WARNINGS
Neuroleptic Malignant Syndrome (NMS)
There have been rare reports of an uncommon but
potentially fatal symptom complex sometimes referred to as
Neuroleptic Malignant Syndrome (NMS) associated with
metoclopramide. Clinical manifestations of NMS include
hyperthermia, muscle rigidity, altered consciousness, and
evidence of autonomic instability (irregular pulse or blood
pressure, tachycardia, diaphoresis and cardiac
arrhythmias).
The diagnostic evaluation of patients with this syndrome
is complicated. In arriving at a diagnosis, it is important to
identify cases where the clinical presentation includes both
serious medical illness (e.g., pneumonia, systemic infection,
etc.) and untreated or inadequately treated extrapyramidal signs
and symptoms (EPS). Other important considerations in the
differential diagnosis include central anticholinergic toxicity,
heat stroke, malignant hyperthermia, drug fever and primary
central nervous system (CNS) pathology.
The management of NMS should include 1) immediate
discontinuation of metoclopramide and other drugs not essential
to concurrent therapy, 2) intensive symptomatic treatment and
medical monitoring, and 3) treatment of any concomitant serious
medical problems for which specific treatments are available.
Bromocriptine and dantrolene sodium have been used in treatment
of NMS, but their effectiveness have not been established (see
ADVERSE
REACTIONS).
Extrapyramidal Symptoms (EPS)
Acute Dystonic Reactions
Acute dystonic reactions occur in approximately 1
in 500 patients treated with the usual adult dosages of
30-40 mg/day of metoclopramide. These usually are seen
during the first 24-48 hours of treatment with
metoclopramide, occur more frequently in pediatric
patients and adult patients less than 30 years of age
and are even more frequent at the higher doses used in
prophylaxis of vomiting due to cancer chemotherapy.
These symptoms may include involuntary movements of
limbs and facial grimacing, torticollis, oculogyric
crisis, rhythmic protrusion of tongue, bulbar type of
speech, trismus, or dystonic reactions resembling
tetanus. Rarely, dystonic reactions may present as
stridor and dyspnea, possibly due to laryngospasm. If
these symptoms should occur, inject 50 mg
Benadryl® (diphenhydramine hydrochloride)
intramuscularly, and they usually will subside.
Cogentin® (benztropine mesylate), 1 to
2 mg intramuscularly, may also be used to reverse these
reactions.
Tardive Dyskinesia
(See Boxed Warnings)
Treatment with metoclopramide can cause tardive
dyskinesia (TD), a potentially irreversible and
disfiguring disorder characterized by involuntary
movements of the face, tongue, or extremities. The risk
of developing tardive dyskinesia increases with the
duration of treatment and the total cumulative dose. An
analysis of utilization patterns showed that about 20%
of patients who used metoclopramide took it for longer
than 12 weeks. Treatment with metoclopramide for longer
than the recommended 12 weeks should be avoided in all
but rare cases where therapeutic benefit is thought to
outweigh the risk of developing TD.
Although the risk of developing TD in the general
population may be increased among the elderly, women,
and diabetics, it is not possible to predict which
patients will develop metoclopramide-induced TD. Both
the risk of developing TD and the likelihood that TD
will become irreversible increase with duration of
treatment and total cumulative dose.
Metoclopramide should be discontinued in patients
who develop signs or symptoms of TD. There is no known
effective treatment for established cases of TD,
although in some patients, TD may remit, partially or
completely, within several weeks to months after
metoclopramide is withdrawn.
Metoclopramide itself may suppress, or partially
suppress, the signs of TD, thereby masking the
underlying disease process. The effect of this
symptomatic suppression upon the long-term course of TD
is unknown. Therefore, metoclopramide should not be used
for the symptomatic control of TD.
Parkinsonian-like Symptoms
Parkinsonian-like symptoms, including
bradykinesia, tremor, cogwheel rigidity, or mask-like
facies, have occurred more commonly within the first 6
months after beginning treatment with metoclopramide,
but occasionally after longer periods. These symptoms
generally subside within 2-3 months following
discontinuance of metoclopramide. Patients with
preexisting Parkinson’s disease should be given
metoclopramide cautiously, if at all, since such
patients may experience exacerbation of parkinsonian
symptoms when taking metoclopramide.
Depression
Mental depression has occurred in patients with and
without prior history of depression. Symptoms have ranged from
mild to severe and have included suicidal ideation and suicide.
Metoclopramide should be given to patients with a prior history
of depression only if the expected benefits outweigh the
potential risks.
PRECAUTIONS
General
In one study in hypertensive patients, intravenously
administered metoclopramide was shown to release catecholamines;
hence, caution should be exercised when metoclopramide is used
in patients with hypertension.
Intravenous injections of undiluted metoclopramide should
be made slowly allowing 1 to 2 minutes for 10 mg since a
transient but intense feeling of anxiety and restlessness,
followed by drowsiness, may occur with rapid
administration.
Because metoclopramide produces a transient increase in
plasma aldosterone, certain patients, especially those with
cirrhosis or congestive heart failure, may be at risk of
developing fluid retention and volume overload. If these side
effects occur at any time during metoclopramide therapy, the
drug should be discontinued.
Intravenous administration of REGLAN Injection diluted in
a parenteral solution should be made slowly over a period of not
less than 15 minutes.
Giving a promotility drug such as metoclopramide
theoretically could put increased pressure on suture lines
following a gut anastomosis or closure. This possibility should
be considered and weighed when deciding whether to use
metoclopramide or nasogastric suction in the prevention of
postoperative nausea and vomiting.
Information for Patients
A patient Medication Guide is available for REGLAN
Injection. The prescriber or health professional should instruct
patients, their families, and their caregivers to read the
Medication Guide and should assist them in understanding its
contents. Patients should be given the opportunity to discuss
the contents of the Medication Guide and to obtain answers to
any questions they may have. Refer to accompanying Medication
Guide.
Metoclopramide may impair the mental and/or physical
abilities required for the performance of hazardous tasks such
as operating machinery or driving a motor vehicle. The
ambulatory patient should be cautioned accordingly.
Drug Interactions
The effects of metoclopramide on gastrointestinal
motility are antagonized by anticholinergic drugs and narcotic
analgesics. Additive sedative effects can occur when
metoclopramide is given with alcohol, sedatives, hypnotics,
narcotics, or tranquilizers.
The finding that metoclopramide releases catecholamines
in patients with essential hypertension suggests that it should
be used cautiously, if at all, in patients receiving monoamine
oxidase inhibitors.
Absorption of drugs from the stomach may be diminished
(e.g., digoxin) by metoclopramide, whereas the rate and/or
extent of absorption of drugs from the small bowel may be
increased (e.g., acetaminophen, tetracycline, levodopa, ethanol,
cyclosporine).
Gastroparesis (gastric stasis) may be responsible for
poor diabetic control in some patients. Exogenously administered
insulin may begin to act before food has left the stomach and
lead to hypoglycemia. Because the action of metoclopramide will
influence the delivery of food to the intestines and thus the
rate of absorption, insulin dosage or timing of dosage may
require adjustment.
Carcinogenesis, Mutagenesis, Impairment of Fertility
A 77‑week study was conducted in rats with oral doses up
to about 40 times the maximum recommended human daily dose.
Metoclopramide elevates prolactin levels and the elevation
persists during chronic administration. Tissue culture
experiments indicate that approximately one-third of human
breast cancers are prolactin-dependent in vitro, a factor of
potential importance if the prescription of metoclopramide is
contemplated in a patient with previously detected breast
cancer. Although disturbances such as galactorrhea, amenorrhea,
gynecomastia, and impotence have been reported with
prolactin-elevating drugs, the clinical significance of elevated
serum prolactin levels is unknown for most patients. An increase
in mammary neoplasms has been found in rodents after chronic
administration of prolactin-stimulating neuroleptic drugs and
metoclopramide. Neither clinical studies nor epidemiologic
studies conducted to date, however, have shown an association
between chronic administration of these drugs and mammary
tumorigenesis; the available evidence is too limited to be
conclusive at this time.
An Ames mutagenicity test performed on metoclopramide was
negative.
Pregnancy Category B
Reproduction studies performed in rats, mice and rabbits
by the IM, IV, subcutaneous (SC), and oral routes at maximum
levels ranging from 12 to 250 times the human dose have
demonstrated no impairment of fertility or significant harm to
the fetus due to metoclopramide. There are, however, no adequate
and well-controlled studies in pregnant women. Because animal
reproduction studies are not always predictive of human
response, this drug should be used during pregnancy only if
clearly needed.
Nursing Mothers
Metoclopramide is excreted in human milk. Caution should
be exercised when metoclopramide is administered to a nursing
mother.
Pediatric Use
Safety and effectiveness in pediatric patients have not
been established except as stated to facilitate small bowel
intubation (see OVERDOSAGE and DOSAGE AND
ADMINISTRATION).
Care should be exercised in administering metoclopramide
to neonates since prolonged clearance may produce excessive
serum concentrations (see CLINICAL PHARMACOLOGY - Pharmacokinetics). In
addition, neonates have reduced levels of NADH-cytochrome
b5 reductase which, in combination with the
aforementioned pharmacokinetic factors, make neonates more
susceptible to methemoglobinemia (see OVERDOSAGE).
The safety profile of metoclopramide in adults cannot be
extrapolated to pediatric patients. Dystonias and other
extrapyramidal reactions associated with metoclopramide are more
common in the pediatric population than in adults. (See
WARNINGS and ADVERSE REACTIONS - Extrapyramidal
Reactions.)
Geriatric Use
Clinical studies of REGLAN Injection did not include
sufficient numbers of subjects aged 65 and over to determine
whether elderly subjects respond differently from younger
subjects.
The risk of developing parkinsonian-like side effects
increases with ascending dose. Geriatric patients should receive
the lowest dose of REGLAN Injection that is effective. If
parkinsonian-like symptoms develop in a geriatric patient
receiving REGLAN Injection, REGLAN Injection should generally be
discontinued before initiating any specific anti-parkinsonian
agents (see WARNINGS).
The elderly may be at greater risk for tardive dyskinesia
(see WARNINGS - Tardive Dyskinesia).
Sedation has been reported in REGLAN Injection users.
Sedation may cause confusion and manifest as over-sedation in
elderly (see CLINICAL
PHARMACOLOGY, PRECAUTIONS - Information for Patients and
ADVERSE REACTIONS - CNS Effects).
REGLAN Injection is known to be substantially excreted by
the kidney, and the risk of toxic reactions to this drug may be
greater in patients with impaired renal function (see DOSAGE AND ADMINISTRATION - Use in Patients With Renal or
Hepatic Impairment).
For these reasons, dose selection for an elderly patient
should be cautious, usually starting at the low end of the
dosing range, reflecting the greater frequency of decreased
renal function, concomitant disease, or other drug therapy in
the elderly (see Use
in Patients With Renal or Hepatic
Impairment).
Other Special Populations
Patients with NADH-cytochrome b5 reductase
deficiency are at an increased risk of developing
methemoglobinemia and/or sulfhemoglobinemia when metoclopramide
is administered. In patients with G6PD deficiency who experience
metoclopramide-induced methemoglobinemia, methylene blue
treatment is not recommended (see OVERDOSAGE).
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