Each five-sided dye free MOTOFEN® tablet contains:

Difenoxin (as the hydrochloride) . . .. . . . . . . . . . . . . . . . . . . .1.0 mg

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

Difenoxin hydrochloride, 1-(3-cyano-3,3-diphenylpropyl)-4-phenyl-4-piperidinecarboxylic acid monohydrochloride, is an orally administered antidiarrheal agent which is chemically related to the narcotic meperidine.

The structural formula is:

Difenoxin Hydrochloride

Atropine sulfate is present to discourage deliberate overdosage.

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

Inactive ingredients: calcium stearate, cellulose, lactose, corn starch.

Last updated on RxList: 5/12/2009

MOTOFEN® (difenoxin hydrochloride with atropine sulfate) is indicated as adjunctive therapy in the management of acute nonspecific diarrhea and acute exacerbations of chronic functional diarrhea.

The recommended starting dose of MOTOFEN® tablets in adults is 2 tablets (2 mg), then 1 tablet (1 mg) after each loose stool or 1 tablet (1 mg) every 3 to 4 hours as needed, but the total dosage during any 24-hour treatment period should not exceed 8 tablets (8 mg). In the treatment of diarrhea, if clinical improvement is not observed in 48 hours, continued administration of this type of medication is not recommended. For acute diarrheas and acute exacerbations of functional diarrhea, treatment beyond 48 hours is usually not necessary.

Studies in children below the age of 12 have been inadequate to evaluate the safety and effectiveness of MOTOFEN® in this age group. MOTOFEN® is contraindicated in children under 2 years of age.

MOTOFEN® is available as a white, dye-free, five-sided, scored tablet with “0500” on the scored side and “V” on the other. Each tablet contains 1.0 mg difenoxin (as the hydrochloride salt) and 0.025 mg atropine sulfate. Supplied in bottles of 50 tablets (NDC 0187-0500-01) and in bottles of 100 tablets (NDC 0187-0500-02).

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

Manufactured for : Valeant Pharmaceuticals International, 3300 Hyland Ave., Costa Mesa, CA 92626 U.S.A. By West-ward Pharmaceutical Corp., Eatontown, NJ 07724. Rev. 12/04

Last updated on RxList: 5/12/2009

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 lightheadedness, 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® (difenoxin hydrochloride with atropine sulfate) 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 the dosage on their own initiative.

Since the chemical structure of difenoxin hydrochloride is similar to meperidine hydrochloride, the concurrent use of MOTOFEN® with monoamine oxidase inhibitors may, in theory, precipitate a hypertensive crisis.

MOTOFEN® may potentiate the action of barbiturates, tranquilizers, narcotics, and alcohol. When these medications are used concomitantly with MOTOFEN®, the patient should be closely monitored.

Diphenoxylate hydrochloride, from which the principal active metabolite difenoxin is derived, was found to inhibit the hepatic microsomal enzyme system at a dose of 2 mg/kg/day in studies conducted with male rats. Therefore, difenoxin 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.

Last updated on RxList: 5/12/2009

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® (difenoxin hydrochloride with atropine sulfate) 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.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No evidence of carcinogenesis was found in a long-term study of difenoxin hydrochloride/atropine in the rat. In this 104 week study, rats received dietary doses of 0, 1.25, 2.5, or 5 mg/kg/day difenoxin/atropine (20:1 ratio).

No experiments have been conducted to determine the mutagenic potential of MOTOFEN®. MOTOFEN® did not significantly impair fertility in rats.

Pregnancy

Teratogenic Effects

Pregnancy Category C. Reproduction studies in rats and rabbits with doses at 31 and 61 times the human therapeutic dose respectively, on a mg/kg basis, demonstrated no evidence of teratogenesis due to MOTOFEN® (difenoxin hydrochloride with atropine sulfate).

Pregnant rats receiving oral doses of difenoxin hydrochloride/atropine 20 times the maximum human dose had an increase in delivery time as well as a significant increase in the percent of stillbirths.

Neonatal survival in rats was also reduced with most deaths occurring within four days of delivery.

There are no well controlled studies in pregnant women. MOTOFEN® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

Because of the potential for serious adverse reactions in nursing infants from MOTOFEN®, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

SAFETY AND EFFECTIVENESS IN CHILDREN BELOW THE AGE OF 12 HAVE NOT BEEN ESTABLISHED. MOTOFEN® IS CONTRAINDICATED IN CHILDREN UNDER 2 YEARS OF AGE. See OVERDOSAGE section for information on hazards from accidental poisoning in children.

Last updated on RxList: 5/12/2009

Diagnosis and Treatment

In the event of overdosage (initial signs may include dryness of the skin and mucous membranes, flushing, hyperthermia and tachycardia followed by lethargy or coma, hypotonic reflexes, nystagmus, pinpoint pupils and respiratory depression) gastric lavage, establishment of a patent airway and possibly mechanically assisted respiration are advised.

The narcotic antagonist naloxone may be used in the treatment of respiratory depression caused by narcotic analgesics or pharmacologically related compounds such as MOTOFEN® tablets. When naloxone is administered intravenously, the onset of action is generally apparent within two minutes. Naloxone may be administered subcutaneously or intramuscularly providing a slightly less rapid onset of action but a more prolonged effect.

To counteract respiratory depression caused by MOTOFEN overdosage, the following dosage schedule for naloxone should be followed:

Adult Dosage

The usual initial adult dose of naloxone is 0.4 mg (one mL) administered intravenously. If respiratory function does not adequately improve after the initial dose, the same IV dose may be repeated at two-to-three minute intervals.

Children

The usual adult dose of naloxone for children is 0.01 mg/kg of body weight administered intravenously and repeated at twoto-three minute intervals if necessary.

Since the duration of action of difenoxin hydrochloride is longer than that of naloxone, improvement of respiration following administration may be followed by recurrent respiratory depression. Consequently, continuous observation is necessary until the effect of difenoxin hydrochloride on respiration (which effect may persist for many hours) has passed. Supplemental intramuscular doses of naloxone may be utilized to produce a longer lasting effect. TREAT ALL POSSIBLE MOTOFEN® OVERDOSAGES AS SERIOUS AND MAINTAIN MEDICAL OBSERVATION FOR AT LEAST 48 HOURS, PREFERABLY UNDER CONTINUOUS HOSPITAL CARE.

Although signs of overdosage and respiratory depression may not be evident soon after ingestion of difenoxin hydrochloride, respiratory depression may occur from 12 to 30 hours later.

MOTOFEN® is contraindicated in patients with diarrhea associated with organisms that penetrate the intestinal mucosa (toxigenic E. coli, Salmonella species, Shigella) and pseudomembranous colitis associated with broad spectrum antibiotics. Antiperistaltic agents should not be used in these conditions because they may prolong and/or worsen diarrhea.

MOTOFEN® is contraindicated in children under 2 years of age because of the decreased margin of safety of drugs in this class in younger age groups.

MOTOFEN® is contraindicated in patients with a known hypersensitivity to difenoxin, atropine, or any of the inactive ingredients, and in patients who are jaundiced.

Last updated on RxList: 5/12/2009

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.

Last updated on RxList: 5/12/2009

CAUTION PATIENTS TO ADHERE STRICTLY TO RECOMMENDED DOSAGE SCHEDULES. THE MEDICATION SHOULD BE KEPT OUT OF REACH OF CHILDREN SINCE ACCIDENTAL OVERDOSAGE MAY RESULT IN SEVERE, EVEN FATAL, RESPIRATORY DEPRESSION.

MOTOFEN® may produce drowsiness or dizziness. The patient should be cautioned regarding activities requiring mental alertness, such as driving or operating dangerous machinery.

Last updated on RxList: 5/12/2009

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

DIFENOXIN/ATROPINE - ORAL

(dye-fen-OX-in/AT-trow-peen)

COMMON BRAND NAME(S): Motofen

USES: This medication is used to treat diarrhea. It helps to decrease the number and frequency of bowel movements. It works by slowing the movement of the intestines. Difenoxin is similar to narcotic pain relievers, but it acts mainly to slow the gut. Atropine belongs to a class of drugs known as anticholinergics, which help to dry up body fluids and also slow gut movement.

HOW TO USE: Take this medication by mouth, usually after each loose stool, or every 3 or 4 hours as needed or as directed by your doctor. Dosage is based on your medical condition and response to therapy. For adults, do not take more than 8 milligrams of difenoxin in any 24-hour period. If you need to continue treatment once your diarrhea is controlled, your doctor may direct you to lower your dosage. Do not increase your dose, take it more often, or use it for longer than prescribed.

It is important that you drink the proper amount of fluids and minerals (electrolytes) to prevent loss of body water (dehydration). Tell your doctor immediately if you develop signs of dehydration (e.g., extreme thirst, decreased urination, muscle cramps, weakness, fainting). You may also need to change to a bland diet during this time to reduce irritation to your stomach/intestines. Consult your doctor or pharmacist for more information.

This medication may cause dependence, especially if it has been used regularly for an extended time or if it has been used in high doses. In such cases, withdrawal reactions (e.g., stomach cramps, nausea, vomiting) may occur if you suddenly stop this drug. To prevent withdrawal reactions when stopping extended, regular treatment with this drug, gradually reduce the dosage as directed. Consult your doctor or pharmacist for more details, and report any withdrawal reactions immediately.

Inform your doctor if your condition does not improve after 2 days.

SIDE EFFECTS: See also Precautions for side effects seen in children.

Drowsiness, dizziness, headache, tiredness, blurred vision, dry mouth, and loss of appetite may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: stomach/abdominal pain or swelling, severe nausea, vomiting, mental/mood changes (e.g., confusion, depression), restlessness, numbness/tingling of arms/legs.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before taking difenoxin with atropine, tell your doctor or pharmacist if you are allergic to either drug; or if you have any other allergies.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: liver disease (e.g., obstructive jaundice, cirrhosis), diarrhea caused by certain types of infections (pseudomembranous colitis following recent antibiotic therapy, bacterial infection of the gut caused by E. coli, Salmonella, Shigella).

Before using this medication, tell your doctor or pharmacist your medical history, especially of: current dehydration or mineral imbalance, a certain type of bowel disease (acute ulcerative colitis).

This drug may make you dizzy or drowsy. Use caution while driving, using machinery, or doing any activity that requires alertness. Limit alcoholic beverages.

This drug is not recommended for use in children younger than 2 years. Caution is advised when using this drug in children, particularly those with Down's syndrome, because they may be more sensitive to the following side effects: high fever, fast heartbeat, decreased urination, flushing, dry skin/mouth, thirst. Very serious (possibly life-threatening) effects may occur if too much of this medication is taken by children.

During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor.

This medication passes into breast milk. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first.

This drug should not be used with the following medications because very serious interactions may occur: ambenonium, pramlintide.

If you are currently using any of the medications listed above, tell your doctor or pharmacist before starting difenoxin with atropine.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: MAO inhibitors (e.g., furazolidone, isocarboxazid, linezolid, moclobemide, phenelzine, procarbazine, rasagiline, selegiline, tranylcypromine), naltrexone, potassium tablets/capsules.

Tell your doctor or pharmacist if you also take drugs that cause drowsiness such as: certain antihistamines (e.g., diphenhydramine), anti-seizure drugs (e.g., carbamazepine), barbiturates (e.g., phenobarbital), medicine for sleep or anxiety (e.g., alprazolam, diazepam, zolpidem), muscle relaxants, narcotic pain relievers (e.g., codeine), psychiatric medicines (e.g., chlorpromazine, risperidone, amitriptyline, trazodone).

Check the labels on all your medicines (e.g., cough-and-cold products) because they may contain drowsiness-causing ingredients. Ask your pharmacist about using those products safely.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center. Symptoms of overdose may include: severe drowsiness, muscle weakness, fast heartbeat, high fever, unusually fast/slow/irregular breathing, seizures, loss of consciousness.

NOTES: Do not share this medication with others. It is against the law.

MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature between 59-86 degrees F (15-30 degrees C) away from light and moisture. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised August 2008 Copyright(c) 2008 First DataBank, Inc.