principal Display Panel
9. Diphenoxylate W/atrop2.5/.025mg(cv)tab
10. Principal Display Panel - 2.5/0.025mg
11. Diphenoxylate Hydrochloride And Atropine Sulfate
12. No Title 1572456349
13. Description
14. Clinical Pharmacology
15. Indications And Usage
16. Contraindications
17. Warnings
18. Precautions
19. Adverse Reactions
20. Drug Abuse And Dependence
21. Overdosage
22. Dosage And Administration
23. How Supplied
24. Diphenoxylate Hydrochloride And Atropine Sulfate
25. Diphenoxylate Hydrochloride And Atropine Sulfate Tablet
26. Description
27. Clinical Pharmacology
28. Indications And Usage
29. Contraindications
30. Warnings
31. Precautions
32. Adverse Reactions
33. Drug Abuse And Dependence
34. Overdosage
35. Dosage And Administration
36. How Supplied
37. Repackaging Information
38. Principal Display Panel

No Title 1572555380 ⮝

PRINCIPAL DISPLAY PANEL - 2.5 mg/0.025 mg

NDC 33261-0685-30

Diphenoxylate HCl*
and Atropine Sulfate
Tablets, USP

CV

2.5 mg/0.025 mg

Rx 30 TABLETS

Each tablet contains:
Diphenoxylate HCl, USP 2.5 mg
Atropine Sulfate, USP 0.025 mg

*WARNING: May Be Habit
Forming

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

Keep container tightly closed.

Keep this and all medication out of the reach of
children.

Pharmacist: Dispense with a child-resistant closure only.

SPECIAL NOTE: Diphenoxylate HCl and Atropine Sulfate
is not recommended for children under 2 years of age.

Usual Adult Dosage: Two tablets (5 mg) four times
daily. For maintenance, less according to response.
See insert. Children 2 to 12 years: Use oral solution,
tablets are not recommended for this age group.

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

Protect from light.

Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.

www.mylan.com

RM0415MM2

DIPHENOXYLATE HYDROCHLORIDE AND ATROPINE SULFATE diphenoxylate hydrochloride and atropine sulfate tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:33261-685(NDC:0378-0415) 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 SILICON DIOXIDE (UNII: ETJ7Z6XBU4) CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) STARCH, CORN (UNII: O8232NY3SJ) STEARIC ACID (UNII: 4ELV7Z65AP)

Product Characteristics Color WHITE Score no score Shape ROUND Size 6mm Flavor Imprint Code M;15 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:33261-685-15 15 in 1 BOTTLE, PLASTIC 2 NDC:33261-685-30 30 in 1 BOTTLE, PLASTIC

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA085762 11/30/2010

Labeler - Aidarex Pharmaceuticals LLC (801503249)

Revised: 12/2013 Document Id: f88e1600-0e18-433a-90ae-1dcc7817bb59 34391-3 Set id: 51536429-1544-4bdd-9cf7-7753d2978841 Version: 1 Effective Time: 20131229 Aidarex Pharmaceuticals LLC

Diphenoxylate Hydrochloride And Atropine Sulfate ⮝

DIPHENOXYLATE HYDROCHLORIDE AND ATROPINE SULFATE diphenoxylate hydrochloride and atropine sulfate tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:50090-3452(NDC:62559-490) 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 LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X) STARCH, CORN (UNII: O8232NY3SJ) SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2) SUCROSE (UNII: C151H8M554) MAGNESIUM STEARATE (UNII: 70097M6I30)

Product Characteristics Color WHITE Score no score Shape ROUND Size 6mm Flavor Imprint Code 490 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:50090-3452-0 20 in 1 BOTTLE; Type 0: Not a Combination Product 05/09/2018

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA086727 07/07/2017

Labeler - A-S Medication Solutions (830016429)

Establishment
Name	Address	ID/FEI	Business Operations
A-S Medication Solutions		830016429	RELABEL(50090-3452) , REPACK(50090-3452)

Revised: 9/2018 Document Id: 6e02edee-75e5-4165-8a91-5a7517abb5ef 34391-3 Set id: 96e19512-870e-4eaf-b9e2-ae223371159c Version: 1 Effective Time: 20180928 A-S Medication Solutions

Principal Display Panel - 2.5 Mg/0.025 Mg Tablet Bottle Label ⮝

NDC 76385-107-01

Diphenoxylate
Hydrochloride and
Atropine Sulfate
Tablets, USP
CV

2.5 mg/0.025 mg*

100 Tablets
Rx only

DIPHENOXYLATE HYDROCHLORIDE AND ATROPINE SULFATE diphenoxylate hydrochloride and atropine sulfate tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:76385-107 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 MANNITOL (UNII: 3OWL53L36A) STARCH, CORN (UNII: O8232NY3SJ) HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO) SILICON DIOXIDE (UNII: ETJ7Z6XBU4) MAGNESIUM STEARATE (UNII: 70097M6I30)

Product Characteristics Color WHITE Score no score Shape ROUND Size 6mm Flavor Imprint Code BY3; Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:76385-107-01 100 in 1 BOTTLE; Type 0: Not a Combination Product 05/15/2019 2 NDC:76385-107-10 1000 in 1 BOTTLE; Type 0: Not a Combination Product 05/15/2019

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA210819 05/15/2019

Labeler - Bayshore Pharmaceuticals, LLC (968737416)

Revised: 5/2019 Document Id: b027f635-b063-4daa-bf46-db435ba7bb24 34391-3 Set id: 5117f26c-488f-4ba6-b115-22baf12557f3 Version: 1 Effective Time: 20190515 Bayshore Pharmaceuticals, LLC

Description  ⮝

Each tablet for oral administration contains:

diphenoxylate hydrochloride, USP (Warning May be habit forming)	2.5 mg
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 (corn) and stearic acid.

Principal Display Panel - 2.5 Mg/0.025 Mg ⮝

DIPHENOXYLATE HYDROCHLORIDE AND ATROPINE SULFATE diphenoxylate hydrochloride and atropine sulfate tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:12634-531(NDC:0378-0415) 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 SILICON DIOXIDE (UNII: ETJ7Z6XBU4) CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) STARCH, CORN (UNII: O8232NY3SJ) STEARIC ACID (UNII: 4ELV7Z65AP)

Product Characteristics Color white Score no score Shape ROUND Size 6mm Flavor Imprint Code M;15 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:12634-531-00 10 in 1 BOTTLE; Type 0: Not a Combination Product 10/04/2016 2 NDC:12634-531-50 50 in 1 BOTTLE; Type 0: Not a Combination Product 10/04/2013 3 NDC:12634-531-54 14 in 1 BLISTER PACK; Type 0: Not a Combination Product 10/04/2013 4 NDC:12634-531-55 15 in 1 BLISTER PACK; Type 0: Not a Combination Product 10/04/2013 5 NDC:12634-531-59 30 in 1 BLISTER PACK; Type 0: Not a Combination Product 10/04/2013 6 NDC:12634-531-60 60 in 1 BOTTLE; Type 0: Not a Combination Product 10/04/2013 7 NDC:12634-531-61 10 in 1 BLISTER PACK; Type 0: Not a Combination Product 10/04/2013 8 NDC:12634-531-79 25 in 1 BOTTLE; Type 0: Not a Combination Product 10/04/2016 9 NDC:12634-531-80 20 in 1 BOTTLE; Type 0: Not a Combination Product 10/04/2013 10 NDC:12634-531-82 12 in 1 BOTTLE; Type 0: Not a Combination Product 10/04/2013 11 NDC:12634-531-91 1 in 1 BLISTER PACK; Type 0: Not a Combination Product 10/04/2013 12 NDC:12634-531-95 5 in 1 BOTTLE; Type 0: Not a Combination Product 10/04/2013 13 NDC:12634-531-97 7 in 1 BOTTLE; Type 0: Not a Combination Product 10/04/2013

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA085762 11/17/1977

Labeler - Apotheca Inc. (051457844)

Establishment
Name	Address	ID/FEI	Business Operations
Apotheca Inc.		051457844	relabel(12634-531) , repack(12634-531)

Revised: 1/2016 Document Id: 2a2ec5f4-ddaa-383d-e054-00144ff8d46c 34391-3 Set id: 620bf3e4-46ef-4eaf-95b8-f3ffc1a937ad Version: 14 Effective Time: 20160125 Apotheca Inc.

Storage ⮝

Store below 25 C (77 F).

Diphenoxylate Hydrochloride And Atropine Sulfate ⮝

DIPHENOXYLATE HYDROCHLORIDE AND ATROPINE SULFATE diphenoxylate hydrochloride and atropine sulfate tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:50090-2872(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:50090-2872-0 15 in 1 BOTTLE; Type 0: Not a Combination Product 02/16/2017 2 NDC:50090-2872-1 20 in 1 BOTTLE; Type 0: Not a Combination Product 03/02/2017 3 NDC:50090-2872-2 30 in 1 BOTTLE; Type 0: Not a Combination Product 03/02/2017

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA AUTHORIZED GENERIC NDA012462 02/27/2013

Labeler - A-S Medication Solutions (830016429)

Establishment
Name	Address	ID/FEI	Business Operations
A-S Medication Solutions		830016429	RELABEL(50090-2872) , REPACK(50090-2872)

Revised: 7/2018 Document Id: 580fd296-b63e-4abb-b68f-2c854b849029 34391-3 Set id: aae3896d-0e79-480d-8a9d-a12ff2e0318a Version: 9 Effective Time: 20180703 A-S Medication Solutions

Package/label Principal Display Panel  ⮝

Diphenoxylate Hydrochloride and Atropine Sulfate Tablets USP, CV
2.5 mg/0.025 mg
NDC 62559-490-01
Rx only
100 Tablets

DIPHENOXYLATE HYDROCHLORIDE AND ATROPINE SULFATE diphenoxylate hydrochloride and atropine sulfate tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:62559-490 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 LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X) STARCH, CORN (UNII: O8232NY3SJ) SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2) SUCROSE (UNII: C151H8M554) MAGNESIUM STEARATE (UNII: 70097M6I30)

Product Characteristics Color WHITE Score no score Shape ROUND Size 6mm Flavor Imprint Code 490 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:62559-490-01 100 in 1 BOTTLE; Type 0: Not a Combination Product 07/07/2017 2 NDC:62559-490-10 1000 in 1 BOTTLE; Type 0: Not a Combination Product 07/07/2017

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA086727 07/07/2017

Labeler - ANI Pharmaceuticals, Inc. (145588013)

Registrant - ANI Pharmaceuticals, Inc. (145588013)

Revised: 10/2019 Document Id: a26cdbca-2573-43fe-bf94-dee4115314b3 34391-3 Set id: 73dc5f91-d562-44c5-a556-66c96ed1dd82 Version: 4 Effective Time: 20191018 ANI Pharmaceuticals, Inc.

Diphenoxylate W/atrop2.5/.025mg(cv)tab ⮝

DIPHENOXYLATE HYDROCHLORIDE AND ATROPINE SULFATE diphenoxylate hydrochloride and atropine sulfate tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:71335-0311(NDC:62559-490) Route of Administration ORAL DEA Schedule CII

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 LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X) STARCH, CORN (UNII: O8232NY3SJ) SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2) SUCROSE (UNII: C151H8M554) MAGNESIUM STEARATE (UNII: 70097M6I30)

Product Characteristics Color WHITE Score no score Shape ROUND Size 6mm Flavor Imprint Code 490 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:71335-0311-1 20 in 1 BOTTLE; Type 0: Not a Combination Product 10/27/2017 2 NDC:71335-0311-2 30 in 1 BOTTLE; Type 0: Not a Combination Product 10/27/2017 3 NDC:71335-0311-3 15 in 1 BOTTLE; Type 0: Not a Combination Product 10/27/2017 4 NDC:71335-0311-4 10 in 1 BOTTLE; Type 0: Not a Combination Product 10/27/2017 5 NDC:71335-0311-5 40 in 1 BOTTLE; Type 0: Not a Combination Product 10/27/2017 6 NDC:71335-0311-6 60 in 1 BOTTLE; Type 0: Not a Combination Product 10/27/2017 7 NDC:71335-0311-7 90 in 1 BOTTLE; Type 0: Not a Combination Product 10/27/2017

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA086727 07/07/2017

Labeler - Bryant Ranch Prepack (171714327)

Establishment
Name	Address	ID/FEI	Business Operations
Bryant Ranch Prepack		171714327	REPACK(71335-0311) , RELABEL(71335-0311)

Revised: 2/2018 Document Id: 46a0375d-9594-4223-afdc-17aadad64e67 34391-3 Set id: bd08ed90-dd26-4629-83c0-0f75af6ebb95 Version: 4 Effective Time: 20180221 Bryant Ranch Prepack

Principal Display Panel - 2.5/0.025mg ⮝

NDC 43353-594 - Diphenoxylate HCl Atropine Sulfate 2.5/0.025mg - Rx Only

DIPHENOXYLATE HYDROCHLORIDE AND ATROPINE SULFATE diphenoxylate hydrochloride and atropine sulfate tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:43353-594(NDC:62559-490) 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 LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X) STARCH, CORN (UNII: O8232NY3SJ) SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2) SUCROSE (UNII: C151H8M554) MAGNESIUM STEARATE (UNII: 70097M6I30)

Product Characteristics Color WHITE Score no score Shape ROUND Size 6mm Flavor Imprint Code 490 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:43353-594-30 30 in 1 BOTTLE; Type 0: Not a Combination Product 07/26/2017 2 NDC:43353-594-53 60 in 1 BOTTLE; Type 0: Not a Combination Product 07/26/2017 3 NDC:43353-594-60 90 in 1 BOTTLE; Type 0: Not a Combination Product 07/26/2017 4 NDC:43353-594-70 120 in 1 BOTTLE; Type 0: Not a Combination Product 07/26/2017 5 NDC:43353-594-80 180 in 1 BOTTLE; Type 0: Not a Combination Product 07/26/2017 6 NDC:43353-594-90 240 in 1 BOTTLE; Type 0: Not a Combination Product 07/26/2017

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA086727 06/20/2017

Labeler - Aphena Pharma Solutions - Tennessee, LLC (128385585)

Establishment
Name	Address	ID/FEI	Business Operations
Aphena Pharma Solutions - Tennessee, LLC		128385585	REPACK(43353-594)

Revised: 8/2017 Document Id: ef69e563-7239-4c78-8fb4-3cd641fbff17 34391-3 Set id: 435e5e75-5a4c-4806-8d9e-d4be3fef9229 Version: 1 Effective Time: 20170831 Aphena Pharma Solutions - Tennessee, LLC

Diphenoxylate Hydrochloride And Atropine Sulfate ⮝

Each Diphenoxylate Hydrochloride and Atropine Sulfate Tablet USP contains:

Diphenoxylate Hydrochloride USP . 2.5 mg

Atropine Sulfate USP...................... 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-( )- -(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.

Each diphenoxylate hydrochloride and atropine sulfate tablet contains the following inactive ingredients: confectioner s sugar, corn starch, lactose monohydrate, magnesium stearate, and sodium starch glycolate.

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 and atropine sulfate 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.

Diphenoxylate Hydrochloride and Atropine Sulfate Tablets USP are indicated as adjunctive therapy in the management of diarrhea in patients 13 years of age and older.

Diphenoxylate hydrochloride and atropine sulfate tablets are 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.

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 diphenoxylate hydrochloride and atropine sulfate tablets. Diphenoxylate hydrochloride and atropine sulfate tablets are 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 this product have been reported. The initial presenting symptoms may be delayed by up to 30 hours due to prolonged gastric emptying time induced by the 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 drowsiness (see OVERDOSAGE).

Dehydration and Electrolyte Imbalance

The use of diphenoxylate hydrochloride and atropine sulfate tablets should be accompanied by appropriate fluid and electrolyte therapy, when indicated. If severe dehydration or electrolyte imbalance is present, diphenoxylate hydrochloride and atropine sulfate tablets 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.

Gastrointestinal Complications in Patients with Infectious Diarrhea

Diphenoxylate hydrochloride and atropine sulfate tablets are contraindicated in patients with diarrhea associated with organisms that penetrate the GI mucosa (toxigenic E. coli, Salmonella, Shigella), and pseudomembranous enterocolitis (Clostridium difficile) associated with broad-spectrum antibiotics (see CONTRAINDICATIONS). Antiperistaltic agents, including diphenoxylate hydrochloride and atropine sulfate, slow gastrointestinal motility and may enhance bacterial overgrowth and the release of bacterial exotoxins. Diphenoxylate hydrochloride and atropine sulfate has been reported to result in serious GI complications in patients with infectious diarrhea, including sepsis, prolonged and/or worsened diarrhea. Prolonged fever and the delay in the resolution of stool pathogens were reported in study of Shigellosis in adults who used diphenoxylate hydrochloride and atropine sulfate vs. placebo.

Toxic Megacolon in Patients with Acute Ulcerative Colitis

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 and atropine sulfate therapy should be discontinued promptly if abdominal distention occurs or if other untoward symptoms develop.

Interaction with Meperidine Hydrochloride

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

Hepatorenal Disease

Diphenoxylate hydrochloride and atropine sulfate tablets 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.

Interaction with CNS Depressants

Diphenoxylate hydrochloride may potentiate the action of other drugs that cause dizziness or drowsiness, including barbiturates, benzodiazepines and other sedatives/hypnotics, anxiolytics, and tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, and alcohol. Therefore, the patient should be closely observed when any of these are used concomitantly.

Atropinism

Since a subtherapeutic dose of atropine has been added to the diphenoxylate hydrochloride, consideration should be given to the development of adverse reactions associated with atropine (see WARNINGS). Diphenoxylate hydrochloride and atropine sulfate has caused atropinism (hyperthermia, tachycardia, urinary retention, flushing, dryness of the skin and mucous membranes) particularly in pediatric patients with Down's Syndrome. Diphenoxylate hydrochloride and atropine sulfate tablets are 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 diphenoxylate hydrochloride and atropine sulfate tablets in children, especially in those less than 6 years of age, may result in severe respiratory depression and coma. Instruct patients to take steps to store diphenoxylate hydrochloride and atropine sulfate tablets securely and out of reach of children, and to dispose of unused diphenoxylate hydrochloride and atropine sulfate tablets (see WARNINGS).

To take diphenoxylate hydrochloride and atropine sulfate tablets 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.

Diphenoxylate hydrochloride and atropine sulfate tablets 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 diphenoxylate hydrochloride and atropine sulfate tablets do not affect them adversely.

To use fluid and electrolyte therapy, if prescribed along with diphenoxylate hydrochloride and atropine sulfate tablets, 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 diphenoxylate hydrochloride and atropine sulfate tablets and contact their healthcare provider.

Drug Interactions

Alcohol

Alcohol may increase the CNS depressant effects of diphenoxylate hydrochloride and atropine sulfate and may cause drowsiness (see WARNINGS). Avoid concomitant use of diphenoxylate hydrochloride and atropine sulfate tablets with alcohol.

Other Drugs that Cause CNS Depression

The concurrent use of diphenoxylate hydrochloride and atropine sulfate with other drugs that cause CNS depression (e.g., barbiturates, benzodiazepines, opioids, buspirone, antihistamines, muscle relaxants), may potentiate the effects of diphenoxylate hydrochloride and atropine sulfate (see WARNINGS). Either diphenoxylate hydrochloride and atropine sulfate tablets 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 diphenoxylate hydrochloride and atropine sulfate tablets in patients who take MAOIs and monitor for signs and symptoms of hypertensive crisis (headache, hyperthermia, hypertension).

Carcinogenesis, Mutagenesis, and 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 and atropine sulfate 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. Diphenoxylate hydrochloride and atropine sulfate tablets should be used during pregnancy only if the anticipated benefit justifies the potential risk to the fetus.

Nursing Mothers

Caution should be exercised when diphenoxylate hydrochloride and atropine sulfate tablets are 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 diphenoxylate hydrochloride and atropine sulfate tablets 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 this product has not been established in pediatric patients less than 13 years of age.

Diphenoxylate hydrochloride and atropine sulfate tablets are 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 death (see CONTRAINDICATIONS).

Diphenoxylate hydrochloride and atropine sulfate has caused atropinism, particularly in pediatric patients with Down s Syndrome (see PRECAUTIONS).

In case of accidental ingestion of diphenoxylate hydrochloride and atropine sulfate tablets by pediatric patients, see OVERDOSAGE for recommended treatment.

The following serious adverse reactions are described elsewhere in the labeling:

Respiratory and/or CNS depression (see WARNINGS)

Anticholinergic and opioid-toxicities, including atropinism (see WARNINGS and PRECAUTIONS)

Dehydration and electrolyte imbalance (see WARNINGS)

GI Complications in patients with infectious diarrhea (see WARNINGS)

Toxic megacolon in patients with acute ulcerative colitis (see WARNINGS)

At therapeutic doses of diphenoxylate hydrochloride and atropine sulfate, the following other adverse reactions 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, hallucination.

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

Gastrointestinal system: megacolon, paralytic ileus, pancreatitis, vomiting, nausea, anorexia, abdominal discomfort.

The following adverse reactions related to atropine sulfate are listed in decreasing order of severity, but not of frequency: hyperthermia, tachycardia, urinary retention, flushing, dryness of the skin and mucous membranes.

Controlled Substance

Diphenoxylate hydrochloride and atropine sulfate tablets are 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.

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 diphenoxylate hydrochloride and atropine sulfate 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 diphenoxylate hydrochloride and atropine sulfate. Refer to the prescribing information for naloxone. Consider diphenoxylate hydrochloride and atropine sulfate 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 of the management of poisoning or overdosage.

Management of Diarrhea in Patients 13 Years of Age and Older

Diphenoxylate hydrochloride and atropine sulfate tablets are 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 diphenoxylate hydrochloride and atropine sulfate. The use of this product should be accompanied by appropriate fluid and electrolyte therapy, when indicated. If severe dehydration or electrolyte imbalance is present, do not administer diphenoxylate hydrochloride and atropine sulfate tablets 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 two diphenoxylate hydrochloride and atropine sulfate 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 diphenoxylate hydrochloride and atropine sulfate dosage may be reduced to meet individual requirements. Control may often be maintained with as little as two diphenoxylate hydrochloride and atropine sulfate 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 diphenoxylate hydrochloride and atropine sulfate tablets as symptoms are unlikely to be controlled by further administration.

Diphenoxylate Hydrochloride and Atropine Sulfate Tablets USP are available as round white tablets debossed 490 on one side and plain on the other side. Each tablet contains 2.5 mg of diphenoxylate hydrochloride and 0.025 mg of atropine sulfate

DIPHENOXYLATE HYDROCHLORIDE AND ATROPINE SULFATE diphenoxylate hydrochloride and atropine sulfate tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:61919-405(NDC:62559-490) 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 SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2) LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X) STARCH, CORN (UNII: O8232NY3SJ) SUCROSE (UNII: C151H8M554) MAGNESIUM STEARATE (UNII: 70097M6I30)

Product Characteristics Color white Score no score Shape ROUND Size 6mm Flavor Imprint Code 490 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:61919-405-20 20 in 1 BOTTLE; Type 0: Not a Combination Product 03/13/2018

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA086727 03/13/2018

Labeler - DIRECT RX (079254320)

Registrant - DIRECT RX (079254320)

Establishment
Name	Address	ID/FEI	Business Operations
DIRECT RX		079254320	repack(61919-405)

Revised: 3/2018 Document Id: 674c447f-244c-0538-e053-2a91aa0a79cc 34391-3 Set id: 674c447f-244b-0538-e053-2a91aa0a79cc Version: 1 Effective Time: 20180313 DIRECT RX

No Title 1572456349 ⮝

PRINCIPAL DISPLAY PANEL - 2.5 mg/0.025 mg

NDC 33261-0685-30

Diphenoxylate HCl*
and Atropine Sulfate
Tablets, USP

CV

2.5 mg/0.025 mg

Rx 30 TABLETS

Each tablet contains:
Diphenoxylate HCl, USP 2.5 mg
Atropine Sulfate, USP 0.025 mg

*WARNING: May Be Habit
Forming

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

Keep container tightly closed.

Keep this and all medication out of the reach of
children.

Pharmacist: Dispense with a child-resistant closure only.

SPECIAL NOTE: Diphenoxylate HCl and Atropine Sulfate
is not recommended for children under 2 years of age.

Usual Adult Dosage: Two tablets (5 mg) four times
daily. For maintenance, less according to response.
See insert. Children 2 to 12 years: Use oral solution,
tablets are not recommended for this age group.

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

Protect from light.

Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.

www.mylan.com

RM0415MM2

DIPHENOXYLATE HYDROCHLORIDE AND ATROPINE SULFATE diphenoxylate hydrochloride and atropine sulfate tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:33261-685(NDC:0378-0415) 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 SILICON DIOXIDE (UNII: ETJ7Z6XBU4) CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) STARCH, CORN (UNII: O8232NY3SJ) STEARIC ACID (UNII: 4ELV7Z65AP)

Product Characteristics Color WHITE Score no score Shape ROUND Size 6mm Flavor Imprint Code M;15 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:33261-685-15 15 in 1 BOTTLE, PLASTIC 2 NDC:33261-685-30 30 in 1 BOTTLE, PLASTIC

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA085762 11/30/2010

Labeler - Aidarex Pharmaceuticals LLC (801503249)

Revised: 12/2013 Document Id: f88e1600-0e18-433a-90ae-1dcc7817bb59 34391-3 Set id: 51536429-1544-4bdd-9cf7-7753d2978841 Version: 1 Effective Time: 20131229 Aidarex Pharmaceuticals LLC

Description  ⮝

Each Diphenoxylate Hydrochloride and Atropine Sulfate Tablet USP contains:

2.5 mg of diphenoxylate hydrochloride USP (equivalent to 2.3 mg of diphenoxylate) and

0.025 mg of atropine sulfate USP (equivalent to 0.01 mg of atropine)

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-( )- -(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.

Each diphenoxylate hydrochloride and atropine sulfate tablet contains the following inactive ingredients: confectioner s sugar, corn starch, lactose monohydrate, magnesium stearate, and sodium starch glycolate.

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 diphenoxylate hydrochloride and atropine sulfate 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 and Atropine Sulfate Tablets USP are indicated as adjunctive therapy in the management of diarrhea in patients 13 years of age and older.

Contraindications  ⮝

Diphenoxylate hydrochloride and atropine sulfate tablets are 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 diphenoxylate hydrochloride and atropine sulfate tablets. Diphenoxylate hydrochloride and atropine sulfate tablets are 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 this product have been reported. The initial presenting symptoms may be delayed by up to 30 hours due to prolonged gastric emptying time induced by the 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 drowsiness (see OVERDOSAGE).

Dehydration and Electrolyte Imbalance

The use of diphenoxylate hydrochloride and atropine sulfate tablets should be accompanied by appropriate fluid and electrolyte therapy, when indicated. If severe dehydration or electrolyte imbalance is present, diphenoxylate hydrochloride and atropine sulfate tablets 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.

Gastrointestinal Complications in Patients with Infectious Diarrhea

Diphenoxylate hydrochloride and atropine sulfate tablets are contraindicated in patients with diarrhea associated with organisms that penetrate the GI mucosa (toxigenic E. coli, Salmonella, Shigella), and pseudomembranous enterocolitis (Clostridium difficile) associated with broad-spectrum antibiotics (see CONTRAINDICATIONS). Antiperistaltic agents, including diphenoxylate hydrochloride and atropine sulfate, slow gastrointestinal motility and may enhance bacterial overgrowth and the release of bacterial exotoxins. Diphenoxylate hydrochloride and atropine sulfate has been reported to result in serious GI complications in patients with infectious diarrhea, including sepsis, prolonged and/or worsened diarrhea. Prolonged fever and the delay in the resolution of stool pathogens were reported in study of Shigellosis in adults who used diphenoxylate hydrochloride and atropine sulfate vs. placebo.

Toxic Megacolon in Patients with Acute Ulcerative Colitis

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 and atropine sulfate therapy should be discontinued promptly if abdominal distention occurs or if other untoward symptoms develop.

Interaction with Meperidine Hydrochloride

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

Hepatorenal Disease

Diphenoxylate hydrochloride and atropine sulfate tablets 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.

Interaction with CNS Depressants

Diphenoxylate hydrochloride may potentiate the action of other drugs that cause dizziness or drowsiness, including barbiturates, benzodiazepines and other sedatives/hypnotics, anxiolytics, and tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, and alcohol. Therefore, the patient should be closely observed when any of these are used concomitantly.

Precautions  ⮝

Atropinism

Since a subtherapeutic dose of atropine has been added to the diphenoxylate hydrochloride, consideration should be given to the development of adverse reactions associated with atropine (see WARNINGS). Diphenoxylate hydrochloride and atropine sulfate has caused atropinism (hyperthermia, tachycardia, urinary retention, flushing, dryness of the skin and mucous membranes) particularly in pediatric patients with Down's Syndrome. Diphenoxylate hydrochloride and atropine sulfate tablets are 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 diphenoxylate hydrochloride and atropine sulfate tablets in children, especially in those less than 6 years of age, may result in severe respiratory depression and coma. Instruct patients to take steps to store diphenoxylate hydrochloride and atropine sulfate tablets securely and out of reach of children, and to dispose of unused diphenoxylate hydrochloride and atropine sulfate tablets (see WARNINGS).

To take diphenoxylate hydrochloride and atropine sulfate tablets 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.

Diphenoxylate hydrochloride and atropine sulfate tablets 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 diphenoxylate hydrochloride and atropine sulfate tablets do not affect them adversely.

To use fluid and electrolyte therapy, if prescribed along with diphenoxylate hydrochloride and atropine sulfate tablets, 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 diphenoxylate hydrochloride and atropine sulfate tablets and contact their healthcare provider.

Drug Interactions

Alcohol

Alcohol may increase the CNS depressant effects of diphenoxylate hydrochloride and atropine sulfate and may cause drowsiness (see WARNINGS). Avoid concomitant use of diphenoxylate hydrochloride and atropine sulfate tablets with alcohol.

Other Drugs that Cause CNS Depression

The concurrent use of diphenoxylate hydrochloride and atropine sulfate with other drugs that cause CNS depression (e.g., barbiturates, benzodiazepines, opioids, buspirone, antihistamines, muscle relaxants), may potentiate the effects of diphenoxylate hydrochloride and atropine sulfate (see WARNINGS). Either diphenoxylate hydrochloride and atropine sulfate tablets 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 diphenoxylate hydrochloride and atropine sulfate tablets in patients who take MAOIs and monitor for signs and symptoms of hypertensive crisis (headache, hyperthermia, hypertension).

Carcinogenesis, Mutagenesis, and 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 and atropine sulfate 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. Diphenoxylate hydrochloride and atropine sulfate tablets should be used during pregnancy only if the anticipated benefit justifies the potential risk to the fetus.

Nursing Mothers

Caution should be exercised when diphenoxylate hydrochloride and atropine sulfate tablets are 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 diphenoxylate hydrochloride and atropine sulfate tablets 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 this product has not been established in pediatric patients less than 13 years of age.

Diphenoxylate hydrochloride and atropine sulfate tablets are 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 death (see CONTRAINDICATIONS).

Diphenoxylate hydrochloride and atropine sulfate has caused atropinism, particularly in pediatric patients with Down s Syndrome (see PRECAUTIONS).

In case of accidental ingestion of diphenoxylate hydrochloride and atropine sulfate tablets by pediatric patients, see OVERDOSAGE for recommended treatment.

Adverse Reactions  ⮝

The following serious adverse reactions are described elsewhere in the labeling:

Respiratory and/or CNS depression (see WARNINGS)

Anticholinergic and opioid-toxicities, including atropinism (see WARNINGS and PRECAUTIONS)

Dehydration and electrolyte imbalance (see WARNINGS)

GI Complications in patients with infectious diarrhea (see WARNINGS)

Toxic megacolon in patients with acute ulcerative colitis (see WARNINGS)

At therapeutic doses of diphenoxylate hydrochloride and atropine sulfate, the following other adverse reactions 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, hallucination.

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

Gastrointestinal system: megacolon, paralytic ileus, pancreatitis, vomiting, nausea, anorexia, abdominal discomfort.

The following adverse reactions related to atropine sulfate are listed in decreasing order of severity, but not of frequency: hyperthermia, tachycardia, urinary retention, flushing, dryness of the skin and mucous membranes.

Drug Abuse And Dependence  ⮝

Controlled Substance

Diphenoxylate hydrochloride and atropine sulfate tablets are 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.

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 diphenoxylate hydrochloride and atropine sulfate 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 diphenoxylate hydrochloride and atropine sulfate. Refer to the prescribing information for naloxone. Consider diphenoxylate hydrochloride and atropine sulfate 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 of the management of poisoning or overdosage.

Dosage And Administration  ⮝

Management of Diarrhea in Patients 13 Years of Age and Older

Diphenoxylate hydrochloride and atropine sulfate tablets are 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 diphenoxylate hydrochloride and atropine sulfate. The use of this product should be accompanied by appropriate fluid and electrolyte therapy, when indicated. If severe dehydration or electrolyte imbalance is present, do not administer diphenoxylate hydrochloride and atropine sulfate tablets 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 two diphenoxylate hydrochloride and atropine sulfate 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 diphenoxylate hydrochloride and atropine sulfate dosage may be reduced to meet individual requirements. Control may often be maintained with as little as two diphenoxylate hydrochloride and atropine sulfate 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 diphenoxylate hydrochloride and atropine sulfate tablets as symptoms are unlikely to be controlled by further administration.

How Supplied  ⮝

Product: 50090-3452

NDC: 50090-3452-0 20 TABLET in a BOTTLE

Diphenoxylate Hydrochloride And Atropine Sulfate ⮝

DIPHENOXYLATE HYDROCHLORIDE AND ATROPINE SULFATE diphenoxylate hydrochloride and atropine sulfate tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:50090-0040(NDC:0378-0415) 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 SILICON DIOXIDE (UNII: ETJ7Z6XBU4) MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U) STARCH, CORN (UNII: O8232NY3SJ) STEARIC ACID (UNII: 4ELV7Z65AP)

Product Characteristics Color WHITE Score no score Shape ROUND Size 6mm Flavor Imprint Code M;15 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:50090-0040-0 20 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product 11/28/2014

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA085762 11/17/1977

Labeler - A-S Medication Solutions (830016429)

Establishment
Name	Address	ID/FEI	Business Operations
A-S Medication Solutions		830016429	RELABEL(50090-0040) , REPACK(50090-0040)

Revised: 1/2019 Document Id: 0d1cd6bf-73d1-440f-aa0b-b266fefc484c 34391-3 Set id: 0eaf5362-9df0-40a1-af8b-84a1e65ae9cf Version: 8 Effective Time: 20190123 A-S Medication Solutions

Diphenoxylate Hydrochloride And Atropine Sulfate Tablet ⮝

DIPHENOXYLATE HYDROCHLORIDE AND ATROPINE SULFATE diphenoxylate hydrochloride and atropine sulfate tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:17856-1061(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:17856-1061-1 100 in 1 CONTAINER 05/11/2017 1 1 in 1 DOSE PACK ; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA AUTHORIZED GENERIC NDA012462 02/27/2013

Labeler - Atlantic Biologicals Corps (047437707)

Establishment
Name	Address	ID/FEI	Business Operations
Atlantic Biologicals Corps		047437707	RELABEL(17856-1061) , REPACK(17856-1061)

Revised: 6/2017 Document Id: 2fd64c85-4b05-4479-ac8a-883c39074539 34391-3 Set id: dec09873-1ccc-4efe-918d-337b3926384d Version: 3 Effective Time: 20170616 Atlantic Biologicals Corps

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

• Known hypersensitivity to diphenoxylate or atropine,
• Obstructive jaundice,
• 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.

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, diphenoxylate hydrochloride 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.

Information for Patients

INFORM THE PATIENT (PARENT OR GUARDIAN) NOT TO EXCEED THE RECOMMENDED DOSAGE AND TO KEEP THIS PRODUCT 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 and atropine sulfate 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 this product 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. Diphenoxylate hydrochloride and atropine sulfate 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 and atropine sulfate 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. This product should be used during pregnancy only if the anticipated benefit justifies the potential risk to the fetus.

Nursing Mothers

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

Pediatric Use

Diphenoxylate hydrochloride and atropine sulfate 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 AND ATROPINE SULFATE IS NOT RECOMMENDED FOR CHILDREN UNDER 2 YEARS OF AGE. Diphenoxylate hydrochloride and atropine sulfate 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.

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.

Drug Abuse And Dependence ⮝

Controlled Substance

Diphenoxylate hydrochloride and atropine sulfate tablets are classified as a Schedule V controlled substance. 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.

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.

Diagnosis

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 33261-0685-15
bottles of 15 tablets

NDC 33261-0685-30
bottles of 30 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.

Mylan Pharmaceuticals Inc.
Morgantown, WV 26505

Repackaged By :
Aidarex Pharmaceuticals LLC,
Corona, CA 92880

REVISED NOVEMBER 2009
DPXAS:R12

Repackaging Information ⮝

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.

Repackaged by:

Cookeville, TN 38506

20160610JH

Principal Display Panel  ⮝

NDC 43353-083 - Diphenoxylate Hydrochloride and Atropine Sulfate Tablets 2.5/0.025mg - Rx Only

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)

Revised: 6/2016 Document Id: a923a016-80b4-4a98-9494-ada455890843 34391-3 Set id: 59934cee-4e1f-4958-9e97-6de53b39daf3 Version: 1 Effective Time: 20160610 Aphena Pharma Solutions - Tennessee, LLC