Loperamide Hydrochloride (Page 2 of 4)

PRECAUTIONS

GENERAL PRECAUTIONS

Allergic Reactions

Extremely rare allergic reactions including anaphylaxis and anaphylactic shock have been reported.

Hepatic Impairment

The effects of hepatic impairment on the pharmacokinetics of loperamide have not been studied. Use Loperamide Hydrochloride Capsules with caution in such patients because the systemic exposure to loperamide may be increased due to reduced metabolism. Monitor patients with hepatic impairment closely for signs of central nervous system (CNS) toxicity.

Renal Impairment

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 are excreted mainly in the feces, dosage adjustments in patients with renal impairment are not required.

Geriatric Use

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.

In general, elderly patients may be more susceptible to drug-associated effects on the QT interval. Avoid Loperamide Hydrochloride Capsules in elderly patients taking drugs that can result in prolongation of the QT interval (for example, Class IA or III antiarrhythmics) or in patients with risk factors for Torsades de Pointes (see WARNINGS).

INFORMATION FOR PATIENTS


Advise patients:

  • to take Loperamide Hydrochloride Capsules at the prescribed dosage. Use of a higher than prescribed dosage is not recommended (see WARNINGS). Report to a healthcare facility if you or someone you are caring for taking Loperamide Hydrochloride Capsules experiences fainting episode, a rapid or irregular heartbeat or become unresponsive.
  • with acute diarrhea, that if clinical improvement is not observed in 48 hours, discontinue Loperamide Hydrochloride Capsules and contact their healthcare provider.
  • to contact their healthcare provider if they see blood in their stools, or if they develop a fever or abdominal distention.
  • to use caution when driving a car or operating machinery, as tiredness, dizziness, or drowsiness may occur in the setting of diarrheal syndromes treated with Loperamide Hydrochloride Capsules. (see ADVERSE REACTIONS) to tell their healthcare provider about all the medications they are taking, including prescription and over-the-counter medications, vitamins and herbal supplements, especially if they take Class 1A (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmics, antipsychotics (e.g., chlorpromazine, haloperidol, thioridazine, ziprasidone), antibiotics (e.g., moxifloxacin), or any other drug known to prolong the QT interval (e.g., pentamidine, levomethadyl acetate, methadone).

DRUG INTERACTIONS

Effects of Other Drugs on Loperamide

Concomitant use of Loperamide Hydrochloride Capsules with inhibitors of CYP3A4 (e.g., itraconazole) or CYP2C8 (e.g., gemfibrozil) or inhibitors of P-glycoprotein (e.g., quinidine, ritonavir) can increase exposure to loperamide. The increased systemic exposure to loperamide may increase a risk for cardiac adverse reactions especially in patients who are taking multiple CYP enzyme inhibitors, or in patients with underlying cardiac conditions (see WARNINGS). Monitor patients for cardiac adverse reactions.

CYP3A4 Inhibitors

Itraconazole

Concomitant administration of multiple doses of 100 mg itraconazole twice daily, an inhibitor of both CYP3A4 and P-glycoprotein, with a single 4-mg dose of loperamide hydrochloride increased the peak plasma concentration and the systemic exposure to loperamide by 2.9-fold and 3.8-fold, respectively.

CYP2C8 Inhibitors

Gemfibrozil

When a single 4-mg dose of loperamide hydrochloride was co-administered with 600 mg gemfibrozil, a strong inhibitor of CYP2C8, on day 3 of a 5-day treatment with gemfibrozil twice daily, the mean peak plasma concentration and the systemic exposure to loperamide was increased by 1.6-fold and 2.2-fold, respectively.

CYP3A4 and CYP2C8 Inhibitors

When multiple doses of both 100 mg itraconazole and 600 mg gemfibrozil twice daily were administered with a single 4-mg dose of loperamide hydrochloride, the mean peak plasma concentration and the systemic exposure to loperamide was increased by 4.2-fold and 12.6-fold, respectively.

P-glycoprotein Inhibitors

Concomitant administration of a 16 mg single dose of loperamide hydrochloride with a 600 mg single dose of quinidine or ritonavir, both of which are P-glycoprotein inhibitors, resulted in a 2- to 3-fold increase in loperamide plasma concentrations. Due to the potential for enhanced CNS adverse reactions when loperamide is co-administered with quinidine and with ritonavir, caution should be exercised when Loperamide Hydrochloride Capsules USP, 2 mg is administered at the recommended dosages (2 mg, up to 16 mg maximum daily dose) with P-glycoprotein inhibitors.

Effects of Loperamide on Other Drugs

Saquinavir

When a single 16-mg dose of loperamide hydrochloride 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 Hydrochloride Capsules 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 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.

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