Loperamide

Loperamide is an Anti-motility belonging to Antidiarrheal agent.

Loperamide is a long acting antidiarrheal used to control nonspecific diarrhea and chronic diarrhea caused by inflammatory bowel disease, or gastroenteritis.

Absorbed from the gastrointestinal tract. Bioavailability: Approximately 0.3%. Time to peak plasma concentration: 2.5 hours (oral solution); approximately 5 hours (cap). Loperamide Enters breast milk (in small amounts). Plasma protein binding is 95%, mainly to albumin. Metabolised in the liver mainly via oxidative N-demethylation primarily by CYP3A4 and CYP2C8 isoenzymes; undergoes extensive first-pass metabolism.

Mainly via faeces (as unchanged drug and metabolites) and in urine (small amounts). Elimination half-life is Approximately 11 hours (range: 9-14 hours).

Loperamide shows side effects like Dizziness, Constipation, abdominal cramps, nausea.

Loperamide is available in the form of Oral Tablet, Oral capsule, Oral Solution, oral Suspension.

Loperamide is available in India, US, Canada, China, Japan, Italy, Malaysia, and Australia.

Loperamide belongs to the Antidiarrheal agent acts as an Anti-motility.

Loperamide acts directly on circular and longitudinal intestinal muscles, through the opioid receptor, to inhibit peristalsis and prolong transit time; reduces fecal volume, increases viscosity, and diminishes fluid and electrolyte loss; demonstrates antisecretory activity. Loperamide increases tone on the anal sphincter.

The onset and duration of action of Loperamide is not clinically established.

The Tmax of Loperamide is approximately 2.5 hours (oral liquid) and ~5hours (oral capsule).

Loperamide is a very effective anti-diarrhea medication. It is used to relieve the symptoms of diarrhea that starts suddenly and lasts for a few days. It is also used to treat long-term diarrhea associated with other diseases.

Loperamide is approved for use in the following clinical indications

Adult indication

• Diarrhea, acute
• Diarrhea, cancer treatment-induced
• Diarrhea, chronic
• Enterocutaneous fistula or ileostomy, high output

Paediatric indication

• Acute diarrhea
• Chronic diarrhea; secondary to intestinal failure, short-bowel syndrome, or other non-infectious causes
• Irinotecan-induced diarrhea

Adult Dose

• Diarrhea, acute

Oral: Initial: 4 mg, followed by 2 mg after each loose stool; maximum: 16 mg/day (OTC: 8 mg/day).

• Diarrhea, cancer treatment-induced

Oral: Initial: 4 mg, followed by 2 mg every 2 to 4 hours or after each loose stool; for diarrhea persisting >24 hours, administer 2 mg every 2 hours (or 4 mg every 4 hours). Continue until 12 hours have passed without a loose bowel movement.

• Diarrhea, chronic

Oral

Initial: 4 mg, followed by 2 mg after each loose stool; maximum: 16 mg/day.

Maintenance dosage: Once diarrhea is controlled, use lowest dosage required to control symptoms; usual maintenance dose: 4 to 8 mg/day as a single dose or in divided doses (eg, 2 mg before meals).

• Enterocutaneous fistula or ileostomy, high output

Oral: 4 mg administered 3 to 4 times per day or 2 mg administered 2 to 3 times per day.

Pediatric Dose

• Acute diarrhea

Children 2 to <12 years: Oral:

2 to 5 years weighing 13 to <21 kg: Initial: 1 mg with first loose stool followed by 1 mg/dose after each subsequent loose stool; maximum daily dose: 3 mg/day.

6 to 8 years weighing 21 to 27 kg: Initial: 2 mg with first loose stool followed by 1 mg/dose after each subsequent loose stool; maximum daily dose: 4 mg/day.

9 to 11 years weighing 27.1 to 43 kg: Initial: 2 mg with first loose stool followed by 1 mg/dose after each subsequent loose stool; maximum daily dose: 6 mg/day.

Children ≥12 years and Adolescents: Oral:

Initial: 4 mg with first loose stool followed by 2 mg/dose after each subsequent loose stool; maximum daily dose: 8 mg/day.

• Chronic diarrhea; secondary to intestinal failure, short-bowel syndrome, or other non-infectious causes

Infants ≥2 months and Children: Oral: 0.08 to 0.24 mg/kg/day divided 2 to 3 times/day was reported in a case series of 10 pediatric patients (age range: 2 to 52 months). In a case series of six infants and young children, higher dosing was described: Initial: 1 to 1.5 mg/kg/day in 4 divided doses with subsequent dose decreased as stool output and diet tolerance improved and patient weight increased. Reported final dose range of 0.25 to 0.5 mg/kg/day in 2 divided doses was used long-term until patient achieved target weight and dietary goals; reported duration of therapy: 6 months to ~2 years; maximum single dose: 2 mg.

• Irinotecan-induced diarrhea

Children ≥2 to 12 years:

<13 kg: Initial: 0.5 mg after the first loose bowel movement, followed by 0.5 mg every 3 hours while awake; during the night, may administer every 4 hours; maximum daily dose: 4 mg/day

13 kg to <20 kg: Initial: 1 mg after the first loose bowel movement, followed by 1 mg every 4 hours; maximum daily dose: 6 mg/day

20 kg to <30 kg: Initial: 2 mg after the first loose bowel movement, followed by 1 mg every 3 hours while awake; during the night, may administer every 4 hours; maximum daily dose: 8 mg/day

30 kg to <43 kg: Initial: 2 mg after the first loose bowel movement, followed by 1 mg every 2 hours while awake; during the night, may administer every 4 hours; maximum daily dose: 12 mg/day

Adolescents weighing ≥43 kg: Initial: 4 mg after the first loose bowel movement, followed by 2 mg after each loose stool; maximum daily dose: 16 mg/day

Weight-directed dosing: Children and Adolescents 2 to <15 years:

Grade 1 or 2: 0.03 mg/kg/dose every 4 hours

Grade 3 or 4: 0.06 mg/kg/dose every 4 hours

Maximum single dose dependent upon weight:

<13 kg: 0.5 mg

13 to <20 kg: 1 mg

20 to <43 kg: Initial: 2 mg; subsequent doses: 1 mg

≥43 kg: Initial: 4 mg; subsequent doses: 2 mg

Loperamide is available in the form of Oral Tablet, Oral capsule, Oral Solution, oral Suspension.

• Dosage Adjustment in Kidney Patient

Mild to severe impairment: No dosage adjustment necessary.

Loperamide is contraindicated in patients with

• In patients with a known hypersensitivity to Loperamide hydrochloride or to any of the excipients.
• In patients with abdominal pain in the absence of diarrhea.
• It is not recommended in infants below 24 months of age.
• Loperamide 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.

• GI effects

Discontinue promptly if constipation, abdominal pain, abdominal distension, blood in stool, or ileus develop. Do not use when peristalsis inhibition should be avoided due to potential for ileus, megacolon and/or toxic megacolon.

• Torsades de pointes and sudden death

Cases of prolongation of the QT/QTc interval, Torsades de Pointes, other ventricular arrhythmias, cardiac arrest, some resulting in death, have been reported in adults with use of higher than recommended doses per day of loperamide. Cases include patients who were abusing or misusing Loperamide hydrochloride. Cases of syncope and ventricular tachycardia have been reported in adult patients receiving the recommended dosage of loperamide. Some of these patients were taking other drugs or had other risk factors that may have increased their risk of cardiac adverse reactions. Additionally, postmarketing cases of cardiac arrest, syncope, and respiratory depression have been reported in pediatric patients less than 2 years of age.

• AIDS

Stop therapy at the first sign of abdominal distention; cases of toxic megacolon have occurred in patients with AIDS and infectious colitis (due to viral or bacterial pathogens).

• Hepatic impairment

Use with caution in patients with hepatic impairment due to reduced first-pass metabolism; monitor for signs of CNS toxicity.

• Older adult

Use with caution in elderly patients; may be more susceptible to drug-associated effects on the QT interval.

• Pediatric

Use with caution in young children as response may be variable because of dehydration. Contraindicated in children <2 years.

• Dosage form specific issues

Benzyl alcohol and derivatives: Some dosage forms may contain sodium benzoate/benzoic acid; benzoic acid (benzoate) is a metabolite of benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse. some data suggests that benzoate displaces bilirubin from protein binding sites avoid or use dosage forms containing benzyl alcohol derivative with caution in neonates.

• Allergic reactions

Rare cases of anaphylaxis and anaphylactic shock have been reported.

• CNS effects

May cause drowsiness or dizziness, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).

Consumption of alcohol during treatment with this medicine may increase the risk of severe side effects. These side effects may include confusion, dizziness, nausea, vomiting, weakness, and fainting

Small amounts of Loperamide may appear in human breast milk. Therefore, Loperamide is not recommended during breast-feeding.

Pregnancy Category C

Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

• Common

Dizziness, Constipation, abdominal cramps, nausea.

• Rare

Abdominal discomfort, abdominal distention, abdominal pain, anaphylactic shock, anaphylactoid reaction, angioedema, bullous rash, drowsiness, dyspepsia, erythema multiforme, fatigue, flatulence, hypersensitivity reaction, megacolon, paralytic ileus, pruritus, skin rash, Stevens-Johnson syndrome, toxic epidermal necrolysis, toxic megacolon, urinary retention, urticaria, vomiting, xerostomia.

• CYP3A4 Inhibitors

Itraconazole: Concomitant administration of multiple doses of 100 mg itraconazole twice daily, an inhibitor of both CYP3A4 and P-glycoprotein, with a single 4-mg dose of Loperamide hydrochloride increased the peak plasma concentration and the systemic exposure to Loperamide by 2.9-fold and 3.8-fold, respectively.

• CYP2C8 Inhibitors

Gemfibrozil: When a single 4-mg dose of Loperamide hydrochloride was co-administered with 600 mg gemfibrozil, a strong inhibitor of CYP2C8, on day 3 of a 5-day treatment with gemfibrozil twice daily, the mean peak plasma concentration and the systemic exposure to Loperamide was increased by 1.6-fold and 2.2-fold, respectively.

• CYP3A4 and CYP2C8 Inhibitors

When multiple doses of both 100 mg itraconazole and 600 mg gemfibrozil twice daily were administered with a single 4-mg dose of Loperamide hydrochloride, the mean peak plasma concentration and the systemic exposure to Loperamide was increased by 4.2-fold and 12.6-fold, respectively.

• P-glycoprotein Inhibitors

Concomitant administration of a 16 mg single dose of Loperamide hydrochloride with a 600 mg single dose of quinidine or ritonavir, both of which are P-glycoprotein inhibitors, resulted in a 2- to 3-fold increase in Loperamide plasma concentrations. Due to the potential for enhanced CNS adverse reactions when Loperamide is co-administered with quinidine and with ritonavir, caution should be exercised when LOPERAMIDE® is administered at the recommended dosages (2 mg, up to 16 mg maximum daily dose) with P-glycoprotein inhibitors.

• Saquinavir

When a single 16-mg dose of Loperamide hydrochloride is coadministered with a 600 mg single dose of saquinavir, Loperamide decreased saquinavir exposure by 54%, which may be of clinical relevance due to reduction of therapeutic efficacy of saquinavir. The effect of saquinavir on Loperamide is of less clinical significance. Therefore, when loperamide is given with saquinavir, the therapeutic efficacy of saquinavir should be closely monitored.

The common side effects of Loperamide include the following

Common side effects

• Constipation, fatigue, Allergic skin reaction, Dizziness, Dry mouth.

Rare side effects

• Rash, red, peeling or blistering skin, hives, itching, wheezing, difficulty breathing, fever, stomach pain or swelling, bloody stools, Bloating, Constipation, Loss of appetite, Severe stomachache, Paralytic ileus.

• Pregnancy

Pregnancy Category C

Teratology studies have been performed in rats using oral Loperamide hydrochloride doses of 2.5, 10, and 40 mg/kg/day, and in rabbits using oral doses of 5, 20, and 40 mg/kg/day. These studies have revealed no evidence of impaired fertility or harm to the fetus at doses up to 10 mg/kg/day in rats (5 times the human dose based on body surface area comparison) and 40 mg/kg/day in rabbits (43 times the human dose based on body surface area comparison). Treatment of rats with oral doses of 40 mg/kg/day (21 times the human dose based on a body surface area comparison) produced marked impairment of fertility. The studies produced no evidence of teratogenic activity. There are no adequate and well controlled studies in pregnant women. Loperamide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

• Nursing Mothers

Small amounts of Loperamide may appear in human breast milk. Therefore, Loperamide is not recommended during breast-feeding.

• Pediatric Use

Loperamide is contraindicated in pediatric patients less than 2 years of age due to the risks of respiratory depression and serious cardiac adverse reactions. Postmarketing cases of cardiac arrest, syncope, and respiratory depression have been reported in pediatric patients less than 2 years of age. Pediatric patients may be more sensitive to CNS effects, such as altered mental status, somnolence, and respiratory depression, than adults. There have been rare reports of paralytic ileus associated with abdominal distention. Most of these reports occurred in the setting of acute dysentery, overdose, and with pediatric patients less than two years of age. Loperamide should be used with special caution in pediatric patients because of their greater variability of response. Dehydration, particularly in pediatric patients less than 6 years of age, may further influence the variability of response to Loperamide. The safety and effectiveness of Loperamide in pediatric patients with chronic diarrhea have not been established. Although Loperamide has been studied in a limited number of pediatric patients with chronic diarrhea; the therapeutic dose for the treatment of chronic diarrhea in a pediatric population has not been established. In case of accidental over dosage of Loperamide by pediatric patients.

• Geriatric Use

No formal studies have been conducted to evaluate the pharmacokinetics of loperamide in elderly subjects. However, in two studies that enrolled elderly patients, there were no major differences in the drug disposition in elderly patients with diarrhea relative to young patients. In general, elderly patients may be more susceptible to drug-associated effects on the QT interval. Avoid loperamide in elderly patients taking drugs that can result in prolongation of the QT interval (for example, Class IA or III antiarrhythmics) or in patients with risk factors for Torsades de Pointes.

Symptoms: CNS depression (e.g. stupor, somnolence, coordination abnormality, miosis, muscular hypertonia, respiratory depression), constipation, urinary retention and ileus. Cardiac events such as syncope, QT interval and QRS complex prolongation, torsades de pointes, other serious ventricular arrhythmias, and cardiac arrest may also occur. Management:Symptomatic and supportive treatment. If vomiting has occurred spontaneously, administer activated charcoal as soon as fluids can be maintained. Perform gastric lavage followed by administration of activated charcoal through the gastric tube in patients who have not vomited. Repeated doses of naloxone may be given as an antidote for CNS depression. Monitor the patient closely for at least 48 hours to detect possible CNS depression.

Pharmacodynamic

Loperamide is an anti-diarrheal agent that provides symptomatic relief of diarrhea.⁸ It decreases peristalsis and fluid secretion in the gastrointestinal tract, delays colonic transit time, and increases the absorption of fluids and electrolytes from the gastrointestinal tract. Loperamide also increases rectal tone, reduces daily fecal volume, and increases the viscosity and bulk density of feces. It also increases the tone of the anal sphincter, thereby reducing incontinence and urgency.The onset of action is about one hour and the duration of action can be up to three days.

Pharmacokinetics

• Absorption

Absorbed from the gastrointestinal tract. Bioavailability: Approximately 0.3%. Time to peak plasma concentration: 2.5 hours (oral solution); approximately 5 hours (cap)

• Distribution

Loperamide Enters breast milk (in small amounts). Plasma protein binding is 95%, mainly to albumin

• Metabolism and Excretion

Metabolized in the liver mainly via oxidative N-demethylation primarily by CYP3A4 and CYP2C8 isoenzymes; undergoes extensive first-pass metabolism.

Mainly via faeces (as unchanged drug and metabolites) and in urine (small amounts). Elimination half-life is Approximately 11 hours (range: 9-14 hours).

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