Imodium

White powder filled in capsules with green cap and dark grey body.
Imodium contains the synthetic antidiarrhoeal for oral use, Loperamide HCl. Imodium is available in capsules. Each capsule contains 2mg Loperamide HCl.

Pharmacotherapeutic group: Antipropulsives. ATC code: A07 DA03.
Pharmacology: Pharmacodynamics: Loperamide binds to the opiate receptor in the gut wall. Consequently, it inhibits the release of acetylcholine and prostaglandins, thereby reducing propulsive peristalsis, and increasing intestinal transit time. Loperamide increases the tone of the anal sphincter, thereby reducing incontinence and urgency.
Pharmacokinetics: Absorption: Most ingested loperamide is absorbed from the gut, but as a result of significant first pass metabolism, systemic bioavailability is only approximately 0.3%. Loperamide HCl formulations (hard and soft capsule, coated and uncoated tablet, chewable and orodispersable tablet, oral solution) are bioequivalent in terms of rate and extent of loperamide absorption.
Distribution: Studies on distribution in rats show a high affinity for the gut wall with a preference for binding to receptors of the longitudinal muscle layer. The plasma protein binding of loperamide is 95%, mainly to albumin. Non-clinical data have shown that loperamide is a P-glycoprotein substrate.
Metabolism: Loperamide is almost completely extracted by the liver, where it is predominantly metabolized, conjugated and excreted via the bile. Oxidative N-demethylation is the main metabolic pathway for loperamide, and is mediated mainly through CYP3A4 and CYP2C8. Due to this very high first pass effect, plasma concentrations of unchanged drug remain extremely low.
Excretion: The half-life of loperamide in man is about 11 hours with a range of 9-14 hours. Excretion of the unchanged loperamide and the metabolites mainly occurs through the faeces.
Paediatric Population: No pharmacokinetic studies were performed in the paediatric population. It is expected that pharmacokinetic behavior of loperamide and drug-drug interactions with loperamide will be similar to those in adults.

Loperamide HCl is indicated for the symptomatic control of acute and chronic diarrhea. In patients with an ileostomy it can be used to reduce the number and volume of stools and to harden their consistency.

Adults and Pediatrics 6 to 17 Years: Capsules: The capsules should be taken with liquid.
Acute diarrhea: the initial dose is 2 capsules (4mg) for adults and 1 capsule (2mg) for children; followed by 1 capsule (2mg) after every subsequent loose stool.
Chronic diarrhea: the initial dose is 2 capsules (4mg) daily for adults and 1 capsule (2mg) daily for children; this initial dose should be adjusted until 1-2 solid stools a day are obtained, which is usually achieved with a maintenance dose of 1-6 capsules (2mg-12mg) daily.
The maximum dose for acute and chronic diarrhea is 8 capsules (16mg) daily for adults; in children it must be related to the body weight (3 capsules/20kg) but should not exceed a maximum of 8 capsules per day.
Elderly: No dose adjustment is required for the elderly.
Renal Impairment No dose adjustment is required for patients with renal impairment.
Hepatic Impairment: Although no pharmacokinetic data are available in patients with hepatic impairment, Loperamide HCl should be used with caution in such patients because of reduced first pass metabolism. (See Warnings and Precautions.)

Symptoms: In case of overdose (including relative overdose due to hepatic dysfunction), CNS depression (stupor, coordination abnormality, somnolence, miosis, muscular hypertonia, and respiratory depression), urinary retention and ileus may occur. Children may be more sensitive to CNS effects than adults.
In individuals who have intentionally ingested overdoses (reported in doses from 40mg up to 792mg per day) of loperamide HCl, prolongation of the QT/QTc interval, Torsades de Pointes, other ventricular arrhythmias and cardiac arrest, have been observed (see Warnings and Precautions). Fatal cases have also been reported. Abuse, misuse and/or overdose with excessively large doses of loperamide, may unmask Brugada syndrome.
Upon cessation, cases of drug withdrawal syndrome, have been observed in individuals abusing, misusing or intentionally overdosing with excessively large doses of loperamide.
Treatment: In case of overdose, ECG monitoring for QT interval prolongation should be initiated.
If CNS symptoms of overdose occur, naloxone can be given as an antidote. Since the duration of action of Loperamide HCl is longer than that of naloxone (1 to 3 hours), repeated treatment with naloxone might be indicated. Therefore, the patient should be monitored closely for at least 48 hours in order to detect possible CNS depression.

Loperamide HCl is contraindicated in patients with a known hypersensitivity to Loperamide HCl or to any of the excipients.
Loperamide HCl should not be used in children under 6 years of age.
Loperamide HCl should not be used as the primary therapy: in patients with acute dysentery, which is characterized by blood in stools and high fever; in patients with acute ulcerative colitis; in patients with bacterial enterocolitis caused by invasive organisms including Salmonella, Shigella, and Campylobacter; in patients with pseudomembranous colitis associated with the use of broad-spectrum antibiotics.
Loperamide HCl should not be used when inhibition of peristalsis is to be avoided due to the possible risk of significant sequelae including ileus, megacolon and toxic megacolon. Loperamide HCl must be discontinued promptly when constipation, abdominal distension or ileus develop.

Loperamide is not recommended for children under 6 years of age. Its use has been associated with fatal episodes of paralytic ileus in infants and young children.
The use of higher than the recommended doses for control of the diarrhea may lead to abnormal heart rhythms and serious cardiac events leading to death. Cases of syncope and ventricular tachycardia have been reported in adult patients receiving the recommended dosage of IMODIUM. Some of these patients were taking other drugs or had other risk factors that may have increased their risk of cardiac adverse reactions.
Abuse and misuse of loperamide, as an opioid substitute, have been described in individuals with opioid addiction (see Overdosage).

Treatment of diarrhea with Loperamide HCl is only symptomatic. Whenever an underlying etiology can be determined, specific treatment should be given when appropriate.
In patients with diarrhea, especially in children, fluid and electrolyte depletion may occur. In such cases administration of appropriate fluid and electrolyte replacement therapy is the most important measure.
In acute diarrhea, if clinical improvement is not observed within 48 hours, the administration of Loperamide HCl should be discontinued and patients should be advised to consult their physician.
Patients with AIDS treated with Loperamide HCl for diarrhea should have therapy stopped at the earliest signs of abdominal distension. There have been isolated reports of obstipation with an increased risk for toxic megacolon in AIDS patients with infectious colitis from both viral and bacterial pathogens treated with Loperamide HCl.
Although no pharmacokinetic data are available in patients with hepatic impairment, Loperamide HCl should be used with caution in such patients because of reduced first pass metabolism. This medicine must be used with caution in patients with hepatic impairment as it may result in a relative overdose leading to CNS toxicity.
Effects of driving ability and use of machinery: Tiredness, dizziness, or drowsiness may occur in the setting of diarrheal syndromes treated with Loperamide HCl. Therefore, it is advisable to use caution when driving a car or operating machinery.

Although there are no indications that Loperamide HCl possesses teratogenic or embryotoxic properties, the anticipated therapeutic benefits should be weighed against potential hazards before Loperamide HCl is given during pregnancy, especially during the first trimester.
Small amount of Loperamide may appear in human breast milk. Therefore, Loperamide HCl is not recommended during breast-feeding. It is not advisable to administer this medicine in pregnancy. Women who are pregnant or breast feeding should therefore be advised to consult their doctor for appropriate treatment.

Throughout this section, adverse reactions are presented. Adverse reactions are adverse events that were considered to be reasonably associated with the use of Loperamide HCl based on the comprehensive assessment of the available adverse event information. A causal relationship with Loperamide HCl cannot be reliably established in individual cases. Further, because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
Clinical Trial Data: Adults and Pediatrics 12 Years and Over: Acute Diarrhea: The safety of Loperamide HCl was evaluated in 2755 patients aged ≥12 years who participated in 26 controlled and uncontrolled clinical trials of Loperamide HCl used for the treatment of acute diarrhea. Adverse reactions reported for ≥1% of Loperamide HCl-treated patients are shown in Table 1. (See Table 1.)

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Adverse reactions reported by <1% of Loperamide HCl-treated patients (N=2755) in the mentioned clinical trial dataset are shown in Table 2. (See Table 2.)

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Chronic Diarrhea: The safety of Loperamide HCl was evaluated in 321 patients who participated in 5 controlled and uncontrolled clinical trials of Loperamide HCl used for the treatment of chronic diarrhea. Treatment periods ranged from 1 week to 52 months. (See Table 3.)

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Adverse reactions reported by <1% of loperamide HCl-treated patients (N=321) in the mentioned clinical trial dataset are shown in Table 4. (See Table 4.)

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Paediatrics Under 12 Years: Acute Diarrhea: The safety of Loperamide HCl was evaluated in 607 patients aged less than 12 years who participated in 13 controlled and uncontrolled clinical trials of Loperamide HCl used for the treatment of acute diarrhea. Adverse reactions reported for ≥1% of Loperamide HCl treated patients are shown in Table 5. (See Table 5.)

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Adverse reactions reported by <1% of Loperamide HCl-treated patients <12 years (N=607) in the mentioned clinical trial dataset are shown in Table 6. (See Table 6.)

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Post marketing Experience: Adverse reactions first identified during post-marketing experience with Loperamide HCl are included in Table 7. In each table, the frequencies are provided according to the following convention: Very common ≥1/10; Common ≥1/100 and <1/10; Uncommon ≥1/1000 and <1/100; Rare ≥1/10000 and <1/1000; Very rare <1/10000 including isolated reports; Not known: Cannot be estimated from the available data.
In Table 7, ADRs are presented by frequency category based on spontaneous reporting rates. (See Table 7.)

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Non-clinical data have shown that loperamide is a P-glycoprotein substrate. Concomitant administration of loperamide (16mg single dose) with quinidine, or ritonavir, which are both P-glycoprotein inhibitors, resulted in a 2 to 3-fold increase in loperamide plasma levels. The clinical relevance of this pharmacokinetic interaction with P-glycoprotein inhibitors, when loperamide is given at recommended dosages, is unknown.
The concomitant administration of loperamide (4mg single dose) and itraconazole, an inhibitor of CYP3A4 and P-glycoprotein, resulted in a 3 to 4-fold increase in loperamide plasma concentrations. In the same study a CYP2C8 inhibitor, gemfibrozil, increased loperamide by approximately 2-fold. The combination of itraconazole and gemfibrozil resulted in a 4-fold increase in peak plasma levels of loperamide and a 13-fold increase in total plasma exposure. These increases were not associated with central nervous system (CNS) effects as measured by psychomotor tests (i.e., subjective drowsiness and the Digit Symbol Substitution Test).
The concomitant administration of loperamide (16mg single dose) and ketoconazole, an inhibitor of CYP3A4 and P-glycoprotein, resulted in a 5-fold increase in loperamide plasma concentrations. This increase was not associated with increased pharmacodynamic effects as measured by pupillometry.
Concomitant treatment with oral desmopressin resulted in a 3-fold increase of desmopressin plasma concentrations, presumably due to slower gastrointestinal motility.
It is expected that drugs with similar pharmacological properties may potentiate loperamide's effect and that drugs that accelerate gastrointestinal transit may decrease its effect.

Store below 30°C.

Antidiarrheals

A07DA03 - loperamide ; Belongs to the class of antipropulsives. Used in the treatment of diarrhea.

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