Prescription Drug Information: Loperamide Hydrochloride (Page 2 of 3)

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY

In an 18-month rat study with oral loperamide hydrochloride doses up to 40 mg/kg/day (21 times the maximum human dose of 16 mg/day, based on a body surface area comparison), there was no evidence of carcinogenesis.

Loperamide was not genotoxic in the Ames test, the SOS chromotest in E. coli, the dominant lethal test in female mice, or the mouse embryo cell transformation assay.

Fertility and reproductive performance was evaluated in rats using oral doses of 2.5, 10, and 40 mg/kg/day (females only) in a second study. Oral administration of 20 mg/kg/day (approximately 11 times the human dose based on a body surface area comparison) and higher, produced a strong impairment of female fertility. Treatment of female rats with up to 10 mg/kg/day (approximately 5 times the human dose based on a body surface area comparison) had no effect on fertility. Treatment of male rats with oral doses of 40 mg/kg/day (approximately 21 times the human dose based on a body surface area comparison) produced impairment of male fertility, whereas administration of up to 10 mg/kg/day (approximately 5 times the human dose based on a body surface area comparison) had no effect.

PREGNANCY

Teratogenic Effects

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

Nonteratogenic Effects

In a peri- and post-natal development study in rats, oral administration of 40 mg/kg/day produced impairment of growth and survival of offspring.

NURSING MOTHERS

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

PEDIATRIC USE

Loperamide Hydrochloride Capsules, 2 mg is contraindicated in pediatric patients less than 2 years of age due to the risks of respiratory depression and serious cardiac adverse reactions (see CONTRAINDICATIONS). Postmarketing cases of cardiac arrest, syncope, and respiratory depression have been reported in pediatric patients less than 2 years of age (see WARNINGS). Pediatric patients may be more sensitive to CNS effects, such as altered mental status, somnolence, and respiratory depression, than adults. There have been rare reports of paralytic ileus associated with

abdominal distention. Most of these reports occurred in the setting of acute dysentery, overdose, and with pediatric patients less than two years of age.

Loperamide Hydrochloride Capsules should be used with special caution in pediatric patients because of their greater variability of response (see WARNINGS). Dehydration, particularly in pediatric patients less than 6 years of age, may further influence the variability of response to Loperamide Hydrochloride Capsules

The safety and effectiveness of Loperamide Hydrochloride Capsules in pediatric patients with chronic diarrhea have not been established. Although Loperamide Hydrochloride Capsules has been studied in a limited number of pediatric patients with chronic diarrhea; the therapeutic dose for the treatment of chronic diarrhea in a pediatric population has not been established.

In case of accidental overdosage of Loperamide Hydrochloride Capsules by pediatric patients, see OVERDOSAGE for suggested treatment.

ADVERSE REACTIONS

Clinical Trial Experience

The adverse effects reported during clinical investigations of Loperamide Hydrochloride Capsules (loperamide hydrochloride) are difficult to distinguish from symptoms associated with the diarrheal syndrome. Adverse experiences recorded during clinical studies with Loperamide Hydrochloride Capsules were generally of a minor and self-limiting nature. They were more commonly observed during the treatment of chronic diarrhea.

The adverse events reported are summarized irrespective of the causality assessment of the investigators.

1) Adverse events from 4 placebo-controlled studies in patients with acute diarrhea The adverse events with an incidence of 1.0% or greater, which were reported at least as often in patients on loperamide hydrochloride as on placebo, are presented in the table below.

Acute Diarrhea
Loperamide Hydrochloride Placebo
No. of treated patients 231 236
Gastrointestinal AE% Constipation 2.6% 0.8%

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: dry mouth, flatulence, abdominal cramp and colic.

2) Adverse events from 20 placebo-controlled studies in patients with chronic diarrhea The adverse events with an incidence of 1.0% or greater, which were reported at least as often in patients on loperamide hydrochloride as on placebo, are presented below in the table below.

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 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.

3) Adverse events from seventy-six controlled and uncontrolled studies in patients with acute or chronic diarrhea The adverse events with an incidence of 1.0% or greater in patients from all studies are given in the table below.

Acute Diarrhea Chronic Diarrhea All Studies a
No. of treated patients 1913 1371 3740
Gastrointestinal AE% NauseaConstipation Abdominal cramps 0.7%1.6%0.5% 3.2%1.9%3.0% 1.8%1.7%1.4%

a. All patients in all studies, including those in which it was not specified if the adverse events occurred in patients with acute or chronic diarrhea.

Postmarketing Experience

The following adverse events have been reported:

Cardiac disorders

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

Skin and subcutaneous tissue disorders

Rash, pruritus, urticaria, and angioedema and extremely rare cases bullous eruption including erythema multiforme, Stevens-Johnson syndrome and Toxic Epidermal Necrolysis have been reported with use of Loperamide Hydrochloride Capsules.

Immune system disorders

Isolated occurrences of allergic reactions and in some cases severe hypersensitivity reactions including anaphylactic shock and anaphylactoid reactions have been reported with the use of Loperamide Hydrochloride Capsules.

Gastrointestinal disorders

Dry mouth, abdominal pain, distention or discomfort, nausea, vomiting, flatulence, dyspepsia, constipation, paralytic ileus, megacolon; including toxic megacolon (see CONTRAINDICATIONS, WARNINGS).

Renal and urinary disorders

Urinary retention

Nervous system disorders

Drowsiness, dizziness

General disorders and administrative site conditions

Tiredness

A number of the adverse events reported during the clinical investigations and post-marketing experience with loperamide are frequent symptoms of the underlying diarrheal syndrome (abdominal pain/discomfort, nausea, vomiting, dry mouth, tiredness, drowsiness, dizziness, constipation, and flatulence). These symptoms are often difficult to distinguish from undesirable drug effects.

DRUG ABUSE AND DEPENDENCE

CONTROLLED SUBSTANCE

Loperamide is not a controlled substance.

ABUSE

Loperamide is a mu-opioid agonist. 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.

DEPENDENCE

In animals, parenteral administration of loperamide hydrochloride can cause physical dependence, cross-tolerance to opioids, and all the other pharmacologic effects typical of mu- opioid agonists. Studies in morphine-dependent monkeys demonstrated that loperamide hydrochloride at doses above those recommended for humans prevented signs of morphine withdrawal.

OVERDOSAGE

The use of higher than recommended Loperamide Hydrochloride Capsules doses may result in life-threatening cardiac, CNS and respiratory adverse reactions.

If over-exposure occurs, call your Poison Control Center at 1-800-222-1222 for current information on the management of poisoning or overdosage.

Cardiac Effects

Symptoms

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. Cases include patients who were abusing (using supratherapeutic doses in place of opioids to induce euphoria) or misusing (taking higher than recommended doses to control diarrhea or to prevent opioid withdrawal) loperamide. The following are representative cases that included cardiac adverse reactions:

  • 25 year old abused loperamide and presented to the hospital on multiple occasions with symptoms of syncope, nausea, vomiting, bradycardia, hypotensive shock. The patient also experienced ventricular tachycardia, a prolonged QTc of 527 ms and QRS interval of 170 ms, frequent premature ventricular contractions, and subsequent cardiac arrest and death (elevated loperamide blood concentration of 32 ng/ml).
  • 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.
  • 26 year old, with prior opioid abuse, presented to the hospital with recurrent syncope and developed Torsades de Pointes requiring electrical cardioversion. An ECG revealed a sinus rhythm with a heart rate of 85 bpm and a markedly prolonged QTc interval of greater than 700 ms. The patient reported ingesting 100 to 250 mg of loperamide hydrochloride with 400 mg of cimetidine daily for several months to simulate the euphoric sensation associated with opioids.

Management

Consider loperamide as a possible cause of cardiac arrhythmias in patients who may have a history of opioid abuse or recent ingestion of unknown drugs and in the differential diagnosis of unstable arrhythmias, prolonged QTc or QRS intervals, and Torsades de Pointes.

If loperamide-induced cardiac toxicity is suspected, promptly discontinue the drug and initiate therapy to manage and prevent cardiac arrhythmias and serious outcomes.

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. Electrical cardioversion and overdrive pacing, and isoproterenol continuous infusion were reported to manage QTc prolongation in the setting of overdose.

Laboratory Testing

Loperamide serum concentrations are not widely available or clinically useful to guide patient management.

CNS and Respiratory Depression

Symptoms

Cases of loperamide overdose (including relative overdose due to hepatic dysfunction), may cause opioid toxic effects including CNS depression (e.g. altered mental status, stupor, coordination disorders, somnolence, miosis, muscular hypertonia, respiratory depression), hypotension, urinary retention, and paralytic ileus. Pediatric patients may be more sensitive to CNS effects, including respiratory depression, than adults.

Management

Loperamide non-cardiac arrhythmia overdosages should be treated as opioid overdosages. Naloxone may reverse the opioid-related toxicity, including CNS and respiratory depression, and hypotension, associated with loperamide overdosage.

In adults and pediatric patients, naloxone may be administered intravenously. Appropriate doses of naloxone, via intranasal, intramuscular, intraosseous, or subcutaneous administration may be necessary if the intravenous route is not available. If the desired degree of opioid- related toxicity counteraction and improvement are not obtained, naloxone may be repeated at two- to three-minute intervals. If no response in opioid-related effects is observed after naloxone has been administered, then diagnosis of opioid-induced toxicity should be questioned.

Refer to the naloxone prescribing information for complete information on initial and subsequent dosages.

For patients whose adverse reactions are responsive to naloxone, monitor vital signs, neurologic and cardiopulmonary status for recurrence of opioid overdose symptoms for at least 24 hours after the last dose of naloxone, due to the prolonged intestinal retention of loperamide and the short duration (one to three hours) of naloxone. Patients with severe CNS or respiratory depression, and those who require multiple doses of naloxone to reverse symptoms, should be admitted to the hospital and may require intensive care.

Laboratory Testing

Standard drug screens for opioids do not include an assay for loperamide; such testing for opioids will yield negative results even in the presence of loperamide.

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