Loperamide hydrochloride

What it is

Loperamide hydrochloride is a synthetic piperidine-derivative opioid that acts almost entirely inside the gut wall. It is sold both as an over-the-counter anti-diarrhoeal and, in the United States, as a prescription capsule with a wider set of indications. The prescription label describes it as binding to the opiate receptor in the gut wall, slowing propulsive peristalsis and increasing intestinal transit time. The same label records that loperamide is about 95% plasma-protein bound and is a P-glycoprotein substrate, which is why very little normally reaches the brain.

What the research says

The evidence is strongest for shortening an episode of acute diarrhoea and for reducing stool frequency; a systematic review in children found diarrhoea resolved faster but serious adverse events occurred only in children given loperamide, all of them under 3 years old. In travellers' diarrhoea, pooled trials show adding loperamide to an antibiotic roughly doubles the odds of early clinical cure. For irritable bowel syndrome with diarrhoea the evidence is thin: the American Gastroenterological Association makes only a conditional recommendation at very low certainty. The dominant harm signal is cardiac: at doses far above those on the label, taken to blunt opioid withdrawal or to get high, loperamide has caused QT and QRS prolongation, Torsades de Pointes, Brugada patterns, cardiac arrest and death, and this is the subject of the prescription product's boxed warning.

Evidence grade: Well established.

How it works

Drug class: Peripherally acting mu-opioid receptor agonist used as an antimotility antidiarrhoeal; not a controlled substance

Loperamide attaches to opioid receptors in the wall of the bowel rather than in the brain. That slows the muscular waves that push contents along, so contents stay in the gut longer, more water is reabsorbed, stool volume falls and stool becomes firmer. It also raises the tone of the anal sphincter, which is why it reduces urgency. At normal doses almost none of the drug reaches the brain, because it is pumped back out of brain capillaries by P-glycoprotein. (Source 1)

Boxed warning

WARNING: TORSADES DE POINTES AND SUDDEN DEATH

(Source 2)

What it is used for

• Pooled placebo-controlled trials in children show faster resolution, and the prescription label carries this indication from 2 years of age. In adults the over-the-counter product is sold for the same purpose. Evidence: established. (Source 3)
• The prescription label carries both indications in adults. The label's own safety tables are drawn from 20 placebo-controlled studies in chronic diarrhoea, but no outcome trial giving absolute benefit in these two settings is quoted on the label or found in the searches recorded in notes. Evidence: limited. (Source 4)
• A systematic review and meta-analysis of nine studies found that adding loperamide to an antibiotic raised the odds of clinical cure at 24 hours to 2.6 (95% CI 1.8-3.6) compared with the antibiotic alone. The over-the-counter carton is sold for travellers' diarrhoea. Evidence: established. (Source 5)
• Not a United States labelled indication. The American Gastroenterological Association made a conditional recommendation for loperamide in IBS-D at very low certainty of evidence. The one randomised placebo-controlled trial recorded here reported better stool consistency and frequency but more night-time abdominal pain on loperamide. Evidence: limited. (Source 6)
• This is misuse, not a supported use. The prescription label records that loperamide is primarily being misused for relief from opioid withdrawal, and chronic ingestion of 70 mg to 1600 mg daily has produced life-threatening arrhythmias and death. A joint toxicology position statement exists because the practice is increasing. Evidence: not-supported. (Source 7)

Interactions

• Itraconazole and other CYP3A4 inhibitors (pharmacokinetic study): Blocking CYP3A4 raises loperamide levels several-fold, which raises the chance of cardiac and central nervous system effects at an ordinary dose. (Source 8)
• Gemfibrozil and other CYP2C8 inhibitors (pharmacokinetic study): Gemfibrozil raised loperamide exposure about twofold in a single-dose study. (Source 8)
• Itraconazole plus gemfibrozil together, and P-glycoprotein inhibitors such as quinidine and ritonavir (pharmacokinetic study): Two inhibitors together raised loperamide exposure more than twelvefold; P-glycoprotein inhibitors raise levels two- to threefold and can let more of the drug reach the brain. (Source 9)
• Quercetin (a plant flavonoid sold as a supplement) and other CYP2C8 inhibitors (theoretical): In laboratory work on human enzymes, quercetin cut the main route by which loperamide is broken down by 40%. This is a test-tube finding; no human study of quercetin with loperamide is recorded on the label. (Source 10)
• Herbal products and medicines that prolong the QT interval (label): The label tells prescribers to avoid loperamide together with any drug or herbal product known to lengthen the QT interval, and names the drug classes. (Source 11)
• Cimetidine, an over-the-counter acid blocker (case reports): One label case describes a man taking 100 to 250 mg of loperamide with 400 mg of cimetidine daily who developed Torsades de Pointes and a QTc over 700 ms. Cimetidine inhibits several metabolising enzymes, so the combination is plausible, but this is a single case. (Source 12)
• Any prescription medicine, when the product is bought over the counter (label): The Drug Facts panel tells the buyer to ask a doctor or pharmacist first if they take a prescription medicine. (Source 13)
• Alcohol (label): No interaction study with alcohol is reported on the prescription or over-the-counter labels read here, and none was found in the literature searched. What the label does say is that tiredness, drowsiness or dizziness may occur, which is the shared effect to be aware of. (Source 13)
• Any prescription medicine, unspecified (label): The over-the-counter panel does not name the drugs. It tells the buyer to ask a doctor or pharmacist first if they are taking any prescription medicine, because loperamide may interact with some of them. The named interactions with figures are on the prescription label, not here. (Source 14)

Stopping it

• There is no taper on the label for ordinary use. The over-the-counter panel says the opposite: stop and ask a doctor if symptoms get worse or diarrhoea lasts more than two days. (Source 13)
• The label also instructs prompt discontinuation if constipation, abdominal distention or ileus develop, which is a stopping rule rather than a tapering one. (Source 15)
• Physical dependence has been shown in animals given loperamide by injection, and in morphine-dependent monkeys high doses prevented signs of morphine withdrawal. No human withdrawal syndrome from ordinary oral use is described on the label. (Source 16)
• Where cardiac toxicity from high-dose use is suspected, the label's instruction is to stop the drug at once and start treatment to manage and prevent arrhythmias, rather than to reduce the dose. It records that magnesium sulfate was often ineffective, and that loperamide blood levels are not a useful guide. (Source 17)
• This carton's own stop rule, which is a stopping instruction rather than a taper: stop and ask a doctor if symptoms get worse, if diarrhoea lasts more than two days, or if abdominal swelling or bulging appears. (Source 18)

What goes wrong

In the same meta-analysis, serious adverse events occurred only in children given loperamide, and only in those under 3 years old. (Source 3)

• Meta-analysis, Moderate certainty.
• Size: 927 children allocated to loperamide, 764 to placebo.
• Who: Children younger than 12 years with acute diarrhoea.
• How long: Within the included trials.
• Result: Serious adverse events (ileus, lethargy or death) in 8/927 on loperamide (0.9%, 95% CI 0.4% to 1.7%) versus 0/764 on placebo (0%, 95% CI 0% to 0.5%); all among children younger than 3 years.
• Funding: not stated.

Serious adverse events, defined as ileus, lethargy, or death, were reported in eight out of 927 children allocated to loperamide (0.9%, 95% CI: 0.4% to 1.7%). Serious adverse events were not reported in any of the 764 children allocated to placebo (0%, 95% CI: 0% to 0.5%). Among the children allocated to loperamide, serious adverse events were reported only among children younger than 3 y.

The authors concluded that in young, malnourished, dehydrated or systemically ill children the harms outweigh the benefits even at low doses. (Source 19)

• Meta-analysis, Moderate certainty.
• Size: Same review.
• Who: Children under 3 years, malnourished, dehydrated, systemically ill, or with bloody diarrhoea.
• How long: Not applicable.
• Result: Authors' conclusion, not a numeric estimate.
• Funding: not stated.

Limit of this finding: The source writes the dose threshold as '<or=0.25 mg/kg/d', its own way of printing 'less than or equal to'; it is quoted as published. This is the review authors' judgement weighing harms against benefits in particular groups of children, not a measured effect size.

In children who are younger than 3 y, malnourished, moderately or severely dehydrated, systemically ill, or have bloody diarrhea, adverse events outweigh benefits even at doses <or=0.25 mg/kg/d. In children who are older than 3 y with no/minimal dehydration, loperamide may be a useful adjunct to oral rehydration and early refeeding.

In the label's own placebo-controlled trials, constipation was the adverse event clearly more common on loperamide than placebo, and far more so in chronic than acute diarrhoea. (Source 20)

• Meta-analysis, Low certainty.
• Size: 4 placebo-controlled acute-diarrhoea studies (231 loperamide, 236 placebo); 20 placebo-controlled chronic-diarrhoea studies (285 loperamide, 277 placebo)
• Who: Patients in the manufacturer's placebo-controlled programme.
• How long: Not stated on the label.
• Result: Constipation 2.6% versus 0.8% in acute diarrhoea; 5.3% versus 0.0% in chronic diarrhoea; dizziness 1.4% versus 0.7% in chronic diarrhoea.
• Funding: industry-funded (sponsor's clinical programme reported in the label)

Limit of this finding: The prescription label's adverse-reaction 'tables' are not tables in the source file at all: the label contains 276 paragraph elements, 91 line breaks and no table markup, so the figures arrive as a flat run of lines. The order of the lines is preserved here exactly as the label prints it, but which column a given percentage belongs to is not encoded in the document and can only be inferred from the order of the headings. Read the numbers as the label's own, and do not treat the loperamide versus placebo column assignment as something the source guarantees.

Chronic Diarrhea Loperamide Hydrochloride Placebo No. of treated patients 285 277 Gastrointestinal AE% Constipation 5.3% 0.0% Central and peripheral nervous system AE% Dizziness 1.4% 0.7%

The prescription product carries a boxed warning for Torsades de Pointes and sudden death at higher than recommended doses. (Source 2)

• Official position, Certainty not rated.
• Size: Not applicable.
• Who: Adults and children 2 years and older taking prescription loperamide.
• How long: Not applicable.
• Result: Regulator-approved warning text; no rate given.
• Funding: not stated.

Limit of this finding: Quotations from this label reproduce its own printing errors, including 'CONTRANIDICATIONS', 'Clostridium difficle', 'others drugs', 'muopioid', 'OVERDOSAGEfor' and 'greater than 30kg'. They are the document's, not transcription slips, and they have been left as printed.

Cases of Torsades de Pointes, cardiac arrest, and death have been reported with the use of a higher than recommended dosages of loperamide hydrochloride (see WARNINGS and OVERDOSAGE). Loperamide hydrochloride is contraindicated in pediatric patients less than 2 years of age (see CONTRANIDICATIONS). Avoid loperamide hydrochloride dosages higher than recommended in adults and pediatric patients 2 years of age and older due to the risk of serious cardiac adverse reactions (see DOSAGE AND ADMINISTRATION).

Syncope and ventricular tachycardia have also been reported at recommended doses, and cardiac arrest and respiratory depression in children under 2. (Source 21)

• Case series, Very low certainty.
• Size: Postmarketing reports; counts not given.
• Who: Adults at recommended doses, some with other risk factors; children under 2 years.
• How long: Not applicable.
• Result: No rates are given; the label reports case occurrence only.
• Funding: industry-funded (sponsor's label)

Cases of syncope and ventricular tachycardia have been reported in adult patients receiving the recommended dosage of loperamide hydrochloride. 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.

Overdose case descriptions on the label document chronic ingestion of 70 mg to 1600 mg daily producing QT and QRS prolongation, Torsades de Pointes, Brugada syndrome, cardiac arrest and death. (Source 22)

• Case series, Very low certainty.
• Size: Representative cases cited on the label.
• Who: People abusing or misusing loperamide.
• How long: Months to years of misuse in the cited cases.
• Result: Doses 70 mg to 1600 mg daily, 4 to 100 times the recommended dose; one 25-year-old had QTc 527 ms, QRS 170 ms, cardiac arrest and death with a loperamide blood concentration of 32 ng/ml.
• Funding: industry-funded (sponsor's label)

Cases of overdosage with loperamide hydrochloride (chronic ingestion of doses ranging from 70 mg to 1600 mg daily; 4 to 100 times the recommended dose) have resulted in life-threatening cardiac adverse reactions, including QT/QTc and QRS interval prolongation, Torsades de Pointes, Brugada syndrome and other ventricular arrhythmias, syncope, cardiac arrest, and death.

Further label cases describe misuse for chronic diarrhoea and for euphoria, with prolonged QT, sinus arrest, polymorphic ventricular tachycardia and Torsades de Pointes. (Source 12)

• Case series, Very low certainty.
• Size: Two further representative cases.
• Who: A 54-year-old self-treating chronic diarrhoea; a 26-year-old with prior opioid abuse.
• How long: Over 2 years, and several months, respectively.
• Result: Up to 144 mg per day with syncope, prolonged QT of 500 ms, sinus arrest with junctional escape rhythm and polymorphic ventricular tachycardia requiring cardioversion and an implantable cardioverter-defibrillator; in the second case QTc greater than 700 ms after 100 to 250 mg loperamide with 400 mg cimetidine daily.
• Funding: industry-funded (sponsor's label)

54 year old misused loperamide hydrochloride (up to 144 mg per day) as a self-treatment for chronic diarrhea for over 2 years. Signs of cardiac toxicity included syncope, prolonged QT of 500 ms sinus arrest with junctional escape rhythm, and polymorphic ventricular tachycardia, which required cardioversion and implantable cardioverter-defibrillator (ICD) management.

A published case report documents Torsade de Pointes and a Type 1 Brugada pattern together in one patient after loperamide misuse. (Source 23)

• Case report, Very low certainty.
• Size: 1 patient.
• Who: A 22-year-old man.
• How long: Single presentation.
• Result: Cardiac arrest from polymorphic ventricular tachycardia consistent with Torsade de Pointes plus a Type 1 Brugada pattern; the authors state no previous case report had shown both in the same patient.
• Funding: not stated.

Limit of this finding: This is a single patient. A case report can show that something is possible; it cannot show how often it happens. Nothing here says how common Torsade de Pointes or a Brugada pattern is among people who take loperamide, and no frequency should be read off it. The poison-centre series is the source for how often serious outcomes were reported.

This case report presents a 22-year-old man who presented in cardiac arrest from polymorphic ventricular tachycardia consistent with TdP and a Type 1 Brugada pattern after intentional loperamide abuse. We discuss this patient's management and the proposed pathophysiology of these two cardiotoxicities, of which, to our knowledge, no previously published case report has displayed both in the same patient after a supratherapeutic loperamide ingestion.

Two deaths with markedly raised loperamide concentrations were reported in an emergency-medicine case series of loperamide abuse. (Source 24)

• Case report, Very low certainty.
• Size: 2 fatalities.
• Who: People abusing oral loperamide as an opioid substitute.
• How long: Not stated.
• Result: Two fatalities in the setting of significantly elevated loperamide concentrations; ventricular dysrhythmias and QRS and QTc prolongation described after oral abuse.
• Funding: not stated.

Ventricular dysrhythmias and prolongation of the QRS duration and QTc interval have been reported after oral loperamide abuse. We describe 2 fatalities in the setting of significantly elevated loperamide concentrations.

United States poison-centre reports of intentional loperamide exposure rose 91% from 2010 to 2015, with 15 deaths. (Source 25)

• Survey study, Low certainty.
• Size: Loperamide exposures reported to the National Poison Data System, 1 January 2010 to 31 December 2015.
• Who: People reported to US poison centres for intentional misuse, abuse or suspected suicide.
• How long: 6 years.
• Result: 91% increase in reported exposures; rise of about 38 cases per year (95% CI 32.5 to 42.9; P<0.0001); 15 deaths, 8 involving single-agent loperamide abuse.
• Funding: not stated.

There was a 91% increase in reported exposures from 2010 to 2015, of which half were single-agent loperamide use only. Loperamide exposures reported to the National Poison Data System increased at approximately 38 cases per year (95% confidence interval [CI] 32.5 to 42.9; P<0.0001). Fifteen deaths were reported during this time frame, of which 8 involved single-agent loperamide abuse.

Among loperamide cases reported to United States poison centres from 2010 to 2022, 13.4% had a serious medical outcome and 59 deaths were recorded. (Source 26)

• Survey study, Low certainty.
• Size: 12,987 cases reported to US poison centres from 2010 to 2022.
• Who: People reported to US poison centres where loperamide was the most likely responsible substance.
• How long: 13 years.
• Result: 13.4% serious medical outcome, 59 deaths (0.5%); 8.1% critical-care admission; of serious outcomes, 38.0% abuse, 15.7% intentional misuse, 27.5% suspected suicide; rate of serious outcomes per 100,000 population rose from 0.03 in 2010 to 0.11 in 2017 (p<0.0001) then fell to 0.04 in 2022 (p<0.0001)
• Funding: not stated.

Limit of this finding: Two cautions about this source. First, its own numbers do not reconcile: it reports 59 deaths and then attributes fatalities as 60.0% (n=33), 20.0% (n=11) and 5.5% (n=3). Those sub-counts add up to 47, not 59, and the percentages imply a denominator of 55. The quotation is faithful to what was published, character for character; no figure should be worked out from those percentages. Second, these are reports made voluntarily to poison centres, not measured rates in the population, and the study is an uncontrolled look at how reports changed over time, so it cannot show how often loperamide harms people nor that any particular action reduced harm.

There were 12,987 cases reported to US poison centers from 2010 to 2022, for which, loperamide was the most likely substance responsible for observed clinical effects. Although 46.1% of these cases were associated with minor or no effect, 13.4% resulted in a serious medical outcome, including 59 deaths (0.5%). Eight percent (8.1%) of cases were admitted to a critical care unit and 5.0% were admitted to a non-critical care unit.

Loperamide is not a controlled substance, but a human abuse-potential study found a minority of experienced opiate users identified it as an opioid, and the label records misuse mainly for opioid withdrawal. (Source 7)

• Randomized trial, Very low certainty.
• Size: 9 subjects who had been active opiate users, double-blind cross-over.
• Who: Former active opiate users.
• How long: Single doses.
• Result: Single loperamide doses up to 60 mg were felt by 44% of subjects and identified as "dope" by 11%; codeine 120 mg was felt by 56% and identified as "dope" by 44%.
• Funding: industry-funded (sponsor's label)

A human abuse potential study of loperamide hydrochloride at single doses up to 60 mg (3.75 times the recommended maximum adult dosage of 16 mg per day) was compared, in a double-blind cross-over design using nine subjects who had been active opiate users, to a threshold dose of codeine sulfate at 120 mg (96 mg base) or placebo. This resulted in one subject (11%) feeling a drug on placebo and identifying it as "dope" (heroin) and liking it slightly. Codeine was felt by 56% of subjects and identified as "dope" by 44%. Loperamide was felt by 44% of subjects and identified as "dope" by 11% and possibly dope mixed with some other kind of drug by another 22%. Loperamide abuse and misuse have been reported, especially at doses of 60 mg or greater. Loperamide can have greater CNS opioid effects at higher doses or with co-administration of drugs that increase systemic exposure and/or increase CNS penetration of loperamide (through inhibition of the CYP450 enzyme system or inhibition of P-glycoprotein). Loperamide is primarily being misused for relief from opioid withdrawal, and abused by a few users who obtain some (reportedly mild-moderate) level of euphoria.

Loperamide is contraindicated in acute dysentery and in diarrhoea caused by invasive bacteria, and in children under 2 years. (Source 27)

• Official position, Certainty not rated.
• Size: Not applicable.
• Who: People with bloody diarrhoea and high fever, invasive bacterial enterocolitis, pseudomembranous colitis, acute ulcerative colitis, or age under 2 years.
• How long: Not applicable.
• Result: Absolute contraindications on the prescription label; no rate given.
• Funding: industry-funded (sponsor's label)

Limit of this finding: Quotations from this label reproduce its own printing errors, including 'CONTRANIDICATIONS', 'Clostridium difficle', 'others drugs', 'muopioid', 'OVERDOSAGEfor' and 'greater than 30kg'. They are the document's, not transcription slips, and they have been left as printed.

patients with acute dysentery, which is characterized by blood in stools and high fever. patients with acute ulcerative colitis. patients with bacterial enterocolitis caused by invasive organisms including Salmonella, Shigella, and Campylobacter. patients with pseudomembranous colitis (e.g., Clostridium difficle) associated with the use of broad-spectrum antibiotics.

The label warns that slowing the bowel can cause ileus, megacolon and toxic megacolon, and that the drug does not replace fluid and electrolyte treatment. (Source 15)

• Official position, Certainty not rated.
• Size: Not applicable.
• Who: Anyone taking loperamide for diarrhoea.
• How long: Not applicable.
• Result: No rates given; the label instructs prompt discontinuation if constipation, abdominal distention or ileus develop.
• Funding: industry-funded (sponsor's label)

In general, loperamide hydrochloride 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 hydrochloride must be discontinued promptly when constipation, abdominal distention or ileus develop.

A joint position statement of two United States toxicology bodies exists specifically because high-dose loperamide use in place of evidence-based opioid treatment is increasing. (Source 28)

• Official position, Certainty not rated.
• Size: Not applicable.
• Who: Clinicians across emergency, critical care, primary care, gastroenterology, addiction medicine and pharmacy.
• How long: Not applicable.
• Result: Position statement; no effect estimate.
• Funding: not stated (collaborative effort of AACT and AAPCC, endorsed by ACMT)

This position statement is a collaborative effort by the American Academy of Clinical Toxicology (AACT) and the American Association of Poison Control Centers (AAPCC) and has been endorsed by the American College of Medical Toxicology (ACMT). The position statement describes loperamide misuse, proposed mechanisms of toxicity, adverse clinical effects, and recommendations for the acute monitoring and management of patients with loperamide toxicity.

The over-the-counter Drug Facts panel carries a heart alert and tells people to stop if diarrhoea lasts more than two days or abdominal swelling develops, but no boxed warning. (Source 13)

• Official position, Certainty not rated.
• Size: Not applicable.
• Who: Adults and children 12 years and over buying the product without a prescription.
• How long: Not applicable.
• Result: Label text only; no rates.
• Funding: industry-funded (sponsor's label)

Heart alert Taking more than directed can cause serious heart problems or death Do not use if you have bloody or black stool if you have difficulty swallowing Ask a doctor before use if you have fever mucus in the stool a history of liver disease a history of abnormal heart rhythm Ask a doctor or pharmacist before use if you are taking a prescription drug. Loperamide may interact with certain prescription drugs. When using this product tiredness, drowsiness or dizziness may occur. Be careful when driving or operating machinery. Stop use and ask a doctor if symptoms get worse diarrhea lasts for more than 2 days you get abdominal swelling or bulging. These may be signs of a serious condition.

The over-the-counter dosing chart forbids use under 2 years and caps adults at four caplets in 24 hours. (Source 29)

• Official position, Certainty not rated.
• Size: Not applicable.
• Who: Over-the-counter purchasers by age and weight band.
• How long: Per 24 hours.
• Result: Adults and children 12 and over: no more than 4 caplets in 24 hours; children 2-5 years: ask a doctor; children under 2 years: do not use.
• Funding: industry-funded (sponsor's label)

Limit of this finding: The chart is quoted exactly as the panel prints it, including the half-caplet sign and the panel's own inconsistent way of writing the weight bands: two of them use a hyphen ('60-95 lbs', '48-59 lbs') and two spell the range out ('34 to 47 lbs', 'up to 33 lbs'). The same Drug Facts panel lists Simethicone 125 mg as a second active ingredient alongside loperamide, so this chart is for a combination product, not for loperamide alone. Nothing here is a dose for the reader.

adults and children 12 years and over 2 caplets after the first loose stool; 1 caplet after each subsequent loose stool; but no more than 4 caplets in 24 hours children 9-11 years (60-95 lbs) 1 caplet after the first loose stool; ½ caplet after each subsequent loose stool; but no more than 3 caplets in 24 hours children 6-8 years (48-59 lbs) 1 caplet after the first loose stool; ½ caplet after each subsequent loose stool; but no more than 2 caplets in 24 hours children 2-5 years (34 to 47 lbs) ask a doctor children under 2 years (up to 33 lbs) do not use

The prescription label's dose section states the under-two contraindication and the do-not-exceed warning immediately above the dose schedules, and the paediatric schedules are weight-banded from 13 kg up. (Source 30)

• Official position, Certainty not rated.
• Size: Not applicable.
• Who: Adults and children 2 years and older; children under 2 years excluded altogether.
• How long: First treatment day for the paediatric schedule.
• Result: Contraindicated under 2 years because of respiratory depression and serious cardiac adverse reactions; adults and children 13 and over initial 4 mg then 2 mg per unformed stool to a maximum of 16 mg a day; first-day paediatric totals 3 mg (two to five years, 13 to 20 kg), 4 mg (six to eight years, 20 to 30 kg) and 6 mg (eight to twelve years, greater than 30 kg)
• Funding: industry-funded (sponsor's label)

Limit of this finding: The label prints 'greater than 30kg' without a space and '2 mg twice daily. (4 mg total daily dosage)' with a stray full stop; both are reproduced as printed. This is the regulator-approved schedule, recorded as a position, not a dose for the reader.

Loperamide hydrochloride capsules are contraindicated in pediatric patients less than 2 years of age due to the risks of respiratory depression and serious cardiac adverse reactions (see CONTRAINDICATIONS).

After the first day the label caps the paediatric daily total at the first day's amount, and sets the adult chronic-diarrhoea maximum at 16 mg a day. (Source 31)

• Official position, Certainty not rated.
• Size: Not applicable.
• Who: Children 2 to 12 years after the first treatment day; adults with chronic diarrhoea.
• How long: Beyond the first treatment day; at least 10 days before judging failure in chronic diarrhoea.
• Result: Subsequent paediatric doses 1 mg per 10 kg body weight only after a loose stool, with the total daily dosage not to exceed the first day's; adult chronic-diarrhoea maintenance 4 to 8 mg a day, maximum 16 mg a day.
• Funding: industry-funded (sponsor's label)

The total daily dosage should not exceed recommended dosages for the first day. Chronic Diarrhea Adults

The label's postmarketing list, which the trial tables do not contain, records QT and QTc prolongation, Torsades de Pointes, other ventricular arrhythmias, cardiac arrest, syncope and death. (Source 32)

• Case series, Very low certainty.
• Size: Spontaneous postmarketing reports; no counts or denominators are given. The all-studies table above it covers 1913 acute, 1371 chronic and 3740 patients in total.
• Who: People taking loperamide, reported after marketing.
• How long: Not stated.
• Result: No rates are given for the cardiac events. In the all-studies table constipation was 1.6% in acute, 1.9% in chronic and 1.7% overall, and abdominal cramps 0.5%, 3.0% and 1.4%.
• Funding: industry-funded (sponsor's label)

Limit of this finding: Postmarketing reports have no denominator, so they cannot give a rate. The placebo-controlled tables higher up the same section show only constipation and dizziness and no cardiac signal at all, which is why this list matters: the cardiac events that the boxed warning is about appear only here and in the overdose section. The prescription label's adverse-reaction 'tables' are not tables in the source file at all: the label contains 276 paragraph elements, 91 line breaks and no table markup, so the figures arrive as a flat run of lines. The order of the lines is preserved here exactly as the label prints it, but which column a given percentage belongs to is not encoded in the document and can only be inferred from the order of the headings. Read the numbers as the label's own, and do not treat the loperamide versus placebo column assignment as something the source guarantees.

Cardiac disorders QT/QTc interval prolongation, Torsades de Pointes, other ventricular arrhythmias, cardiac arrest, syncope, and death (see WARNINGS, OVERDOSAGE).

The label instructs that people with AIDS taking loperamide for diarrhoea have it stopped at the earliest sign of abdominal distention, and records isolated reports of toxic megacolon in that group. (Source 15)

• Case series, Very low certainty.
• Size: Isolated reports; no counts given.
• Who: People with AIDS and infectious colitis from viral and bacterial pathogens.
• How long: Not stated.
• Result: No rate is given; the instruction is to stop therapy at the earliest signs of abdominal distention.
• Funding: industry-funded (sponsor's label)

Patients with AIDS treated with loperamide hydrochloride for diarrhea should have therapy stopped at the earliest signs of abdominal distention.

Where loperamide cardiac toxicity is suspected the label records that magnesium sulfate was often ineffective, names electrical cardioversion, overdrive pacing and isoproterenol, and says serum loperamide levels are not useful. (Source 17)

• Case series, Very low certainty.
• Size: Drawn from reported cases of overdosage; no counts given.
• Who: People with suspected loperamide-induced cardiac toxicity.
• How long: Not applicable.
• Result: Anti-arrhythmic medications such as magnesium sulfate were ineffective in many cases; electrical cardioversion, overdrive pacing and continuous isoproterenol infusion were reported to manage QTc prolongation; loperamide serum concentrations are not widely available or clinically useful.
• Funding: industry-funded (sponsor's label)

In many cases of loperamide overdosage, anti-arrhythmic medications (e.g., magnesium sulfate) were ineffective in resolving the arrhythmias and preventing further episodes of Torsades de Pointes.

The over-the-counter Drug Facts panel on this carton carries an allergy alert and a heart alert stating that taking more than directed can cause serious heart problems or death. (Source 33)

• Official position, Certainty not rated.
• Size: Not applicable; this is a regulated label panel, not a study.
• Who: Adults and children 12 years and over buying the product without a prescription.
• How long: Not applicable.
• Result: No rate is given; the panel states the hazard without a frequency.
• Funding: not stated.

Heart alert: Taking more than directed can cause serious heart problems or death

The same carton forbids use altogether in anyone with bloody or black stool and in children under 12 years of age. (Source 34)

• Official position, Certainty not rated.
• Size: Not applicable; this is a regulated label panel, not a study.
• Who: Adults and children 12 years and over buying the product without a prescription.
• How long: Not applicable.
• Result: An absolute prohibition, with no dose offered below 12 years.
• Funding: not stated.

Limit of this finding: Two over-the-counter loperamide products quoted in this entry draw the age line in different places: this carton says not for use under 12 years, while another brand's Drug Facts chart gives doses down to age 2 and tells the buyer to ask a doctor for 2 to 5 year olds. Both are current labels. Neither is a dose for the reader.

• if you have bloody or black stool • in children under 12 years of age

The panel tells buyers with fever, mucus in the stool, a history of liver disease or a history of abnormal heart rhythm to ask a doctor before using it. (Source 35)

• Official position, Certainty not rated.
• Size: Not applicable; this is a regulated label panel, not a study.
• Who: Adults and children 12 years and over buying the product without a prescription.
• How long: Not applicable.
• Result: Four named groups are directed to a doctor first; no risk figure is given.
• Funding: not stated.

• fever • mucus in the stool • a history of liver disease • a history of abnormal heart rhythm

The panel warns that tiredness, drowsiness or dizziness may occur and to be careful driving or operating machinery. (Source 36)

• Official position, Certainty not rated.
• Size: Not applicable; this is a regulated label panel, not a study.
• Who: Adults and children 12 years and over buying the product without a prescription.
• How long: Not applicable.
• Result: No incidence is given on the panel.
• Funding: not stated.

tiredness, drowsiness, or dizziness may occur. Be careful when driving or operating machinery.

The panel directs anyone pregnant or breast-feeding to ask a health professional before use, and offers no safety data of its own. (Source 37)

• Official position, Certainty not rated.
• Size: Not applicable; this is a regulated label panel, not a study.
• Who: Adults and children 12 years and over buying the product without a prescription.
• How long: Not applicable.
• Result: No pregnancy or lactation data appear on the panel.
• Funding: not stated.

If pregnant or breast-feeding, ask a health professional before use.

The panel tells buyers to keep the product out of reach of children and, in case of overdose, to get medical help or contact a Poison Control Center. (Source 38)

• Official position, Certainty not rated.
• Size: Not applicable; this is a regulated label panel, not a study.
• Who: Adults and children 12 years and over buying the product without a prescription.
• How long: Not applicable.
• Result: A named national telephone number, 1-800-222-1222, is printed on the panel.
• Funding: not stated.

Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away (1-800-222-1222).

The Directions panel caps adults and children 12 and over at four softgels, that is 8 mg, in 24 hours, which is half the prescription maximum of 16 mg a day, and it offers no dose below 12 years. (Source 39)

• Official position, Certainty not rated.
• Size: Not applicable; this is a regulated label panel, not a study.
• Who: Adults and children 12 years and over buying the product without a prescription.
• How long: Not applicable.
• Result: Two softgels after the first loose stool, one after each later one, no more than four in 24 hours.
• Funding: not stated.

• adults and children 12 years and over: 2 softgels after the first loose stool; 1 softgel after each subsequent loose stool; but no more than 4 softgels in 24 hours

What the evidence supports

The prescription label's approved uses are acute non-specific diarrhoea from 2 years of age, chronic diarrhoea with inflammatory bowel disease in adults, and reducing ileostomy output. (Source 4)

• Official position, Certainty not rated.
• Size: Not applicable.
• Who: Patients 2 years and older for acute diarrhoea; adults for the chronic indications.
• How long: Not applicable.
• Result: The regulator's position as of the SPL version effective 2026-08-25; a licence, not an effect estimate.
• Funding: industry-funded (sponsor's label)

Loperamide hydrochloride capsules are indicated for the control and symptomatic relief of acute nonspecific diarrhea in patients 2 years of age and older and of chronic diarrhea in adults associated with inflammatory bowel disease. Loperamide hydrochloride capsules are also indicated for reducing the volume of discharge from ileostomies.

In pooled randomised trials in children under 12, loperamide shortened acute diarrhoea and reduced stool counts compared with placebo. (Source 3)

• Meta-analysis, Moderate certainty.
• Size: randomised controlled trials of children younger than 12 years; 927 children allocated to loperamide and 764 to placebo contributed adverse-event data.
• Who: Children younger than 12 years with acute diarrhoea.
• How long: Outcomes at 24 hours and total diarrhoea duration.
• Result: Prevalence ratio for still having diarrhoea at 24 h 0.66 (95% CI 0.57 to 0.78); duration shorter by 0.8 d (95% CI 0.7 to 0.9 d); stool count at 24 h 0.84 (95% CI 0.77 to 0.92)
• Funding: not stated.

Compared with patients who received placebo, patients allocated to loperamide were less likely to continue to have diarrhea at 24 h (prevalence ratio 0.66, 95% confidence interval [CI]: 0.57 to 0.78), had a shorter duration of diarrhea by 0.8 d (95% CI: 0.7 to 0.9 d), and had a lower count of stools at 24 h (0.84, 95% CI: 0.77 to 0.92). Results were similar when random-effects summaries were estimated.

Adding loperamide to an antibiotic in travellers' diarrhoea roughly doubled the odds of clinical cure at 24 and 48 hours. (Source 5)

• Meta-analysis, Moderate certainty.
• Size: 9 studies, 12 adjunctive loperamide-antibiotic regimens; 6 paired comparisons pooled.
• Who: Adults with travellers' diarrhoea treated with antibiotics.
• How long: Clinical cure at 24 h, 48 h and 72 h.
• Result: Summary odds ratio for clinical cure 2.6 (95% CI 1.8-3.6) at 24 h and 2.2 (95% CI 1.5-3.1) at 48 h, with no evidence of heterogeneity.
• Funding: not stated.

Among 6 paired studies comparing antibiotics alone versus antibiotics in combination with loperamide, the odds of clinical cure at 24 h and 48 h favored combination therapy, with summary odds ratios of 2.6 (95% confidence interval, 1.8-3.6; P = .20 by chi(2) heterogeneity statistic) and 2.2 (95% confidence interval, 1.5-3.1; P = .20, by chi(2) heterogeneity statistic), respectively, with no evidence of heterogeneity.

Reported loperamide case rates rose to 2017 and then fell to 2022; the authors say the regulatory warnings, labelling and packaging changes may have contributed, which the study design cannot confirm. (Source 26)

• Survey study, Low certainty.
• Size: Same 12,987 cases.
• Who: US poison-centre reports.
• How long: 2010 to 2022.
• Result: Rate of loperamide cases per 100,000 US population reported to poison centres 0.44 in 2010, 0.36 in 2015 (p = 0.0290), 0.46 in 2017 (p = 0.0013), then a decrease to 0.28 in 2022. The authors' own wording for the cause is that FDA warnings, labeling requirements and packaging restrictions 'may have contributed'.
• Funding: not stated.

Limit of this finding: Two cautions about this source. First, its own numbers do not reconcile: it reports 59 deaths and then attributes fatalities as 60.0% (n=33), 20.0% (n=11) and 5.5% (n=3). Those sub-counts add up to 47, not 59, and the percentages imply a denominator of 55. The quotation is faithful to what was published, character for character; no figure should be worked out from those percentages. Second, these are reports made voluntarily to poison centres, not measured rates in the population, and the study is an uncontrolled look at how reports changed over time, so it cannot show how often loperamide harms people nor that any particular action reduced harm.

The rate of loperamide cases per 100,000 US population reported to US PCs decreased from 0.44 in 2010 to 0.36 in 2015 (p = 0.0290), followed by an increase to 0.46 in 2017 (p = 0.0013), and then a trend reversal with a decrease to 0.28 in 2022

Tolerance to the antidiarrhoeal effect has not been observed in the label's own pharmacodynamic data. (Source 1)

• Expert review, not systematic, Very low certainty.
• Size: Not stated.
• Who: Not stated.
• How long: Not stated.
• Result: A bare statement with no supporting numbers.
• Funding: industry-funded (sponsor's label)

Loperamide prolongs the transit time of the intestinal contents. It reduces daily fecal volume, increases the viscosity and bulk density, and diminishes the loss of fluid and electrolytes. Tolerance to the antidiarrheal effect has not been observed.

Loperamide is broken down by two liver enzymes and leaves the body mainly in the faeces, which is why drugs that block those enzymes or its transporter raise its blood levels. (Source 10)

• Blood level study, Low certainty.
• Size: In vitro enzyme work; no participant count given.
• Who: Human liver enzyme preparations.
• How long: Not applicable.
• Result: Quercetin, a CYP2C8 inhibitor, cut N-demethylation by 40% and ketoconazole, a CYP3A4 inhibitor, by 90%; CYP2B6 and CYP2D6 play a minor role; excretion of unchanged loperamide and its metabolites occurs mainly through the faeces.
• Funding: industry-funded (sponsor's label)

Limit of this finding: This is laboratory work on enzymes, not a study in people, and the label prints 'to form- N-demethyl loperamide' with a stray hyphen, reproduced as printed.

Excretion Excretion of the unchanged loperamide and its metabolites mainly occurs through the feces.

What the evidence does not support

The label's own placebo-controlled data do not support loperamide as a cause of nausea, vomiting, headache or abdominal pain: those were reported more often on placebo than on loperamide. (Source 20)

• Meta-analysis, Low certainty.
• Size: 4 placebo-controlled acute-diarrhoea studies and 20 placebo-controlled chronic-diarrhoea studies.
• Who: Patients in the manufacturer's placebo-controlled programme.
• How long: Not stated on the label.
• Result: In acute diarrhoea, dry mouth, flatulence, abdominal cramp and colic were more frequently reported on placebo. In chronic diarrhoea, nausea, vomiting, headache, meteorism, abdominal pain, abdominal cramp and colic were more frequently reported on placebo. No rates are given for these, only the direction.
• Funding: industry-funded (sponsor's clinical programme reported in the label)

Limit of this finding: The prescription label's adverse-reaction 'tables' are not tables in the source file at all: the label contains 276 paragraph elements, 91 line breaks and no table markup, so the figures arrive as a flat run of lines. The order of the lines is preserved here exactly as the label prints it, but which column a given percentage belongs to is not encoded in the document and can only be inferred from the order of the headings. Read the numbers as the label's own, and do not treat the loperamide versus placebo column assignment as something the source guarantees.

The adverse events with an incidence of 1.0% or greater, which were more frequently reported in patients on placebo than on loperamide hydrochloride were: nausea, vomiting, headache, meteorism, abdominal pain, abdominal cramp and colic.

Where the evidence is mixed

In the one randomised placebo-controlled trial of loperamide in unselected irritable bowel syndrome, the loperamide arm's own stool measures improved while night-time pain increased. (Source 40)

• Randomized trial, Low certainty.
• Size: 90 patients included; 35 on loperamide, 34 on placebo, 21 dropouts, 33 healthy controls.
• Who: Unselected patients with irritable bowel syndrome, multicentre.
• How long: 5 weeks.
• Result: Within the loperamide arm over 5 weeks the abstract reports improved stool consistency (32%), reduced defecation frequency (36%) and reduced intensity of pain (30%), and an increase in nightly pain. No placebo-arm percentages, no between-group difference, no confidence intervals and no p-values are given anywhere in the abstract.
• Funding: not stated.

Limit of this finding: The 32%, 36% and 30% are changes measured inside the loperamide group only. The abstract gives no corresponding placebo figures, no comparison between the two groups, no confidence intervals and no p-values, so these numbers must not be read as the effect of loperamide over placebo. The same abstract records an increase in night-time pain in the loperamide group, and the risk of constipation and abdominal pain, and those belong beside the three percentages.

Throughout the 5 weeks of treatment an improved stool consistency (32%), reduced defecation frequency (36%), and reduced intensity of pain (30%) were found in the loperamide group. An increase in nightly pain was observed in the loperamide group.

A professional-body guideline using GRADE rated the evidence for loperamide in IBS with diarrhoea as very low certainty. (Source 6)

• Official position, Very low certainty.
• Size: 8 recommendations across named agents.
• Who: Adults with irritable bowel syndrome with predominant diarrhoea.
• How long: Not applicable.
• Result: Conditional recommendation for loperamide at very low certainty, alongside moderate-certainty conditional recommendations for eluxadoline, rifaximin and alosetron.
• Funding: Research Support, N.I.H., Extramural (publication type recorded in PubMed)

Limit of this finding: The guideline text is quoted exactly as the journal prints it, including its own slips: 'alosetron, (moderate certainty)' with a stray comma, and 'anstispasmodics' for antispasmodics. The certainty ratings attach to the agents the source attaches them to: moderate for eluxadoline, rifaximin and alosetron, very low for loperamide, low for tricyclic antidepressants and antispasmodics. A conditional recommendation at very low certainty is the weakest thing a GRADE panel can say in favour of something.

The panel made conditional recommendations for eluxadoline, rifaximin, alosetron, (moderate certainty), loperamide (very low certainty), tricyclic antidepressants, and anstispasmodics (low certainty). The panel made a conditional recommendation against the use of selective serotonin reuptake inhibitors (low certainty).

Where the research disagrees

Whether loperamide needs a boxed warning at all. The same molecule carries one on the prescription product and none on the over-the-counter product, where the cardiac risk appears instead as a one-line heart alert inside the Drug Facts panel

• The prescription loperamide label (Direct_Rx ANDA labelling, SPL effective 2026-08-25), parsed for LOINC 34066-1, position: WARNING: TORSADES DE POINTES AND SUDDEN DEATH Cases of Torsades de Pointes, cardiac arrest, and death have been reported with the use of a higher than recommended dosages of loperamide hydrochloride (Source 2)
• The over-the-counter Drug Facts panel for IMODIUM Multi-Symptom Relief (Kenvue Brands LLC, SPL effective 2026-08-25), which has no section coded LOINC 34066-1, position: Heart alert Taking more than directed can cause serious heart problems or death Do not use if you have bloody or black stool (Source 13)

How much the published literature supports loperamide for irritable bowel syndrome with diarrhoea

• Efskind and colleagues, randomised placebo-controlled trial, 1996, rct: The trial shows a benefit of loperamide in an unselected cohort of IBS patients with regard to stool frequency, stool consistency, and the overall pain intensity, but with increased abdominal pain during the night. (Source 40)
• Lembo and colleagues, American Gastroenterological Association guideline panel using GRADE, 2022, position: The panel made conditional recommendations for eluxadoline, rifaximin, alosetron, (moderate certainty), loperamide (very low certainty) (Source 6)

How much

• Reference intake: Dosing is set by the prescriber. The prescription label's position is that the drug is contraindicated altogether in children under 2 years because of respiratory depression and serious cardiac adverse reactions, and that above that age the dose is an initial 4 mg then 2 mg after each unformed stool in adults and children 13 and over, with weight-banded first-day totals of 3 mg, 4 mg and 6 mg for ages 2 to 12. (Source 30)
• Upper limit: The prescription label's stated maximum for adults is 16 mg, eight capsules, a day, and after the first day a child's total must not exceed the first day's amount. One over-the-counter carton's ceiling is lower, no more than 4 softgels, that is 8 mg, in 24 hours, and it is not for use under 12 years. (Source 30)
• Studied: The paediatric meta-analysis judged harms to outweigh benefits in the youngest and sickest children even at doses of 0.25 mg/kg/d or less. (Source 19)
• Studied: The human abuse-potential study on the label used single doses up to 60 mg, 3.75 times the recommended maximum adult daily dose of 16 mg. (Source 7)
• Studied: The overdose cases on the label involved chronic ingestion of 70 mg to 1600 mg daily, 4 to 100 times the recommended dose. (Source 22)
• Studied: In the label's own chronic-diarrhoea trials the average daily maintenance dose was 4 to 8 mg, two to four capsules a day. (Source 31)

A common belief, and what the research shows

The belief: Because loperamide is sold on a supermarket shelf it cannot do serious harm, so taking extra when diarrhoea is bad must be safe.

What the research shows: The over-the-counter Drug Facts panel itself carries the line: “Taking more than directed can cause serious heart problems or death”. United States poison centres recorded, in the words of the published series: “Although 46.1% of these cases were associated with minor or no effect, 13.4% resulted in a serious medical outcome, including 59 deaths (0.5%).” The prescription version of the same molecule carries a boxed warning. The label’s own overdose section describes a man who was not chasing a high at all: “54 year old misused loperamide hydrochloride (up to 144 mg per day) as a self-treatment for chronic diarrhea for over 2 years.”

Questions and answers

What is it?

Loperamide is a man-made opioid-type molecule that works almost entirely in the bowel wall rather than in the brain. It is sold as 2 mg tablets, caplets, soft capsules and a liquid, on the shelf as an anti-diarrhoeal and, in the United States, also on prescription. Almost all of it stays out of the brain because it is heavily protein-bound and is pumped out of brain capillaries by a transporter called P-glycoprotein. (Source 1)

What does it do in the body?

It attaches to opioid receptors in the gut wall, which damps down the release of acetylcholine and prostaglandins and slows the waves that push contents along. Contents then spend longer in the bowel, more water is reabsorbed and stool becomes firmer and less frequent. It also tightens the anal sphincter, which reduces urgency and leakage. (Source 1)

Is it good or bad for you?

It depends entirely on the setting and the dose. For a short bout of watery diarrhoea in an adult, or added to an antibiotic for travellers' diarrhoea, pooled trials show real benefit. In children under three, and in children who are malnourished, dehydrated, systemically unwell or passing blood, a meta-analysis concluded the harms outweigh the benefit even at low doses. At doses far above the label it is dangerous to the heart. (Source 19)

How do you get more of it?

It is a manufactured medicine, not a nutrient, so there is no dietary route. In the United States it is bought over the counter as 2 mg capsules, caplets, softgels or a liquid, and the same molecule is also dispensed on prescription with a wider set of indications. One over-the-counter carton is labelled for adults and children 12 years and over and is not for use below that age. The amount taken is set by the Drug Facts chart or by a prescriber. (Source 41)

If it is harmful, what reduces it?

Loperamide becomes harmful mainly when too much is taken. The label's instruction when cardiac toxicity is suspected is to stop the drug promptly and start treatment to manage and prevent arrhythmias, and it notes that magnesium sulfate was often ineffective and that blood levels are not a useful guide. It is also stopped promptly if constipation, abdominal swelling or ileus develop. Clearance is slow, with an apparent half-life of about 10.8 hours, and the drug and its breakdown products leave mainly in the faeces. (Source 1)

Why might someone be low in it or missing it?

Nobody is naturally short of loperamide; it is a drug, not something the body makes. The question that matters is who should not have it. The prescription label rules it out in children under two, in acute dysentery with blood and fever, in acute ulcerative colitis, in enterocolitis caused by invasive organisms such as Salmonella, Shigella and Campylobacter, in antibiotic-associated pseudomembranous colitis, and in abdominal pain without diarrhoea. (Source 27)

Which whole foods contain it or feed it?

No whole food contains loperamide and no food raises or feeds it; it is a synthetic drug. The nearest food-related instruction on the over-the-counter label is to drink plenty of clear fluids while using it, because the fluid lost in diarrhoea is the real danger and the drug does not replace it. (Source 29)

What happens if you do not have it?

Without it, most short bouts of diarrhoea settle on their own, and the pooled paediatric data show the difference loperamide makes is modest, about 0.8 of a day. What is not optional is replacing lost fluid and salts. The label is explicit that loperamide does not remove that need, and in many situations slowing the bowel is the wrong thing to do. (Source 15)

How can you test for it?

There is no routine blood test to check a loperamide level, and the label says plainly that serum concentrations are not widely available or clinically useful for managing a patient. In suspected toxicity the measurements that matter are electrical, not chemical: the electrocardiogram, specifically the QTc and QRS intervals. Standard opioid drug screens do not detect loperamide at all, so they read negative even when it is present. (Source 17)

References

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