Loperamide Hydrochloride (Page 3 of 5)

ADVERSE REACTIONS

Clinical Trial Experience

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

*
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.

Acute Diarrhea

Chronic Diarrhea

All Studies *

No. of treated patients

1913

1371

3740

Gastrointestinal AE%

Nausea

Constipation

Abdominal cramps

0.7%

1.6%

0.5%

3.2%

1.9%

3.0%

1.8%

1.7%

1.4%

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.

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.

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 postmarketing 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 coadministration 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.

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