General

Extremely rare allergic reactions including anaphylaxis and anaphylactic shock have been reported. In acute diarrhea, if clinical improvement is not observed in 48 hours, the administration of IMODIUM® (loperamide hydrochloride) should be discontinued and patients should be advised to consult their physician. Although no pharmacokinetic data are available in patients with hepatic impairment, IMODIUM should be used with caution in such patients because of reduced first pass metabolism. Patients with hepatic dysfunction should be monitored closely for signs of CNS toxicity. No pharmacokinetic data are available in patients with renal impairment. Since it has been reported that the majority of the drug is metabolized and metabolites or the unchanged drug is excreted mainly in the feces, dosage adjustments in patients with renal impairment are not required. No formal studies have been conducted to evaluate the pharmacokinetics of loperamide in elderly subjects. However, in two studies that enrolled elderly patients, there were no major differences in the drug disposition in elderly patients with diarrhea relative to young patients.

Information for Patients

Patients should be advised to check with their physician if their diarrhea does not improve in 48 hours or if they note blood in their stools, develop a fever or develop abdominal distention. Tiredness, dizziness, or drowsiness may occur in the setting of diarrheal syndromes treated with IMODIUM. Therefore, it is advisable to use caution when driving a car or operating machinery. (see Adverse Reactions).

Drug Interactions

Nonclinical data have shown that loperamide is a P-glycoprotein substrate. Concomitant administration of loperamide (16 mg single dose) with a 600 mg single dose of either quinidine, or ritonavir, both of which are P-glycoprotein inhibitors, resulted in a 2- to 3- fold increase in loperamide plasma levels. Due to the potential for enhanced central effects when loperamide is coadministered with quinidine and with ritonavir, caution should be exercised when loperamide is administered at the recommended dosages (2 mg, up to 16 mg maximum daily dose) with P-glycoprotein inhibitors.

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

Carcinogenesis, mutagenesis, impairment of fertility

In an 18-month rat study with oral 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 strong impairment of female fertility. Treatment of female rats with up to 10 mg/kg/day by mouth (approximately 5 times the human dose based on a body surface area comparison) had no effect on fertility. Treatment of male rats with 40 mg/kg/day by mouth (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

Nursing Mothers

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

Pediatric Use

See the "Warnings" Section for information on the greater variability of response in this age group. In case of accidental overdosage of IMODIUM® by children, see "Overdosage" Section for suggested treatment.

Clinical Trial Data

The adverse effects reported during clinical investigations of IMODIUM® (loperamide hydrochloride) are difficult to distinguish from symptoms associated with the diarrheal syndrome. Adverse experiences recorded during clinical studies with IMODIUM® 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.

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.

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.

Post –marketing experience

The following adverse events have been reported:

Skin and subcutaneous tissue disorders

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

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 IMODIUM.

Gastrointestinal disorders
Dry mouth, abdominal pain, distention or discomfort, nausea, vomiting, flatulence, dyspepsia, constipation, paralytic ileus, megacolon, including toxic megacolon (see Contraindications and 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.

Abuse

A specific clinical study designed to assess the abuse potential of loperamide at high doses resulted in a finding of extremely low abuse potential.

Dependence

Studies in morphine-dependent monkeys demonstrated that loperamide hydrochloride at doses above those recommended for humans prevented signs of morphine withdrawal. However, in humans, the naloxone challenge pupil test, which when positive indicates opiate-like effects, performed after a single high dose, or after more than two years of therapeutic use of IMODIUM® (loperamide hydrochloride), was negative. Orally administered IMODIUM® (loperamide formulated with magnesium stearate) is both highly insoluble and penetrates the CNS poorly.

Acute Diarrhea

Chronic Diarrhea

Children under 2 Years

The use of IMODIUM in children under 2 years is not recommended. 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 very young children less than two years of age.

Elderly

No formal pharmacokinetic studies were conducted in elderly subjects. However, there were no major differences reported in the drug disposition in elderly patients with diarrhea relative to young patients. No dosage adjustment is required in the elderly.

Renal Impairment

No pharmacokinetic data are available in patients with renal impairment. Since the metabolites and the unchanged drug are mainly excreted in the feces, no dosage adjustment is required for patients with renal impairment (see PRECAUTIONS section).

Hepatic Impairment

Although no pharmacokinetic data are available in patients with hepatic impairment, IMODIUM should be used with caution in such patients because of reduced first pass metabolism. (see Precautions).

Store at 15°-25°C (59°-77°F).