Motofen

In view of the small amount of atropine present (0.025 mg/tablet), such effects such as dryness of the skin and mucous membranes, flushing, hyperthermia, tachycardia and urinary retention are very unlikely to occur, except perhaps in children. Many of the adverse effects reported during clinical investigation of MOTOFEN® are difficult to distinguish from symptoms associated with the diarrheal syndrome. However, the following events were reported at the stated frequencies:

Gastrointestinal: Nausea, 1 in 15 patients; vomiting, 1 in 30 patients; dry mouth, 1 in 30 patients; epigastric distress, 1 in 100 patients; and constipation, 1 in 300 patients.

Central Nervous System: Dizziness and light-headedness, 1 in 20 patients; drowsiness, 1 in 25 patients; and headache, 1 in 40 patients; tiredness, nervousness, insomnia and confusion ranged from 1 in 200 to 1 in 600 patients.

Other less frequent reactions: Burning eyes and blurred vision occurred in a few cases.

The following adverse reactions have been reported in patients receiving chemically-related drugs: numbness of extremities, euphoria, depression, sedation, anaphylaxis, angioneurotic edema, urticaria, swelling of the gums, pruritus, toxic megacolon, paralytic ileus, pancreatitis, and anorexia.

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

MOTOFEN® tablets are a Schedule IV controlled substance.

Addiction to (dependence on) difenoxin hydrochloride is theoretically possible at high dosage. Therefore, the recommended dosage should not be exceeded. Because of the structural and pharmacological similarities of difenoxin hydrochloride to drugs with a definite addiction potential, MOTOFEN® should be administered with considerable caution to patients who are receiving addicting drugs, to individuals known to be addiction prone, or to those in whom histories suggest may increase dosage on their own initiative.

MOTOFEN® IS NOT AN INNOCUOUS DRUG AND DOSAGE RECOMMENDATIONS SHOULD BE STRICTLY ADHERED TO. MOTOFEN® 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.

FLUID AND ELECTROLYTE BALANCE - THE USE OF MOTOFEN® DOES NOT PRECLUDE THE ADMINISTRATION OF APPROPRIATE FLUID AND ELECTROLYTE THERAPY. DEHYDRATION, PARTICULARLY IN CHILDREN, MAY FURTHER INFLUENCE THE VARIABILITY OF RESPONSE TO MOTOFEN® AND MAY PREDISPOSE TO DELAYED DIFENOXIN INTOXICATION. DRUG-INDUCED INHIBITION OF PERISTALSIS MAY RESULT IN FLUID RETENTION IN THE COLON, AND THIS MAY FURTHER AGGRAVATE DEHYDRATION AND ELECTROLYTE IMBALANCE.

IF SEVERE DEHYDRATION OR ELECTROLYTE IMBALANCE IS MANIFESTED, MOTOFEN® SHOULD BE WITHHELD UNTIL APPROPRIATE CORRECTIVE THERAPY HAS BEEN INITIATED.

Ulcerative Colitis

In some patients with acute ulcerative colitis, agents which inhibit intestinal motility or delay intestinal transit time have been reported to induce toxic megacolon. Consequently, patients with acute ulcerative colitis should be carefully observed and MOTOFEN® therapy should be discontinued promptly if abdominal distention occurs or if other untoward symptoms develop.

Liver and Kidney Disease

MOTOFEN® should be used with extreme caution in patients with advanced hepatorenal disease and in all patients with abnormal liver function tests since hepatic coma may be precipitated.

Atropine

A subtherapeutic dose of atropine has been added to difenoxin hydrochloride to discourage deliberate overdosage. Usage of MOTOFEN® in recommended doses is not likely to cause prominent anticholinergic side effects, but MOTOFEN® should be avoided in patients in whom anticholinergic drugs are contraindicated. The warnings and precautions for use of anticholinergic agents should be observed. In children, signs of atropinism may occur even with recommended doses of MOTOFEN®, particularly in patients with Down's Syndrome.

Animal studies have shown that difenoxin hydrochloride manifests its antidiarrheal effect by slowing intestinal motility. The mechanism of action is by a local effect on the gastrointestinal wall.

Difenoxin is the principal active metabolite of diphenoxylate.

Following oral administration of MOTOFEN®, difenoxin is rapidly and extensively absorbed. Mean peak plasma levels of approximately 160 ng/mL occurred within 40 to 60 minutes in most patients following an oral dose of 2 mg. Plasma levels decline to less than 10% of their peak values within 24 hours and to less than 1% of their peak values within 72 hours. This decline parallels the appearance of difenoxin and its metabolites in the urine. Difenoxin is metabolized to an inactive hydroxylated metabolite. Both the drug and its metabolites are excreted, mainly as conjugates, in urine and feces.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Bloating
• constipation
• loss of appetite
• stomach pain (severe) with nausea and vomiting

Get emergency help immediately if any of the following symptoms of overdose occur:

• Blurred vision (continuing) or changes in near vision
• drowsiness (severe)
• dryness of mouth, nose, and throat (severe)
• fast heartbeat
• shortness of breath or troubled breathing (severe)
• unusual excitement, nervousness, restlessness, or irritability
• unusual warmth, dryness, and flushing of skin

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Blurred vision
• confusion
• difficult urination
• dizziness or lightheadedness
• drowsiness
• dryness of skin and mouth
• fever
• headache
• trouble in sleeping
• unusual tiredness or weakness

After you stop using this medicine, it may still produce some side effects that need attention. During this period of time, check with your doctor immediately if you notice the following side effects:

• Increased sweating
• muscle cramps
• nausea or vomiting
• shivering or trembling
• stomach cramps

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

• It is used to treat loose stools (diarrhea).

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Feeling sleepy.
• Dizziness.
• Upset stomach.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

Animal studies have shown that difenoxin hydrochloride manifests its antidiarrheal effect by slowing intestinal motility. The mechanism of action is by a local effect on the gastrointestinal wall.

Difenoxin is the principal active metabolite of diphenoxylate.

Following oral administration of Motofen®, difenoxin is rapidly and extensively absorbed. Mean peak plasma levels of approximately 160 ng/mL occurred within 40 to 60 minutes in most patients following an oral dose of 2 mg. Plasma levels decline to less than 10% of their peak values within 24 hours and to less than 1% of their peak values within 72 hours. This decline parallels the appearance of difenoxin and its metabolites in the urine. Difenoxin is metabolized to an inactive hydroxylated metabolite. Both the drug and its metabolites are excreted, mainly as conjugates, in urine and feces.

Motofen® is available as a white, dye-free, five-sided, scored tablet with “0200” on the scored side and "M" on the other side. Each tablet contains 1 mg difenoxin and 0.025 mg atropine sulfate. Supplied in bottles of 100 tablets (NDC 54766-200-10). Store at 20°-25°C (68°-77°F) [See USP Controlled Room Temperature].

Distributed by:

Sebela Pharmaceuticals Inc.

645 Hembree Parkway, Suite I

Roswell, GA 30076

www.sebelapharma.com

Motofen is a registered trademark of Sebela International Limited

PI 20010 0217

Rev. Mar. 2017

Applies to atropine / difenoxin: oral tablet

Gastrointestinal

Gastrointestinal side effects have included nausea (1 in 15 patients), vomiting (1 in 30 patients), dry mouth (1 in 30 patients), epigastric distress (1 in 100 patients), and constipation ( 1 in 300 patients).

In patients receiving chemically-related drugs, toxic megacolon, paralytic ileus, pancreatitis, and anorexia have been reported.[Ref]

Cardiovascular

Cardiovascular side effects have included tachycardia with the use of atropine.[Ref]

Nervous system

Nervous system side effects have included dizziness (1 in 20 patients), lightheadedness (1 in 20 patients), drowsiness (1 in 25 patients), headache (1 in 40 patients). Other less common side effects have included tiredness and insomnia.

Patients receiving chemically-related drugs have reported confusion, numbness of extremities, euphoria, depression, and sedation.[Ref]

Hypersensitivity

Hypersensitivity side effects have included anaphylaxis, angioneurotic edema, urticaria, swelling of the gums, and pruritus.[Ref]

Ocular

Ocular side effects have included burning eyes and blurred vision.[Ref]

General

General side effects reported with use of atropine have included flushing and hyperthermia.[Ref]

Genitourinary

Genitourinary side effects have included urinary retention with use of atropine.[Ref]

Some side effects of Motofen may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.