Approved Drug Label (PDF)
Boxed Warning
WARNING:
TORSADES DE POINTES AND SUDDEN DEATH (Newly added)
Cases of Torsades de Pointes, cardiac arrest, and
death have been reported with the use of a higher than recommended dosages of
IMODIUM®.
IMODIUM® is contraindicated in pediatric patients
less than 2 years of age.
Avoid IMODIUM® dosages higher than recommended in
adults and pediatric patients 2 years of age and older due to the risk of
serious cardiac adverse reactions.
4
Contraindications
IMODIUM® is contraindicated in:
pediatric patients less than 2 years of age due to the risks of respiratory
depression and serious cardiac adverse reactions.
in patients with pseudomembranous colitis (e.g., Clostridium difficle) associated
with the use of broad-spectrum antibiotics. (additions
underlined)
5
Warnings and Precautions
Precautions
(additions and/or revisions underlined)
General
Allergic Reactions
Extremely rare allergic reactions including
anaphylaxis …
Hepatic
Impairment
The effects of
hepatic impairment on the pharmacokinetics of loperamide have not been
studied. Use IMODIUM® 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 (added subsection heading)
No pharmacokinetic data are available in patients
with renal impairment…
Geriatric
Use (added
subsection heading)
No formal studies have been conducted …
In general, elderly patients may be more susceptible
to drug-associated effects on the QT interval. Avoid IMODIUM® 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. (Addition underlined)
Information
for Patients
Advise patients:
- to take IMODIUM® at the prescribed dosage. Use of
a higher than prescribed dosage is not recommended. Report to a healthcare facility if you or
someone you are caring for taking IMODIUM® 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 IMODIUM® 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 IMODIUM®.
- 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).
Pregnancy
Teratogenic
Effects
Pregnancy
Category C
Teratology studies have been performed in rats using
oral loperamide hydrochloride doses of 2.5. 10, and 40mg/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 40 mg/kg/day in rats (5 times the human dose based on body surface area
comparison) and 40 (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. IMODIUM®
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.
Pediatric
Use
IMODIUM® is contraindicated in pediatric patients
less than 2 years of age due to the risks of respiratory depression and serious
cardiac adverse reactions. Postmarketing cases of cardiac arrest, syncope, and
respiratory depression have been reported in pediatric patients less than 2
years of age. 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.
IMODIUM® 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 IMODIUM®.
The safety and effectiveness of IMODIUM® in
pediatric patients with chronic diarrhea have not been established. Although
IMODIUM® 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 IMODIUM® by
pediatric patients, see OVERDOSAGE for suggested treatment.
Warnings
(additions and/or revisions underlined)
Cardiac Adverse Reactions, Including Torsades de
Pointes and Sudden Death Cases of prolongation of the QT/QTc interval, Torsades
de Pointes, other ventricular arrhythmias, cardiac arrest, some resulting in
death, have been reported in adults with use of higher than recommended doses
per day of IMODIUM®. Cases include
patients who were abusing or misusing loperamide hydrochloride. Cases of
syncope and ventricular tachycardia have been reported in adult patients
receiving the recommended dosage of IMODIUM®. Some of these patients were
taking other drugs or had other risk factors that may have increased their risk
of cardiac adverse reactions. Additionally, postmarketing cases of cardiac
arrest, syncope, and respiratory depression have been reported in pediatric
patients less than 2 years of age.
IMODIUM® is contraindicated in pediatric patients
less than 2 years of age due to the risks of respiratory depression and serious
cardiac adverse reactions. Avoid IMODIUM® dosages higher than recommended in
adults and pediatric patients 2 years of age and older due to the risk of
serious cardiac adverse reactions.
Avoid IMODIUM® in:
combination with others
drugs or herbal products that are known to prolong the QT interval, including
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)
patients with risk factors
for QT prolongation, including patients with congenital long QT syndrome, with
a history of cardiac arrhythmias or other cardiac conditions, elderly patients
and those with electrolyte abnormalities.
Dehydration (added subsection heading)
Fluid and electrolyte depletion often occur in
patients who have diarrhea…
Gastrointestinal
Disorders (added subsection heading)
In general, IMODIUM® should not be used when
inhibition of peristalsis is to be avoided due to the possible risk of
significant sequelae including ileus, megacolon and toxic megacolon…
Variability
in Pediatric Response
IMODIUM® should be used with special caution in pediatric
patients because of the greater variability of response in this age group.
Dehydration, particularly in pediatric patients less than 6 years of age,
may further influence the variability of response to IMODIUM®. IMODIUM® is
contraindicated in pediatric patients less than 2 years of age due to the risks
of respiratory depression and serious cardiac adverse reactions.
6
Adverse Reactions
Clinical Trial Experience (replaces Clinical Trial Data)
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. (additions underlined)
7
Drug Interactions
(additions and/or revisions underlined)
Effects
of Other Drugs on Loperamide
Concomitant use of IMODIUM® 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.
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 IMODIUM® 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 …Therefore, when IMODIUM® is given with saquinavir …
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