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LOPERAMIDE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Loperamide is a synthetic opioid analog which inhibits gut motility. It is structurally similar to both haloperidol and diphenoxylate.

Specific Substances

    1) PJ185
    2) R18553
    3) Molecular Formula: C29-H33-Cl-N2-O2
    4) CAS 53179-11-6

Available Forms Sources

    A) FORMS
    1) Loperamide is available as 2 mg capsules; 2 mg liquid-filled capsules, 1 mg/7.5 mL and 1 mg/5 mL oral solution, 2 mg oral tablets, and 2 mg chewable tablets (Prod Info IMODIUM(R) A-D oral liquid, oral caplets, 2006; Prod Info IMODIUM(R) A-D oral liquid, children's, 2006; Prod Info loperamide hcl oral capsules, 2005).
    B) USES
    1) Loperamide inhibits gut mobility and is approved for the treatment of acute diarrhea, including travel's diarrhea. It is also used for chronic diarrhea (irritable bowel syndrome) and high output ileostomy (Prod Info IMODIUM(R) A-D oral liquid, oral caplets, 2006; Prod Info IMODIUM(R) A-D oral liquid, children's, 2006; Prod Info loperamide hcl oral capsules, 2005).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Loperamide is a synthetic opioid medication that is used as an antidiarrheal agent.
    B) PHARMACOLOGY: Loperamide acts directly via opioid receptors on circular and longitudinal intestinal muscles to inhibit peristalsis and prolong transit time. In addition, it causes reduction of fecal volume, increases viscosity, diminishes fluid and electrolyte loss, and shows antisecretory activity. It also increases tone on the anal sphincter.
    C) TOXICOLOGY: The toxicity of loperamide is from its direct action on opioid receptors. In addition, dystonic reactions may develop after toxic doses from the portion of the molecule that is structurally similar to haloperidol.
    D) EPIDEMIOLOGY: Loperamide is widely used worldwide and is readily available. Thousands of exposures are reported to poison centers every year. Severe toxicity is rare, but fatalities have been reported in infants.
    E) WITH THERAPEUTIC USE
    1) Significant adverse reactions that occur include dizziness and gastrointestinal complaints (ie, constipation, abdominal cramping, nausea). Even in therapeutic doses, paralytic ileus has been reported. In case and postmarketing reports, there were reports of abdominal distention and pain, allergic reactions, anaphylactoid reactions and anaphylactic shock, angioedema, bullous eruptions, drowsiness, dyspepsia, erythema multiforme, fatigue, flatulence, paralytic ileus, pruritus, rash, Stevens-Johnson syndrome and toxic epidermal necrolysis, toxic megacolon, urinary retention, urticaria, vomiting and xerostomia.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: The most common reported overdose effects are drowsiness, nausea, vomiting, abdominal pain, and headache. Miosis is also a common finding in overdose. Both bradycardia and respiratory depression can occur. Dystonic reactions have been rarely reported. There is one case report of a loperamide overdose resulting in pancreatitis and another mentions hyponatremia resulting in a seizure.
    2) SEVERE TOXICITY: CNS depression may be severe. Respiratory depression can lead to apnea and respiratory acidosis. Cardiac dysrhythmias (eg, prolonged QRS and QT intervals, monomorphic and polymorphic (torsades de pointes) ventricular dysrhythmias) have been reported in patients abusing large doses of loperamide.
    0.2.20) REPRODUCTIVE
    A) Loperamide is in pregnancy category B. It is not known if loperamide is excreted into human milk. Rat reproduction studies of loperamide showed that doses 150 to 200 times the normal human dose could result in marked female infertility and decreased male fertility.

Laboratory Monitoring

    A) Monitor vital signs and pulse oximetry.
    B) Monitor for CNS and respiratory depression.
    C) Loperamide concentrations are not widely available or clinically useful to guide management.
    D) Obtain serum electrolytes, acetaminophen and salicylate concentrations after deliberate overdose.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Supportive care is the mainstay of treatment. Administer naloxone for CNS or respiratory depression.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Supportive care is the mainstay of treatment. Administer oxygen and monitor for respiratory and CNS depression. Administer naloxone to reverse respiratory or significant CNS depression. Treat dystonic reactions with benztropine (1 to 4 mg IV or orally, maximum 6 mg/day) or diphenhydramine. Assisted ventilation may be needed. Cardiac dysrhythmias (eg, prolonged QRS and QT intervals, monomorphic and polymorphic (torsades de pointes [TdP]) ventricular dysrhythmias) developed in 5 patients with a history of loperamide abuse (doses: 70 mg to 792 mg daily). Treatment with standard anti-arrhythmic agents were ineffective; however, electrical overdrive pacing or isoproterenol continuous infusion were effective in treating dysrhythmias and preventing further episodes of TdP.
    C) DECONTAMINATION
    1) PREHOSPITAL: Prehospital gastrointestinal decontamination is not recommended because of the risk of CNS depression and subsequent aspiration.
    2) HOSPITAL: Activated charcoal may be considered if the patient is alert and cooperative and the ingestion has occurred within the past hour.
    D) AIRWAY MANAGEMENT
    1) Airway management may be an issue for loperamide overdoses, but nearly all cases should be able to avoid intubation by using naloxone.
    E) ANTIDOTE
    1) Naloxone is a pure opioid antagonist that can be used to reverse the effects of loperamide. It should be used in patients with moderate to severe symptoms, especially those with respiratory depression. Initial doses can be from 0.2 to 2 mg and can be titrated to effect.
    F) ENHANCED ELIMINATION PROCEDURE
    1) There is no evidence for the use of dialysis, hemoperfusion, urinary alkalinization, or multiple dose charcoal. As loperamide is highly protein bound (97%) and the drug primarily distributed to the gastrointestinal tract, it is highly unlikely that dialysis or hemoperfusion would have much utility.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: Asymptomatic children over 6 months of age who ingest up to 0.4 mg/kg can be managed at home without gastrointestinal decontamination. Adults who are asymptomatic with inadvertent ingestions may be left at home as well.
    2) OBSERVATION CRITERIA: Any patient who ingested loperamide with self-harm attempt and any patient with symptoms needs to be sent to a healthcare facility for observation. Any infants under the 6 months of age with loperamide ingestion, and children more than 6 months of age who have ingested more than 0.4 mg/kg should be sent to a healthcare facility for observation. Patients can be discharged once they are clearly improving without treatment or asymptomatic.
    3) ADMISSION CRITERIA: Patients with severe CNS or respiratory depression and who require multiple doses of naloxone to reverse symptoms, should be admitted to the hospital. Patients with severe symptoms may require ICU care. Patients may be discharged from the hospital when they are clearly improving without medical intervention.
    4) CONSULT CRITERIA: Consult a medical toxicologist or poison center for patients with severe toxicity or in whom the diagnosis is unclear.
    H) PITFALLS
    1) Pitfalls in management include not using naloxone to reverse symptoms and not recognizing other potential causes of symptoms.
    I) PHARMACOKINETICS
    1) Gastrointestinal absorption of loperamide is poor (0.3%), and it has poor penetration into the central nervous system. It is metabolized hepatically via oxidative N-demethylation. Its half-life of elimination is 7 to 15 hours. Its time to peak in plasma is 2.5 hours in liquid form and 5 hours in capsule form. It is highly protein bound (97%). Loperamide is primarily excreted in the feces (25 to 40%) with minimal (1.3%) excretion in the urine.
    J) DIFFERENTIAL DIAGNOSIS
    1) The differential diagnosis for loperamide ingestions includes other opioid ingestions and other medications/substances that can cause CNS and respiratory depression.

Range Of Toxicity

    A) TOXICITY: Six deaths were reported following complications secondary to misuse of loperamide in infants less than 6.5 months of age. ADULTS: Two fatalities have been reported after loperamide abuse. Both patients had significantly high loperamide concentrations (77 ng/mL and 140 ng/mL, respectively). Even in therapeutic doses, patients may experience mild to more severe toxicity, including paralytic ileus. Repeated low doses (0.12 mg/kg for 3 doses in an infant, 0.27 mg/kg/day in a neonate) have caused CNS and respiratory depression. Cardiac dysrhythmias (eg, prolonged QRS and QT intervals, monomorphic and polymorphic [torsades de pointes] ventricular dysrhythmias) developed in 5 patients with a history of loperamide abuse (doses: 70 mg to 792 mg daily). All patients recovered following supportive care.
    B) THERAPEUTIC DOSE: ADULTS: Initially, 4 mg orally followed by 2 mg after each loose stool up to a maximum of 16 mg/day. CHILDREN: Loperamide should never by given to infants/children under the age of 2 years. Doses depend on age or weight of the child. First day dosage: 2 to 5 years of age (13 to 20 kg): 1 mg orally 3 times daily. 6 to 8 years of age (20 to 30 kg): 2 mg orally twice daily. 8 to 12 years (greater than 30 kg): 2 mg orally 3 times daily. Subsequent daily dosage: 2 to 12 years of age: 1 mg/10 kg of body weight orally only after a loose stool, total daily dose should not exceed dosages for the first day.

Clinical Effects

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) PERSONALITY DISORDER
    1) WITH THERAPEUTIC USE
    a) Irritability, unacceptable behavior, and personality changes occurred after doses of 0.5 mg TID for 3 to 5 days (0.1 to 0.12 mg/kg/day). The effects persisted for 48 hours after the drug was discontinued (Marcovitch, 1980).
    B) CENTRAL NERVOUS SYSTEM DEFICIT
    1) WITH POISONING/EXPOSURE
    a) Overdose has lead to coma, with children more sensitive to CNS effects than adults (Prod Info Imodium(R) capsules, loperamide hydrochloride, 2000; Litovitz et al, 1997; Tan, 1983).
    b) CASE SERIES: In a retrospective survey of 79 overdoses with loperamide-related symptoms, the most common symptom reported was drowsiness or lethargy, occurring in 15.7% (Litovitz et al, 1997).
    c) CASE REPORT: A 26-month-old child had loss of consciousness after receiving 0.09 mg/kg loperamide, and recovered after two doses (0.4 mg/kg per dose) of naloxone (Chanzy et al, 2004).
    C) DYSTONIA
    1) WITH POISONING/EXPOSURE
    a) Dystonic reactions, although rare, have been seen with toxic doses (RMPCC Case Files, 1978).
    D) SEIZURE
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 35-year-old man developed coma, mydriasis, hyponatremia (115 mEq/L) and a single seizure after ingesting 40 loperamide pills (Litovitz et al, 1997).
    E) FATIGUE
    1) WITH THERAPEUTIC USE
    a) Fatigue has been reported rarely with loperamide use (Heel et al, 1978b; Pelemans & Vantrappen, 1976; Demeulenaere et al, 1974).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) GASTRITIS
    1) WITH POISONING/EXPOSURE
    a) In a retrospective survey of 79 symptomatic loperamide overdoses, 4.2% were reported to have vomiting and 3.7% had abdominal pain or distension (Litovitz et al, 1997). Vomiting was reported in an adult following three 20 mg doses within a 24 hour period (Prod Info Imodium(R) capsules, loperamide hydrochloride, 2000).
    b) Xerostomia, dyspepsia and flatulence have occurred following administration of loperamide (Prod Info IMODIUM(R) oral capsules, 2005).
    B) DRUG-INDUCED ILEUS
    1) WITH THERAPEUTIC USE
    a) Paralytic ileus has been reported following administration of loperamide (Prod Info IMODIUM(R) oral capsules, 2005).
    b) Severe abdominal distension and paralytic ileus have been reported in infants given doses varying from 6 to 30 drops/day (Bhutta & Tahir, 1990); or 0.8 mg/kg/day (Motala et al, 1990).
    c) Necrotizing enterocolitis has occurred in two patients (Chow et al, 1988); loperamide may have been implicated in the development of NEC in these patients.
    2) WITH POISONING/EXPOSURE
    a) Paralytic ileus associated with abdominal distress has been reported in the setting of acute dysentery, loperamide overdose, and with very young children (less than 2 years old) (Prod Info Imodium(R) capsules, loperamide hydrochloride, 2000).
    C) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) Constipation has been reported (Prod Info IMODIUM(R) oral capsules, 2005).
    D) PANCREATITIS
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Elevation of pancreatic enzymes (amylase 639 units/L and lipase 1200 units/L) was reported following a suicide attempt with loperamide in an 18-year-old girl. A normal pancreas and undilated biliary tract was shown on abdominal sonogram (Epelde et al, 1996). The authors speculated a spasm of the sphincter of Oddi, an opioid type effect, may have been responsible for the elevated enzyme levels.
    b) CASE REPORT: A 17-year-old girl presented with mild epigastric pain 2 hours after ingesting 600 mg of trimebutine (an antispasmodic) and 18 mg of loperamide. Laboratory results revealed lipase and amylase concentrations of 6417 international Units (IU)/L and 758 IU/L, respectively, 3 hours postingestion. Her lipase and amylase concentrations 3.5 hours later were 3000 IU/L and 591 IU/L, respectively. Following supportive care, her symptoms gradually resolved and her lipase and amylase concentrations normalized within 30 hours after her overdose (Lee et al, 2011).
    E) TOXIC MEGACOLON
    1) WITH THERAPEUTIC USE
    a) Toxic megacolon was associated with the use of loperamide in a patient with ulcerative colitis (Brown, 1979).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) RETENTION OF URINE
    1) WITH THERAPEUTIC USE
    a) Since loperamide has opiate-like properties in large doses and since opiates can cause increased urethral pressure, it is theoretically possible that loperamide could cause urinary retention in patients with structural or neurologic urogenital defects who have borderline retention (Bessada et al, 1979).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) STEVENS-JOHNSON SYNDROME
    1) WITH THERAPEUTIC USE
    a) Stevens-Johnson syndrome has rarely been reported following administration with loperamide (Prod Info IMODIUM(R) oral capsules, 2005).
    B) LYELL'S TOXIC EPIDERMAL NECROLYSIS, SUBEPIDERMAL TYPE
    1) WITH THERAPEUTIC USE
    a) Following administration of loperamide, rare cases of toxic epidermal necrolysis have been reported (Prod Info IMODIUM(R) oral capsules, 2005).
    C) ERYTHEMA MULTIFORME
    1) WITH THERAPEUTIC USE
    a) Erythema multiforme has rarely been reported following administration with loperamide (Prod Info IMODIUM(R) oral capsules, 2005).
    D) URTICARIA
    1) WITH THERAPEUTIC USE
    a) Urticaria and pruritus have been reported following administration with loperamide (Prod Info IMODIUM(R) oral capsules, 2005).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HYPERGLYCEMIA
    1) WITH THERAPEUTIC USE
    a) Doses of 4, 8, and 16 mg significantly increased blood glucose (Caldara et al, 1981).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ACUTE ALLERGIC REACTION
    1) WITH THERAPEUTIC USE
    a) Allergic reactions, angioedema, anaphylactoid reactions and anaphylactic shock, have been reported following administration with loperamide (Prod Info IMODIUM(R) oral capsules, 2005).

Reproductive

    3.20.1) SUMMARY
    A) Loperamide is in pregnancy category B. It is not known if loperamide is excreted into human milk. Rat reproduction studies of loperamide showed that doses 150 to 200 times the normal human dose could result in marked female infertility and decreased male fertility.
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    LOPERAMIDEB
    Reference: Briggs et al, 1998
    B) NO EFFECT
    1) In a prospective cohort study of 105 pregnant women exposed to loperamide during pregnancy, there were no statistically significant differences in pregnancy outcome from controls (eg; spontaneous or therapeutic abortions, major or minor malformations, mean birth weight) (Einarson et al, 2000).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) It is not known if loperamide is excreted into human milk (Prod Info Imodium(R) capsules, loperamide hydrochloride, 2000).
    3.20.5) FERTILITY
    A) FERTILITY DECREASED FEMALE
    1) Rat reproduction studies of loperamide showed that doses 150 to 200 times the normal human dose could result in marked female infertility and decreased male fertility (Prod Info Imodium(R) capsules, loperamide hydrochloride, 2000).

Summary Of Exposure

    A) USES: Loperamide is a synthetic opioid medication that is used as an antidiarrheal agent.
    B) PHARMACOLOGY: Loperamide acts directly via opioid receptors on circular and longitudinal intestinal muscles to inhibit peristalsis and prolong transit time. In addition, it causes reduction of fecal volume, increases viscosity, diminishes fluid and electrolyte loss, and shows antisecretory activity. It also increases tone on the anal sphincter.
    C) TOXICOLOGY: The toxicity of loperamide is from its direct action on opioid receptors. In addition, dystonic reactions may develop after toxic doses from the portion of the molecule that is structurally similar to haloperidol.
    D) EPIDEMIOLOGY: Loperamide is widely used worldwide and is readily available. Thousands of exposures are reported to poison centers every year. Severe toxicity is rare, but fatalities have been reported in infants.
    E) WITH THERAPEUTIC USE
    1) Significant adverse reactions that occur include dizziness and gastrointestinal complaints (ie, constipation, abdominal cramping, nausea). Even in therapeutic doses, paralytic ileus has been reported. In case and postmarketing reports, there were reports of abdominal distention and pain, allergic reactions, anaphylactoid reactions and anaphylactic shock, angioedema, bullous eruptions, drowsiness, dyspepsia, erythema multiforme, fatigue, flatulence, paralytic ileus, pruritus, rash, Stevens-Johnson syndrome and toxic epidermal necrolysis, toxic megacolon, urinary retention, urticaria, vomiting and xerostomia.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: The most common reported overdose effects are drowsiness, nausea, vomiting, abdominal pain, and headache. Miosis is also a common finding in overdose. Both bradycardia and respiratory depression can occur. Dystonic reactions have been rarely reported. There is one case report of a loperamide overdose resulting in pancreatitis and another mentions hyponatremia resulting in a seizure.
    2) SEVERE TOXICITY: CNS depression may be severe. Respiratory depression can lead to apnea and respiratory acidosis. Cardiac dysrhythmias (eg, prolonged QRS and QT intervals, monomorphic and polymorphic (torsades de pointes) ventricular dysrhythmias) have been reported in patients abusing large doses of loperamide.

Heent

    3.4.3) EYES
    A) MIOSIS
    1) WITH POISONING/EXPOSURE
    a) Miosis is a common finding in overdose. This sign may be altered in the presence of hypoxia, severe acidosis, or respiratory depression (Friedli & Haenggeli, 1980).
    B) MYDRIASIS
    1) WITH POISONING/EXPOSURE
    a) Mydriasis has also been reported in one case (Litovitz et al, 1997).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) BRADYCARDIA
    1) WITH POISONING/EXPOSURE
    a) Bradycardia with ventricular ectopic beats was reported in one case (Tan, 1983).
    B) CONDUCTION DISORDER OF THE HEART
    1) WITH POISONING/EXPOSURE
    a) Cardiac dysrhythmias (eg, prolonged QT interval, ventricular tachycardia, torsades de pointes, syncope, cardiac arrest) have been reported in patients who were intentionally misusing and abusing high doses of loperamide, to either reduce opioid withdrawal symptoms or to achieve a feeling of euphoria. From 1976 (initial FDA approval) through December 2015, 48 cases of serious cardiac events (24 syncope, 13 cardiac arrests, 13 prolonged QT interval, 10 ventricular tachycardia, and 7 torsades de pointes), including 10 deaths, were reported to the FDA Adverse Event Reporting System (FAERS) database. The reported mean loperamide dose was 195 mg/day (range, 1 to 1600 mg/day). Despite the use of standard antiarrhythmic medications in these patients, no improvements were observed; however, the use of electrical pacing resulted in control of the dysrhythmias (US Food and Drug Administration (FDA), 2016; Marraffa et al, 2014).
    1) DRUG INTERACTION: Concurrent use of loperamide with drugs that are cytochrome P450 (CYP3A4 or CYP2C8) or P-glycoprotein inhibitors (eg, quinidine), can increase loperamide blood concentrations and result in loperamide toxicity. Cardiac dysrhythmias have been observed in patients taking high doses of loperamide in combination with other medications, to increase loperamide absorption and penetration across the blood-brain barrier, inhibit loperamide metabolism, and enhance its euphoric effects. Drugs that can potentially interact with loperamide include cimetidine, clarithromycin, erythromycin, gemfibrozil, itraconazole, ketoconazole, quinidine, quinine, ranitidine, and ritonavir (US Food and Drug Administration (FDA), 2016).
    b) CASE SERIES: Cardiac dysrhythmias developed in 5 patients with a history of loperamide abuse. All patients had normal or nearly normal electrolyte concentrations (Marraffa et al, 2014).
    1) An ECG of the first patient, a 30-year-old man who was abusing loperamide (up to 200 2-mg loperamide tablets daily for several weeks), revealed a wide QRS and a QTc of over 500 ms, suggesting an accelerated idioventricular rhythm. His condition deteriorated with several episodes of polymorphic ventricular tachycardia and cardiac arrest. He was successfully resuscitated and cardiac catheterization and electrophysiology studies were unremarkable. Following further supportive care, his condition resolved and he was discharged with an ECG showing only T wave inversions over the precordium. On a follow-up visit a month later, his ECG was normal (Marraffa et al, 2014).
    2) The second patient, a 43-year-old woman with a history of opioid abuse, used 144 loperamide tablets (2 mg daily) to manage opioid withdrawal, and developed several episodes of torsades de pointe (TdP) that were unresponsive to lidocaine, amiodarone, sodium bicarbonate, magnesium, lipid rescue therapy, and repeated cardioversion. On presentation, an ECG revealed a sinus rhythm with a QRS of 130 ms and QTc of 684 msec with frequent PVCs. Her symptoms resolved following a transvenous pacemaker insertion with overdrive pacing. On day 5, she was discharged following further supportive care. At that time, an ECG revealed a sinus rhythm with a QRS of 98 msec and QT/QTc of 462/421 msec. On a follow-up visit, her electrophysiology evaluation was normal (Marraffa et al, 2014).
    3) Patient 3 (a 28-year-old man) with a medical history of Crohn's disease and substance abuse, who was taking amitriptyline and loperamide (over 396 loperamide 2-mg tablets; 792 mg daily), presented with syncope and recurrent wide complex tachycardia. An initial ECG revealed a sinus rhythm with a rate of 56 beats/min, QRS of 162 msec, and QT/QTc of 670/647 msec. He developed sustained and nonsustained pulseless ventricular tachycardia that were refractory to magnesium sulfate, potassium chloride, sodium bicarbonate, lidocaine, lipid emulsion therapy, and repeated defibrillation. His symptoms resolved following a transvenous pacemaker insertion with overdrive pacing for 2 days and then received an isoproterenol infusion. On day 5 during the pacemaker wire removal, he developed bradycardia and an episode of torsades de pointe (TdP). He still had prolonged QRS and QTc intervals, with QTc interval of greater than 500 msec lasting until hospital day 10. Laboratory results revealed a serum loperamide concentration of 130 ng/mL (5 hours after presentation). A month later, his ECG was normal. A year after the first presentation, he developed a cardiac arrest, as well as a prolonged QTc and TdP during a surgery for complications of Crohn's disease. He was successfully defibrillated and was transported to the surgical ICU. He was treated with an isoproterenol infusion for about 24 hours with no further dysrhythmias. At this time, he admitted in taking 40 loperamide tablets daily (2 mg each; 80 mg daily). A preoperative ECG revealed sinus rhythm with a rate of 63 beats/min, QRS of 166 msec, and QT/QTc of 584/597 msec. A second ECG after the isoproterenol infusion revealed a sinus rate of 62 beats/min, QRS of 134 msec, and QT/QTc of 388/383 msec. His serum loperamide concentration for the day of the cardiac arrest was 97 ng/mL (Marraffa et al, 2014).
    4) A 33-year-old man who abused loperamide chronically, ingested 60 to 100 loperamide tablets (2 mg each) during a 6-hour period, and presented with shortness of breath. On presentation, he had miosis and an ECG showed sinus rhythm with a QRS of 128 msec and QT/QTc of 566/636 msec. He received sodium bicarbonate (3 ampules), magnesium sulfate, and IV potassium (40 mEq) and remained hemodynamically stable. A second ECG obtained 12 hours after presentation revealed a sinus rhythm, QRS of 124 msec, and QTc of 599 msec. Another ECG 12 hours later revealed sinus rhythm, a QRS of 100 msec and QTc of 409 msec. On presentation, his serum loperamide concentration was 77 ng/mL. He left the hospital 24 hours after presentation against medical advice (Marraffa et al, 2014).
    5) Patient 5, a 33-year-old man, with a history of opioid, ethanol, and loperamide (35 2-mg loperamide tablets) abuse presented with anxiety, panic, and chest tightness after ingesting 140 mg of loperamide during a 7-hour period. An initial ECG revealed a sinus rhythm with a rate of 84 beats/min, QRS of 118 msec, and QTc of 490 msec. Laboratory results revealed normal electrolyte concentrations, except for a potassium of 3.2 mEq/L. Following supportive care, including treatment with potassium supplementation, IV magnesium, and benzodiazepines, his symptoms resolved and he was discharged the next day. At that time, an ECG revealed sinus rhythm, a QRS of 92 msec, and QT/QTc of 448/450 msec. On presentation, his serum loperamide concentration was 33 ng/mL (Marraffa et al, 2014).
    c) CASE REPORT: A 30-year-old man with a history of at least 4 prior hospitalizations for loperamide abuse, presented with a syncopal episode after taking 200 2-mg loperamide tablets daily for the last 7 days. An ECG showed a heart rate of 60 beats/min, a QRS of 192 msec, and a QT of 704 msec. After leaving the healthcare facility against medical advice, he was found pulseless and apneic several hours later. On presentation, he had multiple ventricular dysrhythmias, including one episode of polymorphic ventricular tachycardia. Following supportive care, including a continuous infusion of isoproterenol, his conduction disturbance slowly resolved, resulting in a QRS of 96 msec and QTc of 489 msec on day 9. On day 13, he was discharged with a QRS of 94 msec and a QT/QTc of 406/483 msec. His loperamide concentration on presentation (20 hours after his last reported dose of 400 mg dose) was 120 ng/mL. Other loperamide serum concentrations were 47 ng/mL, 30 ng/mL, 30 ng/mL, and 20 ng/mL obtained about 32 hours, 44 hours, 57 hours, and 70.5 hours postingestion, respectively. Although the reported half-life of loperamide is usually about 9 to 13 hours, longer half lives up to about 40.9 hours have been reported following loperamide doses of 16 mg. The first 2 serum concentrations of this patient were consistent with the reported half-life, the later serum concentrations showed a half-life of about 34.8 hours. Loperamide, a mu-receptor agonist, can reduce gastrointestinal motility and delay absorption of drugs, resulting in prolonged toxicity. Loperamide can also antagonize calcium channels, resulting in reduced gastrointestinal motility. This patient also received agents (amiodarone, buprenorphine) that are inhibitors of both cytochrome P450 3A4 and 2D6 enzymatic metabolism. The inhibition of these enzymes can decrease the conversion of loperamide to the N-demethyl metabolite, resulting in slower elimination of the parent drug (Eggleston et al, 2015).
    d) CASE REPORT: A 30-year-old man with a history of opioid addiction and loperamide abuse, who used about 400 mg of loperamide daily for 7 days, presented to the ED with syncope. An ECG revealed sinus rhythm (HR 60 beats/min), a QRS of 192 msec, and QT of 704 msec. He was later found pulseless and apneic after leaving against medical advice. Following CPR, an ECG revealed multiple ventricular dysrhythmias, including polymorphic ventricular tachycardia (PMVT). His symptoms resolved following treatment with magnesium sulfate. He developed withdrawal symptoms within 24 hours of arrival and was treated with a 12-mg dose of sublingual buprenorphine, but became agitated and combative with hallucinations. Despite treatment with lorazepam, his condition deteriorated and he developed multiple episodes of nonsustained ventricular tachycardia, and later deteriorated to PMVT. Following resuscitation and further supportive care with isoproterenol infusion and sedation with propofol, his condition slowly normalized. On hospital day 9, an ECG revealed a QRS of 96 msec and QTc of 489 msec. His serum loperamide concentration was about 41 ng/mL when buprenorphine was administered (Eggleston et al, 2015a).
    e) CASE REPORT: A 26-year-old man with a history of heroin abuse, developed torsades de pointes and subsequent cardiac arrest after ingesting massive doses of loperamide for 2 months to relieve diarrhea associated with heroin withdrawal. A day before presentation, he increased his daily dose of loperamide to attain a euphoric state. His maximum dose was 192 mg on the day of admission (serum loperamide concentration: 2 ng/mL). He recovered following supportive care, including 2 g of IV magnesium and overdrive pacing with isoproterenol for 48 hours. He was discharged after 8 days of hospitalization (Mukarram et al, 2016).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) ACUTE RESPIRATORY INSUFFICIENCY
    1) WITH POISONING/EXPOSURE
    a) Respiratory depression, leading to apnea and respiratory acidosis may occur (Friedli & Haenggeli, 1980; Tan, 1983).
    1) CASE REPORT: One milligram of loperamide given orally resulted in severe respiratory depression in a 15 month old female following ingestion. Naloxone 0.3 mg intravenously resulted in a good clinical response (Minton & Smith, 1987).

Carcinogenicity

    3.21.3) HUMAN STUDIES
    A) LACK OF EFFECT
    1) No evidence of carcinogenicity was reported in an 18-month rat study following administration of doses up to 133 times the maximum human dose (Prod Info Imodium(R) capsules, loperamide hydrochloride, 2000).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs and pulse oximetry.
    B) Monitor for CNS and respiratory depression.
    C) Loperamide concentrations are not widely available or clinically useful to guide management.
    D) Obtain serum electrolytes, acetaminophen and salicylate concentrations after deliberate overdose.

Methods

    A) LIQUID CHROMATOGRAPHY/ELECTROSPRAY-MASS SPECTROMETRY
    1) Liquid chromatography-electrospray-mass spectrometry was used to determine tissue distribution of loperamide and N-desmethylloperamide in postmortem specimens (Sklerov et al, 2005).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with severe CNS or respiratory depression and who require multiple doses of naloxone to reverse symptoms, should be admitted to the hospital. Patients with severe symptoms may require ICU care. Patients may be discharged from the hospital when they are clearly improving without medical intervention.
    6.3.1.2) HOME CRITERIA/ORAL
    A) SUMMARY: Asymptomatic children over 6 months of age who ingest up to 0.4 mg/kg can be managed at home without gastrointestinal decontamination. Adults who are asymptomatic with inadvertent ingestions may be left at home as well.
    B) As a result of a retrospective survey of 216 loperamide overdoses, it was recommended that acute single ingestions up to 0.4 mg/kg in children over 6 months of age may be safely managed, without gastric decontamination, in the home (Litovitz et al, 1993). Symptomatic children should be referred to a health care facility.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a medical toxicologist or poison center for patients with severe toxicity or in whom the diagnosis is unclear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Any patient who ingested loperamide with self-harm attempt and any patient with symptoms needs to be sent to a healthcare facility for observation. Any infants under the 6 months of age with loperamide ingestion, and children more than 6 months of age who have ingested more than 0.4 mg/kg should be sent to a healthcare facility for observation. Patients can be discharged once they are clearly improving without treatment or asymptomatic.

Monitoring

    A) Monitor vital signs and pulse oximetry.
    B) Monitor for CNS and respiratory depression.
    C) Loperamide concentrations are not widely available or clinically useful to guide management.
    D) Obtain serum electrolytes, acetaminophen and salicylate concentrations after deliberate overdose.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Prehospital gastrointestinal decontamination is not recommended because of the risk of CNS depression and subsequent aspiration.
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) Supportive care is the mainstay of treatment. Administer naloxone for CNS or respiratory depression.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Supportive care is the mainstay of treatment. Administer oxygen and monitor for respiratory and CNS depression. Administer naloxone to reverse respiratory or significant CNS depression. Treat dystonic reactions with benztropine (1 to 4 mg IV or orally, maximum 6 mg/day) or diphenhydramine. Assisted ventilation may be needed. Cardiac dysrhythmias (eg, prolonged QRS and QT intervals, monomorphic and polymorphic (torsades de pointes [TdP]) ventricular dysrhythmias) developed in 5 patients with a history of loperamide abuse (doses: 70 mg to 792 mg daily). Treatment with standard anti-arrhythmic agents were ineffective; however, electrical overdrive pacing or isoproterenol continuous infusion were effective in treating dysrhythmias and preventing further episodes of TdP.
    B) MONITORING OF PATIENT
    1) Monitor vital signs and pulse oximetry.
    2) Monitor for CNS and respiratory depression.
    3) Loperamide concentrations are not widely available or clinically useful to guide management.
    4) Obtain serum electrolytes, acetaminophen and salicylate concentrations after deliberate overdose.
    C) NALOXONE
    1) Except for rare cases where dystonias may be present, loperamide toxicity should be treated much like an opioid intoxication. Naloxone is the mainstay of treatment.
    2) NALOXONE/SUMMARY
    a) Naloxone, a pure opioid antagonist, reverses coma and respiratory depression from all opioids. It has no agonist effects and can safely be employed in a mixed or unknown overdose where it can be diagnostic and therapeutic without risk to the patient.
    b) Indicated in patients with mental status and respiratory depression possibly related to opioid overdose (Hoffman et al, 1991).
    c) DOSE: The initial dose of naloxone should be low (0.04 to 0.4 mg) with a repeat dosing as needed or dose escalation to 2 mg as indicated due to the risk of opioid withdrawal in an opioid-tolerant individual; if delay in obtaining venous access, may administer subcutaneously, intramuscularly, intranasally, via nebulizer (in a patient with spontaneous respirations) or via an endotracheal tube (Vanden Hoek,TL,et al).
    d) Recurrence of opioid toxicity has been reported to occur in approximately 1 out of 3 adult ED opioid overdose cases after a response to naloxone. Recurrences are more likely with long-acting opioids (Watson et al, 1998)
    3) NALOXONE DOSE/ADULT
    a) INITIAL BOLUS DOSE: Because naloxone can produce opioid withdrawal in an opioid-dependent individual leading to severe agitation and hypertension, the initial dose of naloxone should be low (0.04 to 0.4 mg) with a repeat dosing as needed or dose escalation to 2 mg as indicated (Vanden Hoek,TL,et al).
    1) This dose can also be given intramuscularly or subcutaneously in the absence of intravenous access (Howland & Nelson, 2011; Prod Info naloxone HCl IV, IM, subcutaneous injection solution, 2008; Maio et al, 1987; Wanger et al, 1998).
    b) Larger doses may be needed to reverse opioid effects. Generally, if no response is observed after 8 to 10 milligrams has been administered, the diagnosis of opioid-induced respiratory depression should be questioned (Howland & Nelson, 2011; Prod Info naloxone HCl IV, IM, subcutaneous injection solution, 2008). Very large doses of naloxone (10 milligrams or more) may be required to reverse the effects of a buprenorphine overdose (Gal, 1989; Jasinski et al, 1978).
    1) Single doses of up to 24 milligrams have been given without adverse effect (Evans et al, 1973).
    c) REPEAT DOSE: The effective naloxone dose may have to be repeated every 20 to 90 minutes due to the much longer duration of action of the opioid agonist used(Howland & Nelson, 2011).
    1) OPIOID DEPENDENT PATIENTS: The goal of naloxone therapy is to reverse respiratory depression without precipitating significant withdrawal. Starting doses of naloxone 0.04 mg IV, or 0.001 mg/kg, have been suggested as appropriate for opioid-dependent patients without severe respiratory depression (Howland & Nelson, 2011). If necessary the dose may be repeated or increased gradually until the desired response is achieved (adequate respirations, ability to protect airway, responds to stimulation but no evidence of withdrawal) (Howland & Nelson, 2011). In the presence of opioid dependence, withdrawal symptoms typically appear within minutes of naloxone administration and subside in about 2 hours. The severity and duration of the withdrawal syndrome are dependant upon the naloxone dose and the degree and type of dependence.(Prod Info naloxone HCl IV, IM, subcutaneous injection solution, 2008)
    2) PRECAUTION should be taken in the presence of a mixed overdose of a sympathomimetic with an opioid. Administration of naloxone may provoke serious sympathomimetic toxicity by removing the protective opioid-mediated CNS depressant effects. Arrhythmogenic effects of naloxone may also be potentiated in the presence of severe hyperkalemia (McCann et al, 2002).
    d) NALOXONE DOSE/CHILDREN
    1) LESS THAN 5 YEARS OF AGE OR LESS THAN 20 KG: 0.1 mg/kg IV/intraosseous/IM/subcutaneously maximum dose 2 mg; may repeat dose every 2 to 5 minutes until symptoms improve (Kleinman et al, 2010; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008)
    2) 5 YEARS OF AGE OR OLDER OR GREATER THAN 20 KG: 2 mg IV/intraosseous/IM/subcutaneouslymay repeat dose every 2 to 5 minutes until symptoms improve (Kleinman et al, 2010; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Krauss & Green, 2006). Although naloxone may be given via the endotracheal tube for pediatric resuscitation, optimal doses are unknown. Some experts have recommended using 2 to 3 times the IV dose (Kleinman et al, 2010)
    3) AVOIDANCE OF OPIOID WITHDRAWAL: In cases of known or suspected chronic opioid therapy, a lower dose of 0.01 mg/kg may be considered and titrated to effect to avoid withdrawal: INITIAL DOSE: 0.01 mg/kg body weight given IV. If this does not result in clinical improvement, an additional dose of 0.1 mg/kg body weight may be given. It may be given by the IM or subQ route if the IV route is not available (Prod Info naloxone HCl IV, IM, subcutaneous injection solution, 2008)
    e) NALOXONE DOSE/NEONATE
    1) The American Academy of Pediatrics recommends a neonatal dose of 0.1 mg/kg IV or intratracheally from birth until age 5 years or 20 kilograms of body weight (AAP, 1989; Kleinman et al, 2010).
    2) Smaller doses (10 to 30 mcg/kg IV) have been successful in the setting of exposure via maternal administration of narcotics or administration to neonates in therapeutic doses for anesthesia (Wiener et al, 1977; Welles et al, 1984; Fischer & Cook, 1974; Brice et al, 1979).
    3) POTENTIAL OF WITHDRAWAL: The risk of precipitating withdrawal in an addicted neonate should be considered. Withdrawal seizures have been provoked in infants from opioid-abusing mothers when the infants were given naloxone at birth to stimulate breathing (Gibbs et al, 1989).
    4) In cases of inadvertent administration of an opioid overdose to a neonate, larger doses may be required. In one case of oral morphine intoxication, 0.16 milligram/kilogram/hour was required for 5 days (Tenenbein, 1984).
    f) NALOXONE/ALTERNATE ROUTES
    1) If intravenous access cannot be rapidly established, naloxone can be administered via subcutaneous or intramuscular injection, intranasally, or via inhaled nebulization in patients with spontaneous respirations.
    2) INTRAMUSCULAR/SUBCUTANEOUS ROUTES: If an intravenous line cannot be secured due to hypoperfusion or lack of adequate veins then naloxone can be administered by other routes.
    3) The intramuscular or subcutaneous routes are effective if hypoperfusion is not present (Prod Info naloxone HCl IV, IM, subcutaneous injection solution, 2008). The delay required to establish an IV, offsets the slower rate of subcutaneous absorption (Wanger et al, 1998).
    4) Naloxone Evzio(TM) is a hand-held autoinjector intended for the emergency treatment of known or suspected opioid overdose. The autoinjector is equipped with an electronic voice instruction system to assist caregivers with administration. It is available as 0.4 mg/0.4 mL solution for injection in a pre-filled auto-injector (Prod Info EVZIO(TM) injection solution, 2014).
    5) INTRANASAL ROUTE: Intranasal naloxone has been shown to be effective in opioid overdose; bioavailability appears similar to the intravenous route (Kelly & Koutsogiannis, 2002). Based on several case series of patients with suspected opiate overdose, the average response time of 3.4 minutes was observed using a formulation of 1 mg/mL/nostril by a mucosal atomization device (Kerr et al, 2009; Kelly & Koutsogiannis, 2002). However, a young adult who intentionally masticated two 25 mcg fentanyl patches and developed agonal respirations (6 breaths per minute), decreased mental status and mitotic pupils did not respond to intranasal naloxone (1 mg in each nostril) administered by paramedics. After 11 minutes, paramedics placed an IV and administered 1 mg of IV naloxone; respirations normalized and mental status improved. Upon admission, 2 additional doses of naloxone 0.4 mg IV were needed. The patient was monitored overnight and discharged the following day without sequelae. Its suggested that intranasal administration can lead to unpredictable absorption (Zuckerman et al, 2014).
    a) Narcan(R) nasal spray is supplied as a single 4 mg dose of naloxone hydrochloride in a 0.1 mL intranasal spray (Prod Info NARCAN(R) nasal spray, 2015).
    b) FDA DOSING: Initial dose: 1 spray (4 mg) intranasally into 1 nostril. Subsequent doses: Use a new Narcan(R) nasal spray and administer into alternating nostrils. May repeat dose every 2 to 3 minutes. Requirement for repeat dosing is dependent on the amount, type, and route of administration of the opioid being antagonized. Higher or repeat doses may be required for partial agonists or mixed agonist/antagonists (Prod Info NARCAN(R) nasal spray, 2015).
    c) AMERICAN HEART ASSOCIATION GUIDELINE DOSING: Usual dose: 2 mg intranasally as soon as possible; may repeat after 4 minutes (Lavonas et al, 2015). Higher doses may be required with atypical opioids (VandenHoek et al, 2010).
    d) ABSORPTION: Based on limited data, the absorption rate of intranasal administration is comparable to intravenous administration. The peak plasma concentration of intranasal administration is estimated to be 3 minutes which is similar to the intravenous route (Kerr et al, 2009). In rare cases, nasal absorption may be inhibited by injury, prior use of intranasal drugs, or excessive secretions (Kerr et al, 2009).
    6) NEBULIZED ROUTE: DOSE: A suggested dose is 2 mg naloxone with 3 mL of normal saline for suspected opioid overdose in patients with some spontaneous respirations (Weber et al, 2012).
    7) ENDOTRACHEAL ROUTE: Endotracheal administration of naloxone can be effective(Tandberg & Abercrombie, 1982), optimum dose unknown but 2 to 3 times the intravenous dose had been recommended by some (Kleinman et al, 2010).
    g) NALOXONE/CONTINUOUS INFUSION METHOD
    1) A continuous infusion of naloxone may be employed in circumstances of opioid overdose with long acting opioids (Howland & Nelson, 2011; Redfern, 1983).
    2) The patient is given an initial dose of IV naloxone to achieve reversal of opioid effects and is then started on a continuous infusion to maintain this state of antagonism.
    3) DOSE: Utilize two-thirds of the initial naloxone bolus on an hourly basis (Howland & Nelson, 2011; Mofenson & Caraccio, 1987). For an adult, prepare the dose by multiplying the effective bolus dose by 6.6, and add that amount to 1000 mL and administer at an IV infusion rate of 100 mL/hour (Howland & Nelson, 2011).
    4) Dose and duration of action of naloxone therapy varies based on several factors; continuous monitoring should be used to prevent withdrawal induction (Howland & Nelson, 2011).
    5) Observe patients for evidence of CNS or respiratory depression for at least 2 hours after discontinuing the infusion (Howland & Nelson, 2011).
    h) NALOXONE/PREGNANCY
    1) In general, the smallest dose of naloxone required to reverse life threatening opioid effects should be used in pregnant women. Naloxone detoxification of opioid addicts during pregnancy may result in fetal distress, meconium staining and fetal death (Zuspan et al, 1975). When naloxone is used during pregnancy, opioid abstinence may be provoked in utero (Umans & Szeto, 1985).
    D) CONTRAINDICATED TREATMENT
    1) Nalorphine and levallorphan have agonist and antagonist properties including respiratory depression. They should no longer be used.
    E) ACUTE LUNG INJURY
    1) The management of narcotic pulmonary edema is that of narcotic overdosage: naloxone, oxygen, and appropriate ventilatory support.
    2) ONSET: Onset of acute lung injury after toxic exposure may be delayed up to 24 to 72 hours after exposure in some cases.
    3) NON-PHARMACOLOGIC TREATMENT: The treatment of acute lung injury is primarily supportive (Cataletto, 2012). Maintain adequate ventilation and oxygenation with frequent monitoring of arterial blood gases and/or pulse oximetry. If a high FIO2 is required to maintain adequate oxygenation, mechanical ventilation and positive-end-expiratory pressure (PEEP) may be required; ventilation with small tidal volumes (6 mL/kg) is preferred if ARDS develops (Haas, 2011; Stolbach & Hoffman, 2011).
    a) To minimize barotrauma and other complications, use the lowest amount of PEEP possible while maintaining adequate oxygenation. Use of smaller tidal volumes (6 mL/kg) and lower plateau pressures (30 cm water or less) has been associated with decreased mortality and more rapid weaning from mechanical ventilation in patients with ARDS (Brower et al, 2000). More treatment information may be obtained from ARDS Clinical Network website, NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary, http://www.ardsnet.org/node/77791 (NHLBI ARDS Network, 2008)
    4) FLUIDS: Crystalloid solutions must be administered judiciously. Pulmonary artery monitoring may help. In general the pulmonary artery wedge pressure should be kept relatively low while still maintaining adequate cardiac output, blood pressure and urine output (Stolbach & Hoffman, 2011).
    5) ANTIBIOTICS: Indicated only when there is evidence of infection (Artigas et al, 1998).
    6) EXPERIMENTAL THERAPY: Partial liquid ventilation has shown promise in preliminary studies (Kollef & Schuster, 1995).
    7) CALFACTANT: In a multicenter, randomized, blinded trial, endotracheal instillation of 2 doses of 80 mL/m(2) calfactant (35 mg/mL of phospholipid suspension in saline) in infants, children, and adolescents with acute lung injury resulted in acute improvement in oxygenation and lower mortality; however, no significant decrease in the course of respiratory failure measured by duration of ventilator therapy, intensive care unit, or hospital stay was noted. Adverse effects (transient hypoxia and hypotension) were more frequent in calfactant patients, but these effects were mild and did not require withdrawal from the study (Wilson et al, 2005).
    8) However, in a multicenter, randomized, controlled, and masked trial, endotracheal instillation of up to 3 doses of calfactant (30 mg) in adults only with acute lung injury/ARDS due to direct lung injury was not associated with improved oxygenation and longer term benefits compared to the placebo group. It was also associated with significant increases in hypoxia and hypotension (Willson et al, 2015).
    F) DRUG-INDUCED DYSTONIA
    1) Should be managed with diphenhydramine or benztropine as first line agents and benzodiazepines as secondary agents.
    2) If reactions occur and are controlled by intravenous administration of the above, oral therapy is recommended for 3 days post reaction.
    3) ADULT
    a) BENZTROPINE: 1 to 4 mg once or twice daily intravenously or intramuscularly; maximum dose: 6 mg/day; 1 to 2 mg of the injection will usually provide quick relief in emergency situations (Prod Info benztropine mesylate IV, IM injection, 2009).
    b) DIPHENHYDRAMINE: 10 to 50 mg intravenously at a rate not exceeding 25 mg/minute or deep intramuscularly; maximum dose: 100 mg/dose; 400 mg/day (Prod Info diphenhydramine hcl injection, 2006).
    4) CHILDREN
    a) DIPHENHYDRAMINE: 5 mg/kg/day or 150 mg/m(2)/day intravenously divided into 4 doses at a rate not to exceed 25 mg/min, or deep intramuscularly; maximum dose: 300 mg/day. Not recommended in premature infants and neonates (Prod Info diphenhydramine hcl injection, 2006).
    G) CONDUCTION DISORDER OF THE HEART
    1) CASE SERIES: Cardiac dysrhythmias (eg, prolonged QRS and QT intervals, monomorphic and polymorphic (torsades de pointes [TdP]) ventricular dysrhythmias) developed in 5 patients with a history of loperamide abuse (doses: 70 mg to 792 mg daily). Treatment with standard anti-arrhythmic agents, including the use of lipid rescue therapy in one patient, were ineffective; however, electrical overdrive pacing or isoproterenol continuous infusion were effective in treating dysrhythmias and preventing further episodes of TdP (Marraffa et al, 2014). Another patient developed cardiac dysrhythmias after taking 200 2-mg loperamide tablets daily for the last 7 days. He recovered following supportive care, including a continuous infusion of isoproterenol (Eggleston et al, 2015).

Enhanced Elimination

    A) SUMMARY
    1) There is no evidence for the use of dialysis, hemoperfusion, urinary alkalinization, or multiple dose charcoal. As loperamide is highly protein bound (97%) and the drug primarily distributed to the gastrointestinal tract, it is highly unlikely that dialysis or hemoperfusion would have much utility.

Abstracts

Case Reports

    A) INFANT
    1) A 4-month-old girl accidentally received 10 mg of loperamide. Eight hours later, she developed respiratory and central nervous system depression. Pupils were miotic. The patient responded to 0.01 mg of IV naloxone (Friedli & Haenggeli, 1980).
    2) A 26-month-old child had loss of consciousness after receiving 0.09 mg/kg loperamide and recovered after two doses (0.4 mg/kg per dose) of naloxone (Chanzy et al, 2004).
    B) ADULT
    1) An adult who took 60 mg (three 20 mg doses) within 24 hours was nauseated after the second dose and vomited after the third (Prod Info, 1988).

Range Of Toxicity

Summary

    A) TOXICITY: Six deaths were reported following complications secondary to misuse of loperamide in infants less than 6.5 months of age. ADULTS: Two fatalities have been reported after loperamide abuse. Both patients had significantly high loperamide concentrations (77 ng/mL and 140 ng/mL, respectively). Even in therapeutic doses, patients may experience mild to more severe toxicity, including paralytic ileus. Repeated low doses (0.12 mg/kg for 3 doses in an infant, 0.27 mg/kg/day in a neonate) have caused CNS and respiratory depression. Cardiac dysrhythmias (eg, prolonged QRS and QT intervals, monomorphic and polymorphic [torsades de pointes] ventricular dysrhythmias) developed in 5 patients with a history of loperamide abuse (doses: 70 mg to 792 mg daily). All patients recovered following supportive care.
    B) THERAPEUTIC DOSE: ADULTS: Initially, 4 mg orally followed by 2 mg after each loose stool up to a maximum of 16 mg/day. CHILDREN: Loperamide should never by given to infants/children under the age of 2 years. Doses depend on age or weight of the child. First day dosage: 2 to 5 years of age (13 to 20 kg): 1 mg orally 3 times daily. 6 to 8 years of age (20 to 30 kg): 2 mg orally twice daily. 8 to 12 years (greater than 30 kg): 2 mg orally 3 times daily. Subsequent daily dosage: 2 to 12 years of age: 1 mg/10 kg of body weight orally only after a loose stool, total daily dose should not exceed dosages for the first day.

Therapeutic Dose

    7.2.1) ADULT
    A) ACUTE DIARRHEA
    1) CAPSULE
    a) Initial dose 4 mg (2 capsules) orally, followed by 2 mg (1 capsule) after each unformed stool, up to 16 mg (8 capsules)/day (Prod Info loperamide HCl oral capsules, 2011).
    2) CHEWABLE TABLET
    a) 4 mg (2 tablets) orally after first loose stool, followed by 2 mg (1 tablet) after each subsequent loose stool, up to 8 mg (4 tablets) in 24 hours (OTC Product Information, as posted to the DailyMed site 11/2010).
    3) FILM-COATED TABLET
    a) 4 mg (2 caplets) orally after first loose stool, followed by 2 mg (1 caplet) after each subsequent loose stool, up to 8 mg (4 caplets) in 24 hours (OTC Product Information, as posted to the DailyMed site 08/2014).
    4) LIQUID-FILLED CAPSULE
    a) 4 mg (2 softgels) orally after first loose stool, followed by 2 mg (1 softgel) after each subsequent loose stool, up to 8 mg (4 softgels) in 24 hours (OTC Product Information, as posted to the DailyMed site 09/2013).
    5) CHRONIC DIARRHEA
    a) CAPSULE
    1) Initial dose 4 mg (2 capsules) orally, followed by 2 mg (1 capsule) after each unformed stool until diarrhea is controlled. The daily dose should then be individualized; the usual daily maintenance dose ranged from 4 to 8 mg (2 to 4 capsules) in clinical trials. The dosage of 16 mg (8 capsules) were rarely exceeded. The daily maintenance dose may be administered in single or divided doses (Prod Info loperamide HCl oral capsules, 2011).
    7.2.2) PEDIATRIC
    A) ACUTE DIARRHEA
    1) CAPSULE
    a) NOTE: The routine use of opiate-related medications for the treatment of acute diarrhea in infants and young children is controversial. The manufacturer recommends the use of the non-prescription liquid formulation of loperamide in children 2 to 5 years of age (20 kg of less). Children 6 to 12 years of age may use the liquid or the capsules. The following dosing recommendations for children 2 to 12 years of age have been reported (Prod Info loperamide HCl oral capsules, 2011).
    1) CHILDREN UNDER 2 YEARS OF AGE: Not recommended. Safety and efficacy have not been established (Prod Info loperamide HCl oral capsules, 2011).
    2) CHILDREN 2 to 5 YEARS OF AGE (13 TO 20 KG): Initial dose, 1 mg orally 3 times daily on first day, followed by 1 mg per 10 kg of body weight after each subsequent loose stool, up to 3 mg in 24 hours (Prod Info loperamide HCl oral capsules, 2011).
    3) CHILDREN 6 to 8 YEARS OF AGE (20 TO 30 KG): Initial dose, 2 mg orally 2 times daily on first day, followed by 1 mg per 10 kg of body weight after each subsequent loose stool, up to 4 mg in 24 hours (Prod Info loperamide HCl oral capsules, 2011).
    4) CHILDREN 8 to 12 YEARS OF AGE (MORE THAN 30 KG): Initial dose, 2 mg orally 3 times daily on first day, followed by 1 mg per 10 kg of body weight after each subsequent loose stool, up to 6 mg in 24 hours (Prod Info loperamide HCl oral capsules, 2011).
    2) CHEWABLE TABLET
    a) CHILDREN UNDER 6 YEARS OF AGE (UP TO 21 KG): Safety and efficacy have not been established (OTC Product Information, as posted to the DailyMed site 11/2010).
    b) CHILDREN 6 TO 8 YEARS OF AGE (22 TO 27 KG): 2 mg (1 tablet) orally after first loose stool, followed by 1 mg (1/2 tablet) after each subsequent loose stool, up to 4 mg (2 tablets) in 24 hours (OTC Product Information, as posted to the DailyMed site 11/2010).
    c) CHILDREN 9 TO 11 YEARS OF AGE (28 TO 43 KG): 2 mg (1 tablet) orally after first loose stool, followed by 1 mg (1/2 tablet) after each subsequent loose stool, up to 6 mg (3 tablets) in 24 hours (OTC Product Information, as posted to the DailyMed site 11/2010).
    d) CHILDREN 12 YEARS OF AGE OR OLDER: 4 mg (2 tablets) orally after first loose stool, followed by 2 mg (1 tablet) after each subsequent loose stool, up to 8 mg (4 tablets) in 24 hours (OTC Product Information, as posted to the DailyMed site 11/2010).
    3) FILM-COATED TABLET
    a) CHILDREN UNDER 6 YEARS OF AGE (UP TO 21 KG): Safety and efficacy have not been established (OTC Product Information, as posted to the DailyMed site 08/2014).
    b) CHILDREN 6 TO 8 YEARS OF AGE (22 TO 27 KG): 2 mg (1 caplet) orally after first loose stool, followed by 1 mg (1/2 caplet) after each subsequent loose stool, up to 4 mg (2 caplets) in 24 hours (OTC Product Information, as posted to the DailyMed site 08/2014).
    c) CHILDREN 9 TO 11 YEARS OF AGE (28 TO 43 KG): 2 mg (1 caplet) orally after first loose stool, followed by 1 mg (1/2 caplet) after each subsequent loose stool, up to 6 mg (3 caplets) in 24 hours (OTC Product Information, as posted to the DailyMed site 08/2014).
    d) CHILDREN 12 YEARS OF AGE OR OLDER: 4 mg (2 caplets) orally after first loose stool, followed by 2 mg (1 caplet) after each subsequent loose stool, up to 8 mg (4 caplets) in 24 hours (OTC Product Information, as posted to the DailyMed site 08/2014).
    4) LIQUID-FILLED CAPSULE
    a) CHILDREN UNDER 12 YEARS OF AGE: Safety and efficacy have not been established (OTC Product Information, as posted to the DailyMed site 09/2013).
    b) CHILDREN 12 YEARS OF AGE OR OLDER: 4 mg (2 softgels) orally after first loose stool, followed by 2 mg (1 softgel) after each subsequent loose stool, up to 8 mg (4 softgels) in 24 hours (OTC Product Information, as posted to the DailyMed site 09/2013).
    B) CHRONIC DIARRHEA
    1) CAPSULE
    a) Safety and efficacy have not been established (Prod Info loperamide HCl oral capsules, 2011).

Minimum Lethal Exposure

    A) Cardiac dysrhythmias (eg, prolonged QT interval, ventricular tachycardia, torsades de pointes, syncope, cardiac arrest) have been reported in patients who were intentionally misusing and abusing high doses of loperamide, to either reduce opioid withdrawal symptoms or to achieve a feeling of euphoria. From 1976 (initial FDA approval) through December 2015, 48 cases of serious cardiac events (24 syncope, 13 cardiac arrests, 13 prolonged QT interval, 10 ventricular tachycardia, and 7 torsades de pointes), including 10 deaths, were reported to the FDA Adverse Event Reporting System (FAERS) database. The reported mean loperamide dose was 195 mg/day (range, 1 to 1600 mg/day). Despite the use of standard antiarrhythmic medications in these patients, no improvements were observed; however, the use of electrical pacing resulted in control of the dysrhythmias (US Food and Drug Administration (FDA), 2016; Marraffa et al, 2014).
    B) CASE REPORTS
    1) PEDIATRIC: Six deaths were reported following complications secondary to misuse of loperamide in infants less than 6.5 months-of-age (Bhutta & Tahir, 1990).
    2) ADULT: Two fatalities have been reported after loperamide abuse. Both patients had significantly high loperamide concentrations (77 ng/mL and 140 ng/mL, respectively) (Eggleston et al, 2016).

Maximum Tolerated Exposure

    A) Cardiac dysrhythmias (eg, prolonged QT interval, ventricular tachycardia, torsades de pointes, syncope, cardiac arrest) have been reported in patients who were intentionally misusing and abusing high doses of loperamide, to either reduce opioid withdrawal symptoms or to achieve a feeling of euphoria. From 1976 (initial FDA approval) through December 2015, 48 cases of serious cardiac events (24 syncope, 13 cardiac arrests, 13 prolonged QT interval, 10 ventricular tachycardia, and 7 torsades de pointes), including 10 deaths, were reported to the FDA Adverse Event Reporting System (FAERS) database. The reported mean loperamide dose was 195 mg/day (range, 1 to 1600 mg/day). Despite the use of standard antiarrhythmic medications in these patients, no improvements were observed; however, the use of electrical pacing resulted in control of the dysrhythmias (US Food and Drug Administration (FDA), 2016; Marraffa et al, 2014).
    B) CASE REPORTS
    1) CASE REPORT: A 26-year-old man with a history of heroin abuse, developed torsades de pointes and subsequent cardiac arrest after ingesting massive doses of loperamide for 2 months to relieve diarrhea associated with heroin withdrawal. A day before presentation, he increased his daily dose of loperamide to attain a euphoric state. His maximum dose was 192 mg on the day of admission (serum loperamide concentration: 2 ng/mL). He recovered following supportive care, including 2 g of IV magnesium and overdrive pacing with isoproterenol for 48 hours. He was discharged after 8 days of hospitalization (Mukarram et al, 2016).
    2) A dose of 2 milligrams/kilogram caused central nervous system and respiratory depression for 24 hours in a 5 kilogram, 4-month-old child (Friedli & Haenggeli, 1980).
    3) A dose of 0.12 milligram/kilogram for 3 doses caused central nervous system depression, bradycardia, and cyanosis which lasted 3 days in an infant (Tan, 1983).
    4) A dose of 0.27 milligram/kilogram/day produced central nervous system and respiratory depression in a newborn (Ramirez et al, 1983).
    5) Doses of 6 to 30 drops (0.6 to 3 milligrams) of loperamide per day were associated with severe abdominal distension and paralytic ileus in 19 infants (aged 2 years and younger) during a 2 month period of time (Bhutta & Tahir, 1990).
    6) A 26-month-old infant required naloxone for impaired consciousness after receiving a total of 0.09 mg/kg loperamide given in three divided doses over the previous day (Chanzy et al, 2004).
    7) A 17-year-old girl presented with mild epigastric pain 2 hours after ingesting 600 mg of trimebutine (an antispasmodic) and 18 mg of loperamide. Laboratory results revealed lipase and amylase concentrations of 6417 international Units (IU)/L and 758 IU/L, respectively, 3 hours postingestion. Her lipase and amylase concentrations 3.5 hours later were 3000 IU/L and 591 IU/L, respectively. Following supportive care, her symptoms gradually resolved and her lipase and amylase concentrations normalized within 30 hours after her overdose (Lee et al, 2011).
    8) Cardiac dysrhythmias (eg, prolonged QRS and QT intervals, monomorphic and polymorphic [torsades de pointes] ventricular dysrhythmias) developed in 5 patients with a history of loperamide abuse (doses: 70 mg to 792 mg daily). All patients recovered following supportive care (Marraffa et al, 2014). Another patient developed cardiac dysrhythmias after taking 200 2-mg loperamide tablets daily for the last 7 days. He recovered following supportive care (Eggleston et al, 2015).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) OVERDOSE: A 30-year-old man with a history of at least 4 prior hospitalizations for loperamide abuse, presented with a syncopal episode after taking 200 2-mg loperamide tablets daily for the last 7 days. An ECG showed a heart rate of 60 beats/min, a QRS of 192 msec, and a QT of 704 msec. After leaving the healthcare facility against medical advice, he was found pulseless and apneic several hours later. On presentation, he had multiple ventricular dysrhythmias, including one episode of polymorphic ventricular tachycardia. Following supportive care, including a continuous infusion of isoproterenol, his conduction disturbance slowly resolved, resulting in a QRS of 96 msec and QTc of 489 msec on day 9. On day 13, he was discharged with a QRS of 94 msec and a QT/QTc of 406/483 msec. His loperamide concentration on presentation (20 hours after his last reported dose of 400 mg dose) was 120 ng/mL. Other loperamide serum concentrations were 47 ng/mL, 30 ng/mL, 30 ng/mL, and 20 ng/mL obtained about 32 hours, 44 hours, 57 hours, and 70.5 hours postingestion, respectively. Although the reported half-life of loperamide is usually about 9 to 13 hours, longer half lives up to about 40.9 hours have been reported following loperamide doses of 16 mg. The first 2 serum concentrations of this patient were consistent with the reported half-life, the later serum concentrations showed a half-life of about 34.8 hours. Loperamide, a mu-receptor agonist, can reduce gastrointestinal motility and delay absorption of drugs, resulting in prolonged toxicity. Loperamide can also antagonize calcium channels, resulting in reduced gastrointestinal motility. This patient also received agents (amiodarone, buprenorphine) that are inhibitors of both cytochrome P450 3A4 and 2D6 enzymatic metabolism. The inhibition of these enzymes can decrease the conversion of loperamide to the N-demethyl metabolite, resulting in slower elimination of the parent drug (Eggleston et al, 2015).
    2) POSTMORTEM
    a) A 26-year-old man who was taking lithium carbonate (300 mg), trazodone (100 mg), and aripiprazole (10 mg), was found dead on the side of the road. It was found that he was also using over-the-counter loperamide frequently. The following postmortem tissue distribution of loperamide and N-desmethylloperamide (major metabolite) were reported (Sklerov et al, 2005):
    1) Central blood (mg/L): loperamide: 1.2; N-desmethylloperamide: 3.3
    2) Peripheral blood (mg/L): loperamide: 2.6; N-desmethylloperamide: 6.4
    3) Gastric (mg): loperamide: 3.9; N-desmethylloperamide: 1.2
    4) Bile (mg/L): loperamide: 8.9; N-desmethylloperamide: 44.6
    5) Kidney (mg/kg): loperamide: 8.5; N-desmethylloperamide: 31.7
    6) Liver (mg/kg): loperamide: 12.5; N-desmethylloperamide: 30.6
    7) Urine (mg/L): loperamide: 9.2; N-desmethylloperamide: 44
    b) ADULT: Two fatalities have been reported after loperamide abuse. Both patients had significantly high loperamide concentrations (Eggleston et al, 2016).
    1) The first patient, a 24-year-old man with a history of substance abuse, who was being treated with buprenorphine, was found unconsciousness with seizure-like activity after taking an unknown amount of loperamide. Six empty loperamide boxes were found next to him. He died despite resuscitative efforts. Pulmonary and cerebral edema, urinary retention, moderate cardiomegaly, and lower extremity venous thrombi were observed during an autopsy. Laboratory results revealed a loperamide concentration of 77 ng/mL (therapeutic range, 0.24 to 3.1 ng/mL), a 7-aminoclonazepam concentration of 180 ng/mL (therapeutic range 23 to 137 ng/mL) and a buprenorphine concentration of 1.8 ng/mL (therapeutic range, 1 to 8 ng/mL). A complete toxicology analysis revealed no other drugs of abuse (Eggleston et al, 2016).
    2) The second patient, a 39-year-old man with a history of opioid addiction, who had been self-treating himself with loperamide after successfully managing his opioid addiction for years with buprenorphine, lost consciousness and died despite resuscitative efforts. Cardiomegaly and severe pulmonary edema were observed during an autopsy. Laboratory results revealed a femoral blood loperamide concentration of 140 ng/mL. A complete toxicology analysis detected no other drugs (Eggleston et al, 2016).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ANIMAL DATA
    1) LD50- (ORAL)MOUSE:
    a) 105 mg/kg ((RTECS, 2000))
    2) LD50- (SUBCUTANEOUS)MOUSE:
    a) 75 mg/kg ((RTECS, 2000))
    3) LD50- (ORAL)RAT:
    a) 98 mg/kg ((RTECS, 2000))

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Loperamide exerts a direct action on the circular and longitudinal muscles of the intestinal wall to inhibit peristaltic activity (Prod Info Imodium(R) capsules, loperamide hydrochloride, 2000) Weintraub et al, 1977). Loperamide prolongs the transit time of the intestinal contents in man.
    B) Loperamide also has antisecretory activity in the intestines by at least 3 mechanisms at the cellular level (Turnberg, 1983). This effect is reversed by naloxone (Sandhu et al, 1983).
    C) Studies support the idea that loperamide has an effect on specific transport systems rather than non-specific passive diffusional processes (Sandhu et al, 1983).
    D) Loperamide may exert its antidiarrheal effect by inhibition of calmodulin (a calcium-dependant regulatory protein used for fluid and electrolyte balance). This effect is not reversed by naloxone (Merritt et al, 1982).

Toxicologic Mechanism

    A) The toxicity of loperamide seems to be primarily related to its opioid-like activity, since the signs and symptoms are identical to those of opioid intoxication and are readily reversible upon administration of naloxone (Prod Info Imodium(R) capsules, loperamide hydrochloride, 2000; Friedli & Haenggeli, 1980).

Physicochemical

Physical Characteristics

    A) Crystals

Molecular Weight

    A) 477.04

Animal Toxicology

Clinical Effects

    11.1.3) CANINE/DOG
    A) Acute overdoses have resulted in hemorrhagic enteritis, vomiting, severe salivation, weight loss, depression, hindlimb paresis (Johnson, 1989), and cerebral and cerebellar deficits, including non-reactive pupils, circling, vocalization, and head pressing (Staley & Staley, 1994).

Treatment

    11.2.4) DECONTAMINATION
    A) GASTRIC DECONTAMINATION
    1) DOG
    a) Activated charcoal slurry, in conjunction with naloxone, was administered to a 7-week-old Samoyed puppy following 3 mg loperamide. The dog recovered (Staley & Staley, 1994).

Range Of Toxicity

    11.3.2) MINIMAL TOXIC DOSE
    A) DOG
    1) 5 mg/kg/day produced hemorrhagic enteritis (Johnson, 1989).
    2) 1.25 to 5 mg/kg/day produced vomiting, depression, severe salivation, and weight loss (Johnson, 1989).
    3) Acute doses of greater than 5 mg/kg produced hindlimb paresis; 0.63 mg/kg produced vomiting (Johnson, 1989).
    4) A total dose of 3 mg (appropriate dose is approximately 0.4 ml/kg; 5ml = 1 mg loperamide) in a 2 kg 7-week-old Samoyed puppy resulted in marked cerebral and cerebellar deficits, including non-reactive pupils, circling, vocalization, and head pressing (Staley & Staley, 1994).

Continuing Care

    11.4.2) DECONTAMINATION
    11.4.2.2) GASTRIC DECONTAMINATION
    A) GASTRIC DECONTAMINATION
    1) DOG
    a) Activated charcoal slurry, in conjunction with naloxone, was administered to a 7-week-old Samoyed puppy following 3 mg loperamide. The dog recovered (Staley & Staley, 1994).
    11.4.3) TREATMENT
    11.4.3.4) PHARMACOLOGIC INTERVENTION
    A) DOG
    1) Naloxone, 0.04 mg/kg, was administered to a Samoyed puppy following a loperamide overdose. The treatment was repeated at 2 hr intervals over a 12 hr period (7 treatments); symptoms had resolved (Staley & Staley, 1994).
    11.4.3.5) SUPPORTIVE CARE
    A) GENERAL
    1) Ongoing treatment is symptomatic and supportive.

Pharmacology Toxicology

    A) DOG
    1) Loperamide increases segmental muscular contractions in the canine small intestine and colon, as well as decreasing longitudinal contractions (Johnson, 1989).

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