Continuing Education Activity

Loperamide is a medication used in the treatment of diarrhea. It classifies as an anti-diarrheal agent. The use of loperamide in high doses has been associated with a significant increase in morbidity and mortality. This activity reviews the indications, contraindications, activity, adverse events, and other key elements of loperamide abuse related to the essential points needed by members of an interprofessional team managing the care of patients with toxicity and its related conditions and sequelae.

Objectives:

• Describe the mechanism of action of loperamide as it relates to toxicity.
• Identify the most common adverse events associated with loperamide toxicity.
• Summarize the management considerations, including the importance of monitoring, in patients with loperamide toxicity.
• Explain the importance of improving care coordination amongst the interprofessional team to enhance the delivery of care for patients with loperamide toxicity.

Indications

Loperamide is an over-the-counter oral antidiarrheal agent made in 1969, first used medically in 1976, and became available without a prescription in 1988.[1] Initially, due to its opioid-like abuse potential, it was categorized as a Schedule V drug by the Federal Drug Administration (FDA).[2] Currently, loperamide has been FDA approved to treat various forms of diarrhea and has also been used off-label to treat the adverse effects of chemotherapy resulting in diarrhea. In recent years, there has been an increased interest in the non-medical use of loperamide, ranging from self-management of opioid withdrawal symptoms and a means to induce euphoria, i.e., getting high. Recently, a new syndrome termed loperamide-induced cardiotoxicity has come to light.[3] Patients can present with different forms of potentially life-threatening dysrhythmias when using loperamide in toxic doses.

Medical use: The FDA approved loperamide for the treatment of various forms of diarrhea, including traveler’s diarrhea, irritable bowel syndrome associated with chronic diarrhea, acute nonspecific diarrhea in patients two years of age and older, and is indicated for reducing ileostomy output.[4] The off-label uses include the management of chemotherapy-related diarrhea.

Illicit drug use and self-medication use: In recent years, there has been a noticeable incline in the use and abuse of loperamide as a means of self-management of opioid withdrawal and an inexpensive method to induce euphoria i.e., to achieve a euphoric state. Vakkalanka et al. found a 91% increase in reported loperamide exposures, including eight deaths, from 2010 to 2015 across Poison Control Centers in the United States.[5] Individuals have used loperamide as a means to self-medicate in an effort to decrease the withdrawal side effects of opioid dependence or slow the tapering process. Recently high-dose loperamide has shown promise for such use.[6]

Mechanism of Action

Loperamide is a highly lipophilic synthetic phenylpiperidine opioid.[7] Loperamide is a mu- receptor agonist.[4] At therapeutic doses, loperamide acts on the mu-opioid receptors directly on the circular and longitudinal intestinal muscles to decrease transition time, inhibit peristalsis electrolyte loss, and increase rectal tone. However, because loperamide is a substrate for P-glycoprotein at higher doses, P-glycoprotein becomes inhibited, allowing loperamide to cross the blood-brain barrier and act on the central nervous system, producing central opioid effects and toxicity.[8]

The peak plasma time is 4 to 5 hours, with a half-life of 7 to 19 hours.[9] It has a low bioavailability of < 1% due to the first-pass metabolism. It has high protein binding and a large volume of distribution. Loperamide is extracted in the GI tract and metabolized in the liver by the cytochrome P450 pathway. It is metabolized in the liver via CYP2C8 and CYP3A4 to desmethylloperamide.[3] This pathway allows for decreased gastrointestinal uptake and thus enhanced elimination through bile excretion. At recommended doses, there is almost no active loperamide available in the systemic circulation.

Loperamide was also found to inhibit both the Na+ gated cardiac channels, which in turn prolongs the QRS complex, and the hERG channel, which increases the QTc interval.[10] QRS and QTc prolongation can cause ventricular dysrhythmias, monomorphic and polymorphic ventricular tachycardia, torsade de pointes, ventricular fibrillation, Brugada syndrome, cardiac arrest, and death.

Administration

Loperamide is available in different formulations, most commonly as tablets, capsules, and orodispersible tablets that melt on the tongue. It is available as 2 mg tablets, capsules, and oral solution of 1 mg / 7.5 ml and 2 mg / 15 ml strengths. The oral solution needs to be shaken well before measuring to administer to the patient. Consider administering loperamide with plenty of fluids to prevent dehydration. 

Adult Dosing

The usual initial recommended dose for acute diarrhea, such as traveler’s diarrhea, is 4 mg starting dose, followed by 2 mg dosing after each unformed stool but not to exceed 8 mg per day for over-the-counter use and 16 mg per day with prescription use. For chronic use, the suggested dose is 2 mg BID. Consider administering loperamide 30 minutes before food four times per day for patients with cancer-induced diarrhea to slow colic reflex.

• According to the Infectious Disease Society of America, use loperamide as adjuvant therapy with close monitoring and concomitant antibiotics in patients with suspected or known dysentery.[11] Loperamide is usually avoided in patients with C. difficile infection; however, some experts approve the use with close monitoring and concomitant antibiotics if the patient has major fluid losses and no contraindications (ileus/colonic distention).[12]

Chemotherapy-induced diarrhea (off-labeled use): Initially administer 4 mg, followed by 2 mg every two to four hours or after each loose stool. For diarrhea persisting more than 24 hours, administer 2 mg every two hours (or 4 mg every four hours). Continue until 12 hours are passed without a loose bowel movement. Experts consider recommending alternative therapy for diarrhea persisting more than 48 hours, and doses more than 16 mg per day might not provide benefit.[13] Loperamide is used in prophylaxis of diarrhea caused by neratinib and irinotecan.

Specific Patient Population

Pediatric Patients

According to the Infectious Disease Society of America, loperamide is not recommended for the management of infectious diarrhea in pediatric patients.[14] For pediatric patients who are younger age, consider calculating dose based on weight. Use minimum effective dose for the possible shortest duration. It is not recommended for children less than age 2.

• 13 kg - 21 kg: 1 mg when first loose stool followed by 1 mg per dose after each subsequent unformed stool, but not more than 3 mg per day.
• 21 kg - 27 kg:  2 mg when first loose stool followed by 1 mg per dose after each subsequent unformed stool, but not more than 4 mg per day.
• 27.1 kg - 43 kg: 2 mg when first loose stool followed by 1 mg per dose after each subsequent unformed stool, but not more than 6 mg per day.
• Children 12 years and older: 4 mg when first loose stool followed by 2 mg per dose after each subsequent unformed stool, but not more than 8 mg per day.

Pregnancy Considerations

There are no adverse effects observed in animal studies. There is a lack of data on loperamide use in pregnant women, and the information is conflicting.[15] For managing acute diarrhea in pregnancy, some experts recommend only oral rehydration and dietary modifications; and loperamide in the least possible amount if the patient’s symptoms are disabling.[16]

Breastfeeding Considerations

Loperamide may be excreted into breast milk. The study on loperamide oxide (prodrug of loperamide) was conducted in breastfeeding women and found variable concentrations of loperamide and loperamide oxide into breastmilk.[17] Manufacturers recommend against breastfeeding. Furthermore, loperamide is contraindicated in children younger than two years of age. 

Patients with Renal Impairment

According to manufacturer labeling, no dose adjustment is required in patients with mild to severe renal impairment. In addition, since it is highly protein-bound, no dose adjustment is needed for dialysis. 

Patient with Hepatic Impairment

There is no dose adjustment provided in the product label; hence, use caution in patients with liver impairment.

Adverse Effects

Common Adverse Effects[4]

• Dry mouth
• Flatulence
• Abdominal cramps
• Nausea
• Ileus
• Constipation
• Urinary retention
• Dizziness
• Drowsiness

Serious Adverse Effects[6]

• Toxic megacolon
• Necrotizing enterocolitis
• Stevens-Johnson syndrome
• Toxic epidermal necrolysis
• Syncope
• QT/QTc interval prolongation, torsades de pointed, ventricular tachycardia[18]
• Other ventricular arrhythmias and/or cardiac arrest[19]

Drug Interactions

It is extracted in the liver and metabolized mainly by CYP3A4, a cytochrome P450 enzyme.[3] It is then conjugated and excreted into the bile. It has significant drug-drug interactions, and it is essential to check concomitant medicines before prescribing loperamide. Patients with hepatic impairment can have changed first-pass metabolism amounts, leading to CNS adverse reactions. Concomitant administration of lonafarnib may increase the plasma concentration of loperamide. When using loperamide with lonafarnib, initially do not use more than 1 mg loperamide per day. If clinically indicated, the dose of loperamide can be cautiously increased.

Contraindications

Loperamide is contraindicated in patients less than two years old, in patients with acute ulcerative colitis, bloody diarrhea, and diarrhea associated with bacterial infections.[20]

Monitoring

Currently, loperamide remains available over the counter in pharmacies with restricted access but without a prescription. Patients should be explained on maximum daily dosing when dispensing loperamide for any labeled or off-label indications. Monitor the clinical status of patients and loperamide efficacy by monitoring numbers of loose stools after each dose. When used in high doses, monitor ECG, signs/symptoms of CNS and respiratory depression.[21]

Toxicity

When loperamide is taken in large quantities and/or with other drugs that may alter its pharmacokinetic effects, such as p- glycoprotein inhibitors, loperamide produces opioid-like symptoms. These include a sensation of euphoria, miosis, central nervous system depression, and respiratory depression. Treatment of loperamide overdose and toxicity is primarily supportive. Naloxone, including an intranasal naloxone bolus, intravenous naloxone bolus, or naloxone infusion, may be used in patients with respiratory depression.[22] As naloxone has a shorter half-life than loperamide, patients should be observed for at least 24 hours after the last naloxone administration to ensure they do not deteriorate clinically.

Taken in large quantities, loperamide can cause systemic effects similar to opioid toxicity (central nervous system depression, respiratory depression) as well as lethal cardiac conduction abnormalities.[3] The patient should be on a cardiac monitor, and an ECG obtained. If there is QRS widening, sodium bicarbonate may be given and can be repeated in boluses or given as an infusion.[23] If there are signs of QTc prolongation (QTc is considered prolonged if greater than 450 ms in males and 470 ms in females), electrolyte abnormalities (magnesium, potassium, phosphate) should be corrected, and isoproterenol or transcutaneous pacing may be an option.[24] Cardiac arrest is manageable using standard ACLS protocols.

Enhancing Healthcare Team Outcomes

Healthcare providers widely prescribe loperamide for different types of diarrhea. Even though it is available as an over-the-counter medication, its use still requires the attention and oversight of an interprofessional healthcare team. Pharmacists and clinicians need to survey the potential for abuse and educate the patient of its potential toxicity in large doses. Nurses can also provide monitoring and counseling in this area. In September 2019, the FDA approved a new package size limitations and unit-dose packaging for certain over-the-counter loperamide products in an effort to improve patient safety. When prescribing or recommending loperamide, the clinician should have the nurse and/or pharmacist reiterate all safety and dosing issues to ensure proper medication use and optimize patient safety, as patients may think that because of its OTC availability, it does not represent any potential for misuse. Interprofessional management of loperamide therapy will result in better patient outcomes with fewer adverse effects. [Level 5]