Loperamide Hydrochloride (Page 3 of 5)

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 mg/kg/day, 10 mg/kg/day, 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. Pregnancy Category C

Teratology studies have been performed in rats using oral loperamide hydrochloride doses of 2.5 mg/kg/day, 10 mg/kg/day, and 40 mg/kg/day, and in rabbits using oral doses of 5 mg/kg/day, 20 mg/kg/day, 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.

Non-Teratogenic 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 are not recommended during breast-feeding.

Pediatric Use

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). 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 have 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 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 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 76 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 *
No. of treated patients 1913 1371 3740
*
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.

Gastrointestinal AE%

Nausea

0.7%

3.2%

1.8%

Constipation

1.6%

1.9%

1.7%

Abdominal cramps

0.5%

3.0%

1.4%

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