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 Category C
Teratology studies have been performed in rats using oral 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 40 mg/kg/day by mouth (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 should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
In cases of overdosage, (including relative overdose due to hepatic dysfunction), urinary retention, paralytic ileus and CNS depression may occur. Children may be more sensitive to CNS effects than adults. Clinical trials have demonstrated that a slurry of activated charcoal administered promptly after ingestion of loperamide hydrochloride can reduce the amount of drug which is absorbed into the systemic circulation by as much as ninefold. If vomiting occurs spontaneously upon ingestion, a slurry of 100 gms of activated charcoal should be administered orally as soon as fluids can be retained.
If vomiting has not occurred, gastric lavage should be performed followed by administration of 100 gms of the activated charcoal slurry through the gastric tube. In the event of overdosage, patients should be monitored for signs of CNS depression for at least 24 hours.
If symptoms of overdose occur, naloxone can be given as an antidote. If responsive to naloxone, vital signs must be monitored carefully for recurrence of symptoms of drug overdose for at least 24 hours after the last dose of naloxone.
In view of the prolonged action of loperamide and the short duration (one to three hours) of naloxone, the patient must be monitored closely and treated repeatedly with naloxone as indicated. Since relatively little drug is excreted in the urine, forced diuresis is not expected to be effective for IMODIUM® (loperamide hydrochloride) overdosage.
In clinical trials an adult who took three 20mg doses within a 24 hour period was nauseated after the second dose and vomited after the third dose. In studies designed to examine the potential for side effects, intentional ingestion of up to 60 mg of loperamide hydrochloride in a single dose to healthy subjects resulted in no significant adverse effects.
IMODIUM is contraindicated in patients with a known hypersensitivity to loperamide hydrochloride or to any of the excipients.
IMODIUM is contraindicated in patients with abdominal pain in the absence of diarrhea.
IMODIUM is not recommended in infants below 24 months of age.
IMODIUM should not be used as the primary therapy:
- -in patients with acute dysentery, which is characterized by blood in stools and high fever,
- -in patients with acute ulcerative colitis,
- -in patients with bacterial enterocolitis caused by invasive organisms including Salmonella, Shigella, and Campylobacter,
- -in patients with pseudomembranous colitis associated with the use of broad-spectrum antibiotics.
DRUG ABUSE AND DEPENDENCE
A specific clinical study designed to assess the abuse potential of loperamide at high doses resulted in a finding of extremely low abuse potential.
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.
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