FDA Label for Loperamide Hydrochloride

Warning: Torsades De Pointes And Sudden Death

• Cases of Torsades de Pointes, cardiac arrest, and death have been reported with the use of a higher than recommended dosages of loperamide hydrochloride capsules (see WARNINGS and OVERDOSAGE).
• Loperamide hydrochloride capsules are contraindicated in pediatric patients less than 2 years of age (see CONTRANIDICATIONS).
• Avoid loperamide hydrochloride capsules dosages higher than recommended in adults and pediatric patients 2 years of age and older due to the risk of serious cardiac adverse reactions (see DOSAGE AND ADMINISTRATION).

Description

Loperamide hydrochloride, 4-(p-chlorophenyl)-4-hydroxy-N,N-dimethyl-a,adiphenyl-1-piperidinebutyramide monohydrochloride, is a synthetic antidiarrheal for oral use.

The molecular formula for loperamide hydrochloride, USP is C ₂₉H ₃₃ClN ₂O ₂HCl, with a molecular weight of 513.50. The structural formula is:

Loperamide Hydrochloride Structural Formula - structure0001

Loperamide hydrochloride, USP is available in 2 mg capsules.

Loperamide hydrochloride capsules, USP contain the following inactive ingredients: colloidal silicon dioxide, lactose monohydrate, microcrystalline cellulose, magnesium stearate, and sodium starch glycolate. The hard-capsule shell is composed of gelatin, sodium lauryl sulfate, and titanium dioxide. The capsules are printed with black ink composed of black iron oxide, potassium hydroxide, propylene glycol, and shellac.

Indications And Usage

Loperamide hydrochloride capsules are indicated for the control and symptomatic relief of acute nonspecific diarrhea in patients 2 years of age and older and of chronic diarrhea in adults associated with inflammatory bowel disease. Loperamide hydrochloride capsules are also indicated for reducing the volume of discharge from ileostomies.

Contraindications

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 WARNINGS).
• patients with a known hypersensitivity to loperamide hydrochloride or to any of the excipients.
• patients with abdominal pain in the absence of diarrhea.
• patients with acute dysentery, which is characterized by blood in stools and high fever.
• patients with acute ulcerative colitis.
• patients with bacterial enterocolitis caused by invasive organisms including Salmonella, Shigella, and Campylobacter.
• patients with pseudomembranous colitis (e.g., Clostridium difficle) associated with the use of broad-spectrum antibiotics.

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).

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.

Teratogenic Effects

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 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 is not recommended during breast-feeding.

Pediatric Use

Loperamide hydrochloride 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 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.

The safety and effectiveness of loperamide hydrochloride in pediatric patients with chronic diarrhea have not been established. Although loperamide hydrochloride 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 by pediatric patients, see OVERDOSAGE for suggested treatment.

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 co-administration 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.

Dependence

In animals, parenteral administration of loperamide hydrochloride can cause physical dependence, cross-tolerance to opioids, and all the other pharmacologic effects typical of mu-opioid agonists.

Studies in morphine-dependent monkeys demonstrated that loperamide hydrochloride at doses above those recommended for humans prevented signs of morphine withdrawal.

Overdosage

The use of higher than recommended loperamide hydrochloride doses may result in life-threatening cardiac, CNS and respiratory adverse reactions.

If over-exposure occurs, call your Poison Control Center at 1-800-222-1222 for current information on the management of poisoning or overdosage.

Dosage And Administration

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).

Avoid loperamide hydrochloride capsules dosages higher than recommended in adult or pediatric patients 2 years of age and older due to the risk of serious cardiac adverse reactions (See WARNINGS and OVERDOSAGE).

(1 capsule = 2 mg) Patients should receive appropriate fluid and electrolyte replacement as needed.

Adults

The recommended initial dose is 4 mg (two capsules) followed by 2 mg (one capsule) after each unformed stool until diarrhea is controlled, after which the dosage of loperamide hydrochloride capsules should be reduced to meet individual requirements. When the optimal daily dosage has been established, this amount may then be administered as a single dose or in divided doses.

The average daily maintenance dosage in clinical trials was 4 mg to 8 mg (two to four capsules per day). The maximum daily dosage is 16 mg (eight capsules per day). If clinical improvement is not observed after treatment with 16 mg per day for at least 10 days, symptoms are unlikely to be controlled by further administration. Loperamide hydrochloride capsules administration may be continued if diarrhea cannot be adequately controlled with diet or specific treatment.

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 dose adjustment is required for the elderly.

In general, elderly patients may be more susceptible to drug-associated effects of 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).

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).

Hepatic Impairment

The pharmacokinetics of loperamide have not been studied in patients with hepatic impairment. Use loperamide hydrochloride capsules with caution in such patients because the systemic exposure may be increased due to reduced metabolism (see PRECAUTIONS).

How Supplied

Loperamide hydrochloride capsules, USP are available containing 2 mg of loperamide hydrochloride, USP. The capsules have a hard-shell gelatin capsule with a white opaque cap and a white opaque body filled with white to off-white powder blend. The capsule is printed with “ LM1” in black ink on the body. Loperamide hydrochloride capsules, USP are supplied in bottles of 100 (NDC 68071-2700-2 BOTTLES OF 20)

Store at 20°C to 25°C (68°F to 77°F) [See USP Controlled Room Temperature].

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

Distributed by:

Bionpharma Inc.

600 Alexander Road,

Princeton, NJ 08540

MADE IN INDIA

Rev. 0321

FDA-02

Principal Display Panel - 2 Mg

pdp - 68071 2700 2