Loperamide (DB00836): A Comprehensive Pharmacological and Clinical Monograph

Section 1: Drug Identification and Physicochemical Properties

This section establishes the fundamental identity of loperamide, providing the necessary chemical, physical, and historical context for the subsequent pharmacological and clinical analysis.

1.1 Nomenclature and Identifiers

Loperamide is a synthetic small molecule drug identified across global databases by a standardized set of names and codes.[1] Its formal chemical name, as designated by the International Union of Pure and Applied Chemistry (IUPAC), is 4-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-N,N-dimethyl-2,2-diphenylbutanamide.[1] The primary identifier for this chemical entity in the Chemical Abstracts Service (CAS) registry is the number 53179-11-6, which refers to the loperamide base.[1] The hydrochloride salt, the form in which the drug is most commonly manufactured and administered, is identified by the related CAS number 34552-83-5.[1]

In major drug and chemical databases, loperamide is cataloged under the DrugBank accession number DB00836, the PubChem Compound ID (CID) 3955, the ChEMBL ID CHEMBL841, and the FDA's Unique Ingredient Identifier (UNII) 6X9OC3H4II.[1] Its widespread use is reflected in a variety of synonyms and international nonproprietary names, including Loperamida (Spanish) and Lopéramide (French).[1] Commercially, it is best known by the brand name Imodium® but is marketed globally under numerous other trade names, such as Imodium A-D®, Kaopectate II®, and Pepto® Diarrhea Control, underscoring its status as a ubiquitous over-the-counter (OTC) medication.[1]

Table 1: Loperamide Chemical and Database Identifiers

Identifier Type	Value	Source(s)
Primary Name	Loperamide	1
IUPAC Name	4-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-N,N-dimethyl-2,2-diphenylbutanamide	1
CAS Number (Base)	53179-11-6	1
CAS Number (HCl Salt)	34552-83-5	1
DrugBank ID	DB00836	1
PubChem CID	3955	2
ChEMBL ID	CHEMBL841	2
UNII	6X9OC3H4II	1
Molecular Formula (Base)	C29​H33​ClN2​O2​	2
Molecular Weight (Base)	477.04 g/mol	1
Molecular Formula (HCl Salt)	C29​H33​ClN2​O2​⋅HCl	3
Molecular Weight (HCl Salt)	513.51 g/mol	3

1.2 Chemical Structure and Formula

The molecular formula for the loperamide base is C29​H33​ClN2​O2​.[2] It is structurally classified as a synthetic piperidine derivative and possesses several key functional groups that define its chemical character: a monocarboxylic acid amide, a monochlorobenzene moiety, and a tertiary alcohol.[1] This complex structure shares similarities with other peripherally acting opioids like diphenoxylate as well as the butyrophenone antipsychotic haloperidol, reflecting its origins in opioid chemistry research.[1] For unambiguous computational representation, its structure is defined by the following chemical descriptors:

• InChI: InChI=1S/C29H33ClN2O2/c1-31(2)27(33)29(24-9-5-3-6-10-24,25-11-7-4-8-12-25)19-22-32-20-17-28(34,18-21-32)23-13-15-26(30)16-14-23/h3-16,34H,17-22H2,1-2H3 [1]
• InChIKey: RDOIQAHITMMDAJ-UHFFFAOYSA-N [1]
• SMILES: CN(C)C(=O)C(CCN1CCC(CC1)(C2=CC=C(C=C2)Cl)O)(C3=CC=CC=C3)C4=CC=CC=C4 [1]

1.3 Physical and Chemical Properties

Loperamide hydrochloride presents as a white to almost white crystalline powder.[3] A defining characteristic of the molecule is its high lipophilicity, which is critical to its absorption and mechanism of action.[1] This property is quantified by a high computed partition coefficient (AlogP) of approximately 5.09.[5] Consistent with its lipophilic nature, loperamide is poorly soluble in water but demonstrates better solubility in organic solvents.[3] The molecule is a weak base, with a reported pKa value between 8.66 and 9.41, meaning it is partially ionized at physiological pH.[5] The hydrochloride salt has a primary melting point of 224 °C.[2]

1.4 Historical Context and Development

The history of loperamide is a compelling narrative of targeted drug design, shifting regulatory perceptions, and the unforeseen consequences of widespread accessibility. Loperamide was first synthesized in 1969 by the team of Dr. Paul Janssen at Janssen Pharmaceutica in Belgium.[14] This discovery was not accidental but was the culmination of a deliberate research program aimed at dissociating the potent antidiarrheal effects of opioids from their centrally-mediated side effects, such as sedation, euphoria, and respiratory depression. This effort followed Janssen's earlier work on the opioid analgesic fentanyl and the antidiarrheal diphenoxylate.[14]

The first clinical reports on loperamide (trial code R-18553) appeared in 1973, and it was launched commercially under the brand name Imodium® the same year.[14] It received approval from the U.S. Food and Drug Administration (FDA) as a prescription medication in December 1976.[14] Its initial regulatory journey in the United States reflects the cautious approach to opioid-related compounds; it was first classified as a Schedule II narcotic, a category for drugs with high abuse potential. However, as evidence of its limited central nervous system (CNS) activity at therapeutic doses mounted, its classification was lowered to Schedule V in 1977 and it was fully decontrolled in 1982.[2]

This de-scheduling paved the way for a pivotal moment in the drug's history: its approval for over-the-counter (OTC) sale in the U.S. in 1988.[14] This transition dramatically increased its availability and solidified its public perception as a safe and accessible remedy for common diarrhea. However, this perception of safety was challenged early on in the pediatric population. In 1990, liquid formulations intended for children were voluntarily withdrawn from the market following reports from Pakistan of fatal paralytic ileus in young children, highlighting the unique vulnerability of this group to the drug's effects.[2]

The historical trajectory of loperamide's regulatory status—from a high-schedule narcotic to an unscheduled, ubiquitous OTC product—is a direct reflection of a shifting understanding of its risk-benefit profile. The initial design goal was to create a peripherally restricted opioid, and for decades, this was believed to be a complete success, justifying its widespread availability. However, this very accessibility, combined with the rise of the opioid epidemic, created an environment where its latent abuse potential could be discovered and exploited. The subsequent emergence of widespread misuse and associated cardiotoxicity has forced a re-evaluation of its safety, leading to new FDA warnings and packaging restrictions in recent years.[17] This history is not static; it represents an ongoing cycle of perceived safety, expanded access, emergent misuse, and subsequent regulatory recalibration, serving as a classic case study in post-marketing surveillance and the complex challenges of regulating essential medicines that also possess a high potential for abuse. In a testament to its therapeutic importance, loperamide was added to the World Health Organization's List of Essential Medicines in 2013.[14]

Section 2: Comprehensive Pharmacological Profile

This section details the molecular mechanisms by which loperamide exerts its therapeutic effects and the pharmacokinetic processes that govern its disposition in the body. Central to this profile is the critical role of the P-glycoprotein efflux pump, which acts as the primary determinant of the drug's safety and its dual nature as both a peripherally restricted therapeutic and a potential systemic toxin.

2.1 Pharmacodynamics: Mechanism of Action

Loperamide's primary therapeutic effect is achieved through its action as a potent, synthetic agonist of μ-opioid receptors.[1] Unlike centrally acting opioids such as morphine, loperamide's effects at therapeutic doses are largely confined to the gastrointestinal tract. It binds with high affinity to μ-opioid receptors located within the myenteric plexus, a network of neurons embedded in the muscular wall of the large intestine.[2]

The binding of loperamide to these receptors initiates a cascade of downstream effects that collectively reduce diarrheal symptoms:

• Inhibition of Peristalsis: Agonism at intestinal μ-receptors inhibits the activity of the myenteric plexus. This leads to a decrease in the tone of both the longitudinal and circular smooth muscles of the intestinal wall, effectively slowing down the coordinated contractions (peristalsis) that propel contents through the gut.[2]
• Antisecretory Effects: Loperamide inhibits the release of pro-motility and pro-secretory neurotransmitters and mediators, including acetylcholine and prostaglandins.[8] This action reduces the secretion of fluid and electrolytes into the intestinal lumen, a key contributor to watery stools.
• Increased Intestinal Transit Time: The combined reduction in motility and secretion significantly increases the residence time of fecal matter within the intestine.[2] This prolonged contact time allows for more thorough absorption of water and electrolytes back into the body, resulting in firmer, less frequent stools.
• Increased Anal Sphincter Tone: Loperamide has also been shown to increase the tone of the anal sphincter, which helps to reduce the symptoms of fecal incontinence and urgency that often accompany severe diarrhea.[22]

While μ-receptor agonism is the principal mechanism, other actions may contribute to loperamide's effects. It has been shown to inhibit calmodulin, a ubiquitous calcium-binding messenger protein, which may play a role in its antisecretory activity.[8] Additionally, database information suggests that loperamide possesses some agonist activity at delta- and kappa-opioid receptors, although the clinical significance of these interactions is considered secondary to its potent effects at the μ-receptor.[7]

2.2 Pharmacokinetics: ADME Profile

The pharmacokinetic profile of loperamide is fundamental to both its efficacy and its safety. The processes of absorption, distribution, metabolism, and excretion (ADME) are characterized by features that strictly limit its systemic exposure at therapeutic doses.

• Absorption: Loperamide exhibits very low oral bioavailability, with estimates ranging from less than 1% down to 0.3%.[2] This poor absorption is a key safety feature and is the result of two powerful, synergistic mechanisms: extensive first-pass metabolism in the gut wall and liver, and active efflux of the drug back into the intestinal lumen by the P-glycoprotein transporter. Following oral administration, peak plasma concentrations are achieved in approximately 2.5 to 5 hours.[9]
• Distribution: Consistent with its high lipophilicity, loperamide has a large volume of distribution and is highly bound to plasma proteins (approximately 95%).[11]
• Metabolism: The drug undergoes extensive and rapid oxidative N-demethylation, primarily in the liver and intestinal wall. This metabolic process is mediated principally by the cytochrome P450 isoenzymes CYP3A4 and CYP2C8, which convert loperamide to its major, largely inactive metabolite, N-desmethyl-loperamide.[11] This efficient metabolic clearance is a primary reason for its low systemic bioavailability.
• Elimination: The apparent elimination half-life of loperamide at therapeutic doses is in the range of 9 to 14 hours, though this can extend to 19-20 hours at higher therapeutic doses and becomes significantly prolonged in overdose situations.[2] The drug and its metabolites are eliminated from the body predominantly through the feces via biliary excretion.[2]

Table 2: Summary of Loperamide Pharmacokinetic Parameters

Parameter	Value / Pathway	Clinical Significance	Source(s)
Oral Bioavailability	<1% (typically ~0.3%)	Primary safety mechanism; prevents significant systemic exposure at therapeutic doses.	11
Peak Plasma Time	2.5–5 hours	Determines the onset of systemic drug levels, though local gut effects may be faster.	11
Elimination Half-life	9–14 hours (dose-dependent)	Can be significantly prolonged in overdose, leading to persistent toxicity.	2
Plasma Protein Binding	~95%	High binding limits the amount of free drug available to exert systemic effects.	11
Primary Metabolism	Oxidative N-demethylation via CYP3A4 and CYP2C8	Extensive first-pass metabolism is a key reason for low bioavailability. This pathway is a major site of drug-drug interactions.	11
Primary Excretion Route	Feces (via bile)	Renal impairment has minimal impact on clearance.	2

2.3 The Critical Role of P-glycoprotein (P-gp)

The pharmacology of loperamide cannot be fully understood without appreciating the central role of P-glycoprotein (P-gp), an ATP-dependent efflux transporter protein. P-gp functions as a biological "gatekeeper," actively pumping a wide range of substances out of critical tissues.

• Blood-Brain Barrier Defense: Loperamide is an avid substrate for P-gp, which is expressed at high levels in the endothelial cells that form the blood-brain barrier (BBB).[12] At therapeutic doses, any loperamide that enters the systemic circulation and reaches the BBB is efficiently captured and transported back into the bloodstream. This efflux mechanism is the principal reason why loperamide is devoid of central opioid effects like euphoria, analgesia, and respiratory depression when used as directed.[12]
• Limiting Gut Absorption: P-gp is also expressed on the apical surface of intestinal epithelial cells. Here, it functions to pump loperamide that has been absorbed from the gut lumen back into the intestine, further contributing to the drug's extremely low oral bioavailability.[23]
• Saturation as the Gateway to Toxicity: The P-gp transport system, like any enzyme or transporter, is saturable. The massive doses ingested during abuse (often exceeding 100 mg per day) are sufficient to overwhelm and saturate the P-gp pumps in both the intestine and the BBB.[11] This saturation has two critical consequences: it allows for a dramatic increase in intestinal absorption and systemic bioavailability, and, most importantly, it permits the drug to breach the BBB and enter the CNS. Once in the brain, loperamide can engage central μ-opioid receptors, unmasking its latent potential to produce opioid-like euphoria and toxicity.[9]

The safety profile of loperamide is therefore not an immutable property of the molecule itself, but rather a delicate, dose-dependent equilibrium. The drug is intrinsically a potent μ-opioid agonist capable of acting on the CNS. Its safety at therapeutic doses is entirely dependent on the body's pharmacokinetic defenses—P-gp efflux and CYP-mediated metabolism—which prevent it from reaching central receptors and keep systemic concentrations low. Any factor that disrupts this equilibrium, such as massive overdose or co-administration of drugs that inhibit P-gp or CYP enzymes, effectively lowers the threshold for toxicity. Taking a P-gp or CYP3A4 inhibitor can thus create a "pharmacokinetic overdose," where a therapeutically intended dose produces dangerously high systemic concentrations, fundamentally altering the drug's safety profile.

Section 3: Clinical Applications and Therapeutic Efficacy

This section outlines the established and emerging clinical uses of loperamide, demonstrating its value in a wide spectrum of diarrheal diseases, from common self-limiting conditions to chronic and severe medical disorders.

3.1 FDA-Approved Indications

The U.S. Food and Drug Administration has approved loperamide for several specific indications, reflecting its utility in both acute and chronic settings.[22]

• Control of Acute Nonspecific Diarrhea: This is the most common indication for loperamide, particularly for the OTC formulations. It is used for the symptomatic relief of acute diarrhea, such as that caused by viral gastroenteritis, in adults and children aged 2 years and older.[2]
• Management of Chronic Diarrhea Associated with Inflammatory Bowel Disease (IBD): Under prescription, loperamide is indicated for the long-term symptomatic management of chronic diarrhea in adults with IBD, which includes conditions such as Crohn's disease and ulcerative colitis.[2] In this context, it helps to reduce stool frequency and improve consistency, thereby enhancing quality of life.
• Reduction of Ileostomy Discharge: Loperamide is also approved for reducing the volume and frequency of discharge in patients who have undergone an ileostomy.[11] By slowing intestinal transit and increasing water absorption, it helps to make the ileostomy output more manageable.

3.2 Off-Label and Investigational Uses

Beyond its approved indications, loperamide is widely used off-label for a variety of conditions, and its unique properties have led to its investigation for novel therapeutic roles.

• Traveler's Diarrhea: Loperamide is a mainstay for the symptomatic treatment of mild to moderate traveler's diarrhea, allowing individuals to manage symptoms while traveling.[2]
• Chemotherapy-Induced Diarrhea (CID): This is a clinically significant off-label use. Certain chemotherapeutic agents, notably irinotecan, can cause severe, dose-limiting diarrhea. High-dose loperamide regimens, administered under close medical supervision, are often employed to manage this debilitating side effect.[2]
• Irritable Bowel Syndrome with Diarrhea (IBS-D): For adult patients whose primary IBS symptom is diarrhea, loperamide is frequently used to reduce stool frequency and urgency.[2]
• Investigational Uses: Preliminary research has suggested potential new applications for loperamide. It has been noted to have a potential role as an anticoronaviral agent, though this is based on early-stage research and is not a clinical application at this time.[1] More surprisingly, a 2020 study reported that loperamide was effective at killing glioblastoma (a type of brain cancer) cells in a laboratory setting, opening an unexpected and novel avenue for oncological research.[14]

The broad clinical utility of loperamide, spanning from a simple OTC remedy for traveler's diarrhea to a crucial off-label medication for managing severe chemotherapy side effects, creates a significant public health challenge. This dual-use profile blurs the lines of perceived risk for the general public. A drug that is widely available on pharmacy and supermarket shelves is also used in high-dose, specialist-managed regimens for life-threatening conditions. This can inadvertently create a "halo effect" of safety, where the public perception of loperamide as a universally safe and simple medicine is not commensurate with the risks associated with the supratherapeutic doses seen in misuse and abuse scenarios. This dynamic complicates risk communication efforts by regulatory bodies and healthcare professionals, as the very effectiveness and accessibility of the drug contribute indirectly to the potential for its misuse.

Section 4: Dosage, Administration, and Special Populations

This section provides detailed, practical guidance on the safe and effective use of loperamide. It emphasizes the critical distinctions between OTC and prescription dosing, pediatric use, and considerations for specific patient populations. Adherence to these guidelines is paramount to avoiding adverse events.

4.1 Adult Dosing Regimens

Dosing for adults differs significantly based on whether the drug is used for self-medication (OTC) or under the direction of a healthcare provider (prescription).

• Acute Diarrhea (OTC/Self-Medication): The standard initial dose is 4 mg (e.g., two 2 mg capsules or tablets), followed by a subsequent dose of 2 mg after each unformed stool. The maximum daily dose for self-medication is strictly limited to 8 mg in a 24-hour period. Use should not exceed 48 hours without consulting a clinician.[11]
• Acute Diarrhea (Prescription): The initial dose is the same: 4 mg, followed by 2 mg after each loose stool. However, under medical supervision, the maximum daily dose can be increased to 16 mg in a 24-hour period.[11]
• Chronic Diarrhea (Prescription): Treatment is initiated with 4 mg, followed by 2 mg after each unformed stool until symptoms are controlled. The dosage is then titrated downwards to the lowest effective maintenance dose, which is typically 4-8 mg per day administered in single or divided doses. While the daily dose should not exceed 16 mg, if clinical improvement is not observed after 10 days of treatment at this maximum dose, it is unlikely that further administration will be beneficial.[29]

4.2 Pediatric Dosing and Safety Considerations

The use of loperamide in children requires extreme caution and strict adherence to age- and weight-based dosing due to their increased sensitivity to the drug's effects.

• Absolute Contraindication: Loperamide is contraindicated in children younger than 2 years of age. This is due to reports of severe and sometimes fatal adverse events in this age group, including respiratory depression and paralytic ileus (a condition where intestinal motility ceases), which can lead to abdominal distention and toxic megacolon.[2]
• Age/Weight-Based Dosing (Clinician-Directed): For children 2 years and older, dosing must be carefully calculated, and liquid formulations are often preferred for accuracy. The following schedule represents the total dosage for the first 24 hours of therapy:
• Ages 2–5 years (13–20 kg): 1 mg administered three times daily (total daily dose: 3 mg).[29]
• Ages 6–8 years (20–30 kg): 2 mg administered twice daily (total daily dose: 4 mg).[29]
• Ages 8–12 years (>30 kg): 2 mg administered three times daily (total daily dose: 6 mg).[29]
• Subsequent Dosing: After the first day of treatment, a dose of 0.1 mg/kg may be administered after each subsequent loose stool, but the total daily dosage must not exceed the maximum recommended for the first day.[31]

The dosing guidelines reveal a critical aspect of loperamide's safety profile: the vast gap between therapeutic and toxic doses. The maximum recommended daily doses for OTC (8 mg) and prescription (16 mg) use are orders of magnitude lower than the doses associated with abuse and cardiotoxicity, which are often reported to be in the range of 100-400 mg per day or even higher.[25] This implies that severe toxicity is not a risk associated with minor, accidental overdosing by a typical patient with diarrhea. Instead, the primary risk is almost exclusively linked to deliberate, massive ingestion by individuals seeking to bypass the drug's peripheral restrictions to achieve central opioid effects. This distinction is crucial for public health interventions, as it suggests that prevention efforts should focus more on restricting access to bulk quantities and educating about the dangers of intentional abuse, rather than on the risk of small dosing errors by typical users.

Table 3: Recommended Dosing Regimens for Loperamide

Indication	Population	Initial Dose	Subsequent Dose	Maximum 24-Hour Dose	Key Precautions
Acute Diarrhea (OTC)	Adults & Children ≥12 years	4 mg	2 mg after each loose stool	8 mg	Do not use for >48 hours without clinician direction.
Acute Diarrhea (Rx)	Adults	4 mg	2 mg after each loose stool	16 mg	Medically supervised use only.
Chronic Diarrhea (Rx)	Adults	4 mg initially, then titrated	Titrated to maintenance dose	16 mg	Discontinue if no improvement after 10 days at 16 mg/day.
Acute Diarrhea (Rx)	Children 8-12 years (>30 kg)	2 mg, three times daily	0.1 mg/kg after each loose stool	6 mg	Total daily dose must not exceed first-day dose.
Acute Diarrhea (Rx)	Children 6-8 years (20-30 kg)	2 mg, twice daily	0.1 mg/kg after each loose stool	4 mg	Total daily dose must not exceed first-day dose.
Acute Diarrhea (Rx)	Children 2-5 years (13-20 kg)	1 mg, three times daily	0.1 mg/kg after each loose stool	3 mg	Use liquid formulation. Total daily dose must not exceed first-day dose.
All Indications	Children <2 years	CONTRAINDICATED	CONTRAINDICATED	CONTRAINDICATED	Risk of fatal paralytic ileus and respiratory depression.

4.3 Use in Special Populations

• Hepatic Impairment: Loperamide should be used with caution in patients with liver disease. Because the drug undergoes extensive first-pass metabolism in the liver, hepatic impairment can significantly reduce its clearance, leading to increased systemic plasma concentrations and a heightened risk of CNS and cardiac toxicity. While specific dosage adjustments are not provided in product labeling, close clinical monitoring is essential.[2]
• Renal Impairment: No dosage adjustment is necessary for patients with renal impairment. As loperamide and its metabolites are primarily excreted in the feces, kidney function has a minimal effect on its elimination.[11]
• Elderly: No specific dosage adjustments are required based on age alone. However, caution is advised, as elderly patients may have a higher prevalence of underlying cardiac conditions and may be more susceptible to the QT-prolonging effects of drugs.[22]
• Pregnancy and Lactation: Loperamide is generally not recommended for use during pregnancy or by nursing mothers. Although animal reproduction studies have not shown evidence of teratogenicity, there is a lack of sufficient and well-controlled studies in pregnant women. Loperamide can be excreted into breast milk, and its use is therefore not advised during breastfeeding.[2]

Section 5: The Duality of Loperamide: Misuse, Abuse, and Cardiotoxicity

This section addresses the most pressing safety concern associated with loperamide in the modern era: its transformation from a trusted OTC remedy into a dangerous drug of abuse. It details the motivations for its misuse, the pharmacokinetic mechanisms that are exploited, and the life-threatening cardiotoxicity that can result.

5.1 The "Poor Man's Methadone"

In recent years, loperamide has gained notoriety as the "poor man's methadone" due to its widespread abuse within communities affected by the opioid epidemic.[8] The motivations for this abuse are twofold:

1. Self-Treatment of Opioid Withdrawal: Individuals with opioid use disorder ingest large quantities of loperamide to mitigate the severe symptoms of withdrawal from other opioids like heroin or prescription painkillers.[9]
2. To Achieve Euphoria: At even higher doses, loperamide is abused for its ability to produce a euphoric "high," similar to that of other centrally acting opioids.[9]

The primary drivers for this pattern of abuse are the drug's low cost, its legal status, and its easy availability as an OTC product in large quantities.[9] To achieve these central effects, abusers must overcome the body's natural pharmacokinetic barriers. This is accomplished by ingesting massive doses—often ranging from 50 mg to over 300 mg per day—which are sufficient to saturate the P-glycoprotein efflux pumps in the gut and at the blood-brain barrier.[11] This allows for increased systemic absorption and penetration into the CNS. This practice is often amplified by the co-ingestion of known P-gp and CYP3A4 inhibitors (such as quinidine, cimetidine, or grapefruit juice) to further enhance CNS exposure.[23]

5.2 Loperamide-Induced Cardiotoxicity: A Life-Threatening Complication

The most severe consequence of loperamide abuse is a distinct syndrome of cardiotoxicity, which has prompted strong regulatory action.

• FDA Boxed Warning: In response to a surge in reports of serious cardiac events and deaths linked to loperamide abuse, the FDA issued a safety communication in 2016 and subsequently mandated a Boxed Warning—the agency's strongest warning—for all loperamide products. This warning explicitly highlights the risk of Torsades de Pointes, cardiac arrest, and sudden death associated with the ingestion of higher-than-recommended doses.[18]
• Clinical Presentation: Patients with loperamide cardiotoxicity typically present with symptoms such as syncope (fainting), dizziness, palpitations, or cardiac arrest.[36] The hallmark electrocardiogram (ECG) findings are a significant prolongation of the QTc interval (a measure of cardiac repolarization) and a widening of the QRS complex (a measure of ventricular depolarization).[11] These electrophysiological disturbances create a substrate for life-threatening ventricular arrhythmias, including monomorphic and polymorphic ventricular tachycardia (specifically Torsades de Pointes), and Brugada-like syndromes.[25]
• Mechanism of Cardiotoxicity: This toxicity is not a typical opioid effect but is an off-target action that occurs at the extremely high plasma concentrations achieved during overdose. Both loperamide and its primary metabolite, N-desmethyl-loperamide, are potent inhibitors of critical cardiac ion channels.[25]
• hERG (IKr) Potassium Channel Blockade: Loperamide potently blocks the hERG potassium channel, which is essential for the repolarization phase of the cardiac action potential. Inhibition of this channel slows repolarization, leading directly to the observed QTc interval prolongation and creating the conditions necessary for Torsades de Pointes to develop.[11] In vitro studies have determined the half-maximal inhibitory concentration (IC50​) for hERG blockade to be approximately 0.390 µM, a concentration that is achievable in overdose scenarios.[40]
• NaV1.5 (INa) Sodium Channel Blockade: Loperamide also inhibits the primary cardiac sodium channel, NaV1.5. This action slows the rapid upstroke of the action potential (depolarization) in ventricular cells, which manifests on the ECG as a widening of the QRS complex. This conduction slowing increases the risk of re-entrant arrhythmias like monomorphic ventricular tachycardia.[11]
• Toxicokinetics and Management: In overdose, the toxicokinetics of loperamide are altered. The elimination half-life of both the parent drug and its active metabolite is significantly prolonged, resulting in persistent cardiotoxicity that can last for several days after the last ingestion. This necessitates prolonged hospitalization with continuous cardiac monitoring until ECG abnormalities resolve.[25] Standard antiarrhythmic drugs are often ineffective, and management may require electrical cardioversion or overdrive pacing.[36]

The emergence of loperamide cardiotoxicity represents a "perfect storm" at the intersection of pharmacology, public health policy, and societal factors. The drug possesses intrinsic, dose-dependent cardiotoxic properties via ion channel blockade. The ongoing opioid epidemic has created a large, vulnerable population actively seeking cheap and accessible alternatives to manage withdrawal or achieve euphoria. Loperamide's OTC status provides this alternative, and the dissemination of abuse techniques via online forums facilitates its misuse. Therefore, the clinical problem of loperamide cardiotoxicity cannot be understood through its pharmacology alone. It is an emergent phenomenon rooted in a combination of molecular toxicology, drug regulation, and the public health crisis of substance use disorder. This implies that effective solutions must be multi-faceted, involving not only pharmacological awareness but also public health education, regulatory changes to limit access, and expanded treatment for opioid addiction.

Section 6: Contraindications, Warnings, and Adverse Effects

This section provides a comprehensive overview of the safety profile of loperamide when used for therapeutic purposes, outlining absolute contraindications, key warnings and precautions, and common and serious adverse reactions.

6.1 Absolute Contraindications

The use of loperamide is strictly contraindicated in several clinical situations where its anti-motility effect can be harmful.

• Pediatric Patients: Loperamide must not be given to children younger than 2 years of age due to the high risk of severe adverse events, including respiratory depression and fatal paralytic ileus.[2]
• Invasive Infectious Diarrhea: It should not be used as the primary therapy for patients with acute dysentery (characterized by high fever and bloody stools) or bacterial enterocolitis caused by invasive organisms such as E. coli O157:H7, Salmonella, or Shigella.[2]
• Inflammatory and Toxin-Mediated Colitis: Loperamide is contraindicated in patients having an acute flare-up of ulcerative colitis and in those with pseudomembranous colitis associated with the use of broad-spectrum antibiotics (i.e., Clostridioides difficile infection).[2]
• Abdominal Pain without Diarrhea: The drug should not be used in patients presenting with stomach pain in the absence of diarrhea.[18]

The majority of these contraindications are rooted in a single, critical principle: peristalsis should not be inhibited when it is serving as a necessary protective mechanism. Diarrhea is often the body's way of rapidly expelling pathogens and their toxins from the gastrointestinal tract. Loperamide works by directly halting this expulsion mechanism. In the context of an invasive bacterial infection, inhibiting peristalsis allows the pathogens more time to adhere to and invade the intestinal wall, potentially leading to systemic infection. In the case of C. difficile, slowing gut motility allows the bacterial toxins to accumulate to dangerous levels, which can precipitate toxic megacolon, a life-threatening dilation of the colon. Therefore, these contraindications are not arbitrary rules but are based on the underlying pathophysiology of the disease. This underscores the critical importance of accurate diagnosis before initiating symptomatic treatment with an anti-motility agent, a significant challenge for an OTC product where the burden of correct self-diagnosis falls upon the consumer.

6.2 Warnings and Precautions

• Discontinuation of Therapy: Loperamide must be discontinued promptly if constipation, abdominal distention, or symptoms of ileus develop.[2] For acute diarrhea, if symptoms do not improve within 48 hours of starting treatment, use should be stopped, and a healthcare provider should be consulted.[28]
• Hepatic Impairment: As loperamide is extensively metabolized by the liver, it should be used with caution in patients with hepatic impairment. Reduced clearance can lead to a relative overdose and increased risk of toxicity.[2]
• Fluid and Electrolyte Replacement: It is crucial to recognize that loperamide only treats the symptom of diarrhea; it does not address the underlying fluid and electrolyte loss. Appropriate oral rehydration therapy is a critical component of management, especially in children and the elderly.[32]
• Cardiac Risk: Even at recommended therapeutic doses, rare cases of syncope and ventricular tachycardia have been reported. Caution is warranted in patients with a personal or family history of cardiac arrhythmias (e.g., long QT syndrome) or in those taking other medications known to prolong the QT interval.[18]

6.3 Common and Serious Adverse Reactions

• Common Side Effects: At therapeutic doses, loperamide is generally well-tolerated. The most frequently reported adverse effects are related to its intended pharmacological action and include constipation, nausea, abdominal cramps, and dizziness. Other common effects are drowsiness, flatulence, and dry mouth.[3]
• Serious Adverse Reactions:
• Gastrointestinal: Although rare, paralytic ileus and toxic megacolon are the most severe gastrointestinal risks and constitute a medical emergency.[2]
• Hypersensitivity: Rare but serious allergic reactions, including skin rash, hives (urticaria), and anaphylaxis, have been reported.[41]
• Central Nervous System: Drowsiness and dizziness can impair coordination and judgment. Children may be more sensitive to these CNS effects than adults.[29]

Section 7: Clinically Significant Drug and Food Interactions

This section details the drug and food interactions that can significantly alter the pharmacology of loperamide, either by reducing its efficacy or, more critically, by dramatically increasing the risk of toxicity. These interactions are categorized by their underlying pharmacokinetic or pharmacodynamic mechanisms.

7.1 Pharmacokinetic Interactions: Increasing Loperamide Exposure

The most dangerous drug interactions are those that inhibit the key pharmacokinetic safety mechanisms that normally limit loperamide's systemic exposure: the metabolic enzymes CYP3A4 and CYP2C8, and the P-glycoprotein (P-gp) efflux transporter. Inhibition of these pathways can lead to a substantial increase in loperamide's plasma concentration, effectively mimicking an overdose and elevating the risk of CNS and cardiac toxicity.[11]

• CYP3A4 Inhibitors: Co-administration with strong inhibitors of CYP3A4 can significantly increase loperamide levels. Common examples include azole antifungals (ketoconazole, itraconazole), macrolide antibiotics (clarithromycin), and certain antiretroviral drugs (ritonavir).[22] A clinical study showed that co-administration with itraconazole, which also inhibits P-gp, increased loperamide systemic exposure by 3- to 4-fold.[22]
• CYP2C8 Inhibitors: Co-administration with strong inhibitors of CYP2C8, such as the lipid-lowering agent gemfibrozil, can also elevate loperamide concentrations. Studies have shown that gemfibrozil can increase loperamide exposure by approximately 2-fold.[22]
• P-glycoprotein (P-gp) Inhibitors: A wide range of drugs inhibit the P-gp transporter, thereby increasing loperamide absorption and/or reducing its efflux from the brain. Examples include quinidine, ritonavir, verapamil, amiodarone, and cyclosporine.[7] Co-administration with P-gp inhibitors like quinidine or ritonavir can result in a 2- to 3-fold increase in loperamide plasma levels.[22]
• Combined Inhibitors: The risk of a pharmacokinetic interaction is dramatically magnified when loperamide is taken with drugs that inhibit multiple pathways. A landmark clinical study demonstrated that when loperamide was co-administered with both itraconazole (a CYP3A4/P-gp inhibitor) and gemfibrozil (a CYP2C8 inhibitor), the systemic exposure (AUC) to loperamide was increased by a staggering 13-fold.[22]

The drug interaction profile of loperamide creates a "hidden" population at risk for toxicity. This group includes not only high-dose abusers but also patients on complex polypharmacy regimens who may take loperamide at or near the recommended dose. A patient taking medications like an azole antifungal and a fibrate for cholesterol could develop diarrhea and take an OTC dose of loperamide, unknowingly creating a state of functional overdose due to the profound inhibition of the drug's clearance pathways. This scenario could lead to cardiac symptoms from a "therapeutic" dose, and the link to loperamide might be easily missed by an unsuspecting clinician. This underscores the need for heightened vigilance and interaction screening by pharmacists and physicians, even for a common OTC product, particularly in polymedicated or elderly patients.

7.2 Pharmacodynamic Interactions: Additive Effects

• QTc Interval Prolongation: Loperamide itself can prolong the QTc interval at high concentrations. Therefore, co-administration with other drugs known to have this effect creates an additive risk for Torsades de Pointes. This is a major clinical concern. Such drugs include Class IA antiarrhythmics (e.g., quinidine), Class III antiarrhythmics (e.g., amiodarone, sotalol), certain antipsychotics (e.g., haloperidol, ziprasidone), and some antibiotics (e.g., moxifloxacin).[18]
• Additive Constipation: Concurrent use of loperamide with other drugs that cause constipation can increase the risk of severe constipation, impaction, and related complications like ileus. These drugs include other opioids, anticholinergic agents, and some tricyclic antidepressants.[2]
• CNS Depression: In situations of loperamide abuse where the drug crosses the blood-brain barrier, its CNS depressant effects are additive with other substances like alcohol, benzodiazepines, and skeletal muscle relaxants, increasing the risk of profound sedation and respiratory depression.[31]

7.3 Drug-Food Interactions

• Tonic Water (Quinine): A specific and often overlooked interaction involves tonic water. The quinine present in tonic water is a known inhibitor of P-glycoprotein. Consuming tonic water while taking loperamide can potentially increase its absorption and systemic exposure, thereby increasing the risk of adverse effects. It is advisable to avoid tonic water when using loperamide.[32]

Table 4: Major Drug Interactions with Loperamide, Categorized by Mechanism

Interacting Drug/Class	Mechanism of Interaction	Clinical Consequence	Management Recommendation	Source(s)
Ketoconazole, Itraconazole, Ritonavir	CYP3A4 and/or P-gp Inhibition	Markedly increased loperamide plasma concentration; increased risk of CNS and cardiac toxicity.	Avoid combination. If unavoidable, monitor closely for adverse effects, including ECG changes.	22
Gemfibrozil	CYP2C8 Inhibition	Increased loperamide plasma concentration; increased risk of toxicity.	Avoid combination or use with extreme caution and clinical monitoring.	22
Quinidine	P-gp Inhibition	Increased loperamide plasma concentration and CNS penetration; increased risk of toxicity.	Avoid combination.	22
Amiodarone, Sotalol, Haloperidol	Additive QTc Prolongation (Pharmacodynamic)	Increased risk of life-threatening ventricular arrhythmias, including Torsades de Pointes.	Avoid combination, especially in patients with other risk factors for QTc prolongation.	18
Other Opioids, Anticholinergics	Additive Constipating Effects (Pharmacodynamic)	Increased risk of severe constipation, abdominal distention, and ileus.	Use with caution; monitor bowel function. Discontinue loperamide if constipation occurs.	2
Tonic Water (containing Quinine)	P-gp Inhibition	Potentially increased loperamide absorption and systemic exposure.	Avoid concurrent consumption.	32

Section 8: Conclusion and Expert Recommendations

This monograph has detailed the complex profile of loperamide, a medication characterized by a profound duality. Its clinical utility and safety are contingent upon a delicate pharmacokinetic balance that, when disrupted, can lead to severe toxicity.

8.1 Synthesis of Findings: A Drug of Profound Duality

Loperamide stands as a prime example of rational drug design. It is a potent peripheral opioid agonist whose clinical success hinges on elegant pharmacokinetic barriers—extensive first-pass metabolism via CYP3A4/CYP2C8 and active efflux via P-glycoprotein—that effectively prevent it from reaching the central nervous system and limit systemic exposure at therapeutic doses. This design makes it a highly effective and safe agent for its intended purpose of controlling diarrhea.

However, these critical safety mechanisms are both saturable and inhibitable. This vulnerability creates the drug's essential duality: at therapeutic doses, it is a safe, gut-specific medication; at supratherapeutic doses, or in the presence of potent metabolic inhibitors, it transforms into a systemic drug with dangerous central opioid effects and life-threatening cardiotoxicity. The modern clinical challenge of loperamide is therefore defined by its abuse potential, which is fueled by the ongoing opioid epidemic and its accessibility as an OTC product. This has led to the emergence of a well-characterized syndrome of severe cardiotoxicity, driven by off-target blockade of cardiac hERG and sodium channels.

8.2 Recommendations for Clinical Practice and Public Health

Based on this comprehensive analysis, the following recommendations are put forth:

For Clinicians and Pharmacists:

• A high index of suspicion for loperamide toxicity should be maintained in any patient presenting with unexplained syncope, significant QRS or QTc interval prolongation, or ventricular arrhythmias, particularly if there is a history of substance use disorder, high-dose loperamide ingestion, or polypharmacy. Loperamide should be considered a potential cause in the differential diagnosis of such cardiac events.
• Before recommending or dispensing loperamide, even as an OTC product, a thorough review of the patient's medication profile for interacting drugs is imperative. Specific attention should be paid to inhibitors of CYP3A4, CYP2C8, and P-glycoprotein, as well as any concomitant medications known to prolong the QT interval.
• Patient counseling must emphasize strict adherence to the dosing guidelines on the product label. Patients should be explicitly warned about the severe cardiac dangers of exceeding the maximum recommended dose and cautioned against the concurrent use of loperamide with alcohol, other CNS depressants, and tonic water.

For Public Health and Regulatory Bodies:

• Efforts to mitigate abuse should continue, including regulatory strategies that limit the sale of large-quantity packages and encourage the placement of loperamide-containing products behind the pharmacy counter to facilitate pharmacist counseling.
• Targeted public awareness campaigns are needed to educate both the general public and at-risk populations about the specific and potentially fatal cardiac risks associated with loperamide overdose. This messaging should clearly differentiate the safety profile at therapeutic doses from the extreme danger at high doses.

8.3 Future Research Directions

Further investigation is warranted to enhance the safe use of loperamide and explore its full therapeutic potential.

• Safer Alternatives: Research should be directed toward the development of novel, peripherally-acting opioid agonists or alternative antidiarrheal agents that lack off-target cardiac ion channel activity, which would provide a safer therapeutic option for all patient populations.
• Chronic Use Studies: Prospective, long-term studies are needed to better characterize the safety profile of chronic, low-dose loperamide use, particularly in patients with inflammatory bowel disease.
• Toxicology and Pharmacogenomics: Further research is needed to better define the precise dose-response relationship for loperamide-induced cardiotoxicity. Pharmacogenomic studies could help identify genetic variants in cardiac ion channels (e.g., KCNH2, SCN5A) or metabolizing enzymes that may predispose certain individuals to toxicity.
• Oncological Potential: The preliminary finding that loperamide may have activity against glioblastoma cells is a novel and exciting avenue of research that warrants significant further exploration to determine its potential as an anticancer agent.

Works cited

1. Loperamide | C29H33ClN2O2 | CID 3955 - PubChem, accessed August 7, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Loperamide
2. Loperamide - Wikipedia, accessed August 7, 2025, https://en.wikipedia.org/wiki/Loperamide
3. CAS 53179-11-6: Loperamide - CymitQuimica, accessed August 7, 2025, https://cymitquimica.com/cas/53179-11-6
4. Loperamide | C29H33ClN2O2 - ChemSpider, accessed August 7, 2025, https://www.chemspider.com/Chemical-Structure.3818.html
5. Compound: LOPERAMIDE HYDROCHLORIDE (CHEMBL1707) - ChEMBL - EMBL-EBI, accessed August 7, 2025, https://www.ebi.ac.uk/chembl/explore/compound/CHEMBL1707
6. Loperamide: MedlinePlus Drug Information, accessed August 7, 2025, https://medlineplus.gov/druginfo/meds/a682280.html
7. Showing BioInteractions for Loperamide (DB00836) | DrugBank Online, accessed August 7, 2025, https://go.drugbank.com/drugs/DB00836/biointeractions
8. What is the mechanism of action of Loperamide (Loperamide)? - Dr.Oracle, accessed August 7, 2025, https://www.droracle.ai/articles/116872/mechanism-of-action-of-loperamide
9. Loperamide cardiotoxicity: “A Brief Review” - PMC - PubMed Central, accessed August 7, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC6931594/
10. Loperamide | 53179-11-6 | FL65067 - Biosynth, accessed August 7, 2025, https://www.biosynth.com/p/FL65067/53179-11-6-loperamide
11. Loperamide - StatPearls - NCBI Bookshelf, accessed August 7, 2025, https://www.ncbi.nlm.nih.gov/books/NBK557885/
12. Loperamide: From antidiarrheal to analgesic, accessed August 7, 2025, https://wmpllc.org/ojs/index.php/jom/article/download/574/544/1122
13. Loperamide | 53179-11-6 - ChemicalBook, accessed August 7, 2025, https://www.chemicalbook.com/ChemicalProductProperty_EN_CB7402928.htm
14. Loperamide - Wikiwand, accessed August 7, 2025, https://www.wikiwand.com/en/articles/Loperamide
15. Anti-diarrheal drug loperamide, a.k.a. Imodium, provides a novel — and deadly — way to get high - Cornerstone of Recovery, accessed August 7, 2025, https://cornerstoneofrecovery.com/anti-diarrheal-drug-loperamide-a-k-a-imodium-provides-a-novel-and-deadly-way-to-get-high/
16. IMODIUM® Heritage - Learn about the history of IMODIUM®, accessed August 7, 2025, https://www.imodium.co.uk/imodium-heritage
17. Loperamide | Consumer Healthcare Products Association, accessed August 7, 2025, https://www.chpa.org/public-policy-regulatory/state-local-government-affairs/critical-ingredients-chemicals/loperamide
18. Continued . . . Imodium® (loperamide) – New Boxed Warning • On November 3, 2016, the FDA approved the addition of a Boxed W, accessed August 7, 2025, https://professionals.optumrx.com/content/dam/optum3/professional-optumrx/news/rxnews/drug-safety/drugsafety_imodium_2016-1111.pdf
19. Label: LOPERAMIDE HYDROCHLORIDE capsule - DailyMed, accessed August 7, 2025, https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=3fcb106c-f72e-17d9-e054-00144ff8d46c
20. Loperamide: Uses, Interactions, Mechanism of Action | DrugBank ..., accessed August 7, 2025, https://go.drugbank.com/drugs/DB00836
21. go.drugbank.com, accessed August 7, 2025, https://go.drugbank.com/drugs/DB00836#:~:text=Loperamide%20inhibits%20the%20release%20of,and%20increasing%20intestinal%20transit%20time.&text=Loperamide%20stimulates%20the%20intestinal%20absorption%20of%20water%20and%20electrolytes%20by%20inhibiting%20calmodulin.
22. IMODIUM Label - accessdata.fda.gov, accessed August 7, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/017690s005lbl.pdf
23. Loperamide and P‐glycoprotein inhibition: assessment of the clinical relevance | Request PDF - ResearchGate, accessed August 7, 2025, https://www.researchgate.net/publication/229692628_Loperamide_and_P-glycoprotein_inhibition_assessment_of_the_clinical_relevance
24. P-Glycoprotein Function at the Blood–Brain Barrier Imaged Using 11C-N-Desmethyl-Loperamide in Monkeys | Journal of Nuclear Medicine, accessed August 7, 2025, https://jnm.snmjournals.org/content/50/1/108
25. Full article: Loperamide-induced severe cardiotoxicity: a toxicokinetic and toxicodynamic analysis derived from a case series and the published literature, accessed August 7, 2025, https://www.tandfonline.com/doi/full/10.1080/15563650.2025.2459763?src=exp-la
26. Coadministration of P-Glycoprotein Modulators on Loperamide Pharmacokinetics and Brain Distribution - ResearchGate, accessed August 7, 2025, https://www.researchgate.net/publication/259626995_Coadministration_of_P-Glycoprotein_Modulators_on_Loperamide_Pharmacokinetics_and_Brain_Distribution
27. IMODIUM® (loperamide hydrochloride) - accessdata.fda.gov, accessed August 7, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/017694s050lbl.pdf
28. Loperamide (oral route) - Side effects & dosage - Mayo Clinic, accessed August 7, 2025, https://www.mayoclinic.org/drugs-supplements/loperamide-oral-route/description/drg-20064573
29. Loperamide: uses, dosing, warnings, adverse events, interactions - MedCentral, accessed August 7, 2025, https://www.medcentral.com/drugs/monograph/4789-382280/loperamide-oral
30. What are the best off-label medications for treating diarrhea?, accessed August 7, 2025, https://www.droracle.ai/articles/84989/best-off-label-medications-for-diarrhea-
31. Imodium, K-Pek II (loperamide) dosing, indications, interactions ..., accessed August 7, 2025, https://reference.medscape.com/drug/imodium-k-pek-ii-loperamide-342041
32. Loperamide: Uses, Dosage, Side Effects, Warnings - Drugs.com, accessed August 7, 2025, https://www.drugs.com/loperamide.html
33. Imodium Dosage Guide - Drugs.com, accessed August 7, 2025, https://www.drugs.com/dosage/imodium.html
34. Who can and cannot take loperamide - NHS, accessed August 7, 2025, https://www.nhs.uk/medicines/loperamide/who-can-and-cannot-take-loperamide/
35. Notes from the Field: Cardiac Dysrhythmias After Loperamide Abuse — New York, 2008–2016 | MMWR - CDC, accessed August 7, 2025, https://www.cdc.gov/mmwr/volumes/65/wr/mm6545a7.htm
36. FDA Drug Safety Communication: FDA warns about serious heart problems with high doses of the antidiarrheal medicine loperamide (Imodium), including from abuse and misuse, accessed August 7, 2025, https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-warns-about-serious-heart-problems-high-doses-antidiarrheal
37. FDA Warning RE Loperamide - American College of Clinical Pharmacology, accessed August 7, 2025, https://accp1.org/Members/ACCP1/5Publications_and_News/FDA_Warning_RE_Loperamide.aspx
38. Loperamide-induced cardiotoxicity: a case overlooked? - BMJ Case Reports, accessed August 7, 2025, https://casereports.bmj.com/content/14/7/e243325
39. pmc.ncbi.nlm.nih.gov, accessed August 7, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC6931594/#:~:text=Recently%2C%20numerous%20reports%20of%20dramatic,%2C%20%26%20Stehlik%2C%202015%3B%20Vaughn
40. The Potential Mechanisms behind Loperamide-Induced Cardiac Arrhythmias Associated with Human Abuse and Extreme Overdose - MDPI, accessed August 7, 2025, https://www.mdpi.com/2218-273X/13/9/1355
41. Imodium: Uses, Side Effects & Interactions - Cleveland Clinic, accessed August 7, 2025, https://my.clevelandclinic.org/health/drugs/20481-loperamide-solution
42. Side effects of loperamide - NHS, accessed August 7, 2025, https://www.nhs.uk/medicines/loperamide/side-effects-of-loperamide/
43. Taking loperamide with other medicines and herbal supplements - NHS, accessed August 7, 2025, https://www.nhs.uk/medicines/loperamide/taking-loperamide-with-other-medicines-and-herbal-supplements/