止泻宁

DESCRIPTION

Each Lomotil tablet contains:

diphenoxylate hydrochloride 2.5 mgatropinesulfate ...............0.025 mg

Diphenoxylate hydrochloride, an antidiarrheal, is ethyl 1-(3-cyano-3,3-diphenylpropyl)4- phenylisonipecotate monohydrochloride and has the following structural formula:

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

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

Inactive ingredients of Lomotil tablets include acacia, corn starch, magnesium stearate, sorbitol, sucrose, and talc.

INDICATIONS

止泻宁is indicated as adjunctive therapy in the management of diarrhea in patients 13 years of age and older.

DOSAGE AND ADMINISTRATION

Management Of Diarrhea In Patients 13 Years Of Age And Older

止泻宁is 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 Lomotil. The use of Lomotil should be accompanied by appropriate fluid and electrolyte therapy, when indicated. If severe dehydration or electrolyte imbalance is present, do not administer Lomotil until appropriate corrective therapy has been indicated (see警告).

Initial And Maximum Recommended Dosage In Patients 13 Years Of Age And Older

The initial adult dosage is 2 Lomotil 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 Lomotil dosage may be reduced to meet individual requirements. Control may often be maintained with as little as two Lomotil 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 Lomotil as symptoms are unlikely to be controlled by further administration.

HOW SUPPLIED

Tablets - round, white, with SEARLE debossed on one side and 61 on the other side and containing 2.5 mg of diphenoxylate hydrochloride and 0.025 mg of atropine sulfate, supplied as:

NDC Number	大小
0025-0061-31	bottle of 100

Store below 25°C (77°F).

This product’s label may have been updated. For current full prescribing information, please visit www.pfizer.com.

Distributed by: Pfizer, G.D.Searle LLC, Division of Pfizer Inc, NY, NY 10017. Revised Oct 2017

SIDE EFFECTS

The following serious adverse reactions are described elsewhere in labeling:

• Respiratory and/or CNS depression (see警告)
• Anticholinergic and opioid-toxicities, including atroponism (see警告andPRECAUTIONS)
• Dehydration and electrolyte imbalance (see警告)
• GI Complications in patients with infectious diarrhea (see警告)
• Toxic megacolon in patients with acute ulcerative colitis (see警告)

Attherapeuticdoses of Lomotil, 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 andmucousmembranes.

DRUG INTERACTIONS

Alcohol

Alcohol may increase the CNS depressant effects of Lomotil and may cause drowsiness (see警告). Avoid concomitant use of Lomotil with alcohol.

Other Drugs That Cause CNS Depression

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

Drug Abuse And Dependence

Controlled Substance

止泻宁is classified as a Schedule V controlled substance by federal regulation. Diphenoxylate hydrochloride is chemically related to thenarcoticanalgesicmeperidine.

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 ofmorphine-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 causescentral nervous system效果。不溶性的苯乙哌啶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, producedopiatewithdrawal symptoms. Since addiction to diphenoxylate hydrochloride is possible at high doses, the recommended dosage should not be exceeded.

警告

Respiratory And/Or CNS Depression In Pediatric Patients Less Than 6 Years Of Age

Cases of severerespiratory depressionand coma, leading to permanent brain damage or death have been reported in patients less than 6 years of age who received Lomotil. Lomotil is contraindicated in patients less than 6 years of age due to these risks (seeCONTRAINDICATIONS).

Anticholinergic And Opioid-Toxicities

Toxicities associated with the atropine and diphenoxylate components of Lomotil have been reported. The initial presenting symptoms may be delayed by up to 30 hours due to prolongedgastricemptying time induced by diphenoxylate hydrochloride. Clinical presentations vary in terms of which toxicity (anticholinergicvs.opioid) will present first or predominate; non-specific findings have been reported and include symptoms such as drowsiness (seeOVERDOSE).

Dehydration And Electrolyte Imbalance

The use of Lomotil should be accompanied by appropriate fluid andelectrolytetherapy, when indicated. If severe dehydration or electrolyte imbalance is present, Lomotil should be withheld until appropriate corrective therapy has been initiated. Drug-induced inhibition ofperistalsismay result in fluid retention in the intestine, which may further aggravate dehydration and electrolyte imbalance.

Gastrointestinal Complications In Patients With Infectious Diarrhea

止泻宁is contraindicated in patients with diarrhea associated with organisms that penetrate theGImucosa(产毒素的E. coli, Salmonella, Shigella), and pseudomembranous enterocolitis (Clostridium difficile) associated with broad-spectrum antibiotics (seeCONTRAINDICATIONS). Antiperistaltic agents, including Lomotil, slowgastrointestinalmotility and may enhance bacterial overgrowth and the release of bacterial exotoxins. Lomotil has been reported to result in serious GI complications in patients with infectious diarrhea, includingsepsis, prolonged and/or worsened diarrhea. Prolonged fever and the delay in the resolution ofstoolpathogens were reported in study ofShigellosisin adults who used Lomotil vs. placebo.

Toxic Megacolon In Patients With Acute Ulcerative Colitis

In some patients with acuteulcerative colitis, agents that inhibit intestinal motility or prolong intestinal transit time have been reported to induce toxic megacolon. Consequently, patients with acute ulcerativecolitisshould be carefully observed and Lomotil therapy should be discontinued promptly if abdominaldistentionoccurs or if other untoward symptoms develop.

Interaction With Meperidine Hydrocholoride

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

Hepatorenal Disease

止泻宁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 Lomotil, consideration should be given to the development of adverse reactions associated with of atropine (see警告).Lomotil has caused atropinism (hyperthermia, tachycardia, urinary retention, flushing, dryness of the skin and mucous membranes) particularly in pediatric patients with Down’s syndrome. Lomotil is not indicated for use in pediatric patients (seeCONTRAINDICATIONSand警告). Monitor patients for signs of atropinism.

Carcinogenesis, Mutagenesis, Impairment Of Fertility

No long-term study in animals has been performed to evaluatecarcinogenicpotential. 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 Lomotil 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, orteratogeniceffects 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. Lomotil should be used during pregnancy only if the anticipated benefit justifies the potential risk to the fetus.

Nursing Mothers

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

儿童使用

The safety and effectiveness of Lomotil 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 Lomotil have not been established in pediatric patients less than 13 years of age.

止泻宁禁忌在儿科患者less than 6 years of age due to the risks of severe respiratory depression and coma, possibly resulting in permanent brain damage or death (seeCONTRAINDICATIONS).

止泻宁has caused atropinism, particularly in pediatric patients with Down’s syndrome (seePRECAUTIONS).

In case of accidental ingestion of Lomotil by pediatric patients, seeOVERDOSEfor recommended treatment.

OVERDOSE

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,mydriasisormiosis, flushing, hyperthermia, tachycardia, hypotonia, tachypnea, toxicencephalopathy, 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 Lomotil overdosages as serious and maintain medical observation/hospitalization until patients become asymptomatic withoutnaloxoneuse.

Treatment

A pure narcoticantagonist(e.g., naloxone) should be used in the treatment of respiratory depression caused by Lomotil. Refer to the prescribing information for naloxone. Consider Lomotil toxicity even in settings of negative toxicology tests.

Following initial improvement of respiratory function, repeated doses of naloxone hydrochloride may be required to counteractrecurrentrespiratory depression.

If over-exposure occurs, call your Poison Control Center at 1-800-222-1222 for current information on the management ofpoisoningor overdosage.

CONTRAINDICATIONS

止泻宁is contraindicated in:

• Pediatric patients less than 6 years of age due to the risks of respiratory and central nervous system (CNS) depression (see警告).
• 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警告).
• Patients with known hypersensitivity to diphenoxylate or atropine.
• Patients with obstructivejaundice.

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 Lomotil 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 circularsmooth muscleof 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.

PATIENT INFORMATION

Advise Patients

• Accidental ingestion of Lomotil in children, especially in those less than 6 years of age, may result in severe respiratory depression or coma. Instruct patients to take steps to store Lomotil securely and out of reach of children, and to dispose of unused Lomotil (see警告).
• 采取止泻宁在规定的剂量。使用higher than prescribed dosage may include opioid and/or anticholinergic effects (seeOVERDOSE). Report to a healthcare facility if they develop anticholinergic symptoms such as hyperthermia, flushing, tachycardia, tachypnea, hypotonia, lethargy, hallucinations,febrileconvulsion,dry mouth, mydriasis or opioid symptoms such as progressive CNS and respiratory depression, miosis, seizures, or paralyticileus.
• 止泻宁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 Lomotil does not affect them adversely.
• To use fluid and electrolyte therapy, if prescribed along with Lomotil, 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 Lomotil and contact their healthcare provider.