Included as part of the "PRECAUTIONS" Section
Metoclopramide can cause tardive dyskinesia (TD), a potentially irreversible and disfiguring disorder characterized by
involuntary movements of the face or tongue, and sometimes of the trunk and/or extremities. Movements may be
choreoathetoic in appearance. The risk of developing TD and the likelihood that TD will become irreversible increases
with the duration of treatment and total cumulative dosage. 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.
Additionally, the risk of developing TD is increased among the elderly, especially elderly women [see Use In Specific Populations], and in patients with diabetes mellitus. Due to the risk of developing TD, avoid treatment with
METOZOLV ODT for longer than 12 weeks and reduce the dosage in elderly patients [see DOSAGE AND ADMINISTRATION].
Discontinue METOZOLV ODT immediately in patients who develop signs and 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several weeks to months after METOZOLV ODT is withdrawn.
METOZOLV ODT 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. METOZOLV ODT is
contraindicated in patients with a history of TD [see CONTRAINDICATIONS]. Avoid METOZOLV ODT in patients
receiving other drugs that can cause TD (e.g., antipsychotics).
Other Extrapyramidal Symptoms
In addition to TD, metoclopramide may cause other extrapyramidal symptoms (EPS), parkinsonian symptoms, and motor
restlessness. Advise patients to seek immediate medical attention if such symptoms occur and to discontinue
- Extrapyramidal symptoms (EPS), such as acute dystonic reactions, occurred in patients treated with
metoclopramide dosages of 30 to 40 mg daily. Such reactions occurred more frequently in adults less than 30
years of age and at higher than recommended dosages. EPS occurred more frequently in pediatric patients
compared to adults (METOZOLV ODT is not approved for use in pediatric patients). Symptoms can occur in the
first 24 to 48 hours after starting metoclopramide. Symptoms included 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 were present as stridor and dyspnea, possibly due to
laryngospasm. Diphenhydramine hydrochloride or benztropine mesylate may be used to treat these adverse
reactions. Avoid METOZOLV ODT in patients receiving other drugs that can cause EPS (e.g., antipsychotics).
- Parkinsonism symptoms (bradykinesia, tremor, cogwheel rigidity, mask-like facies) have occurred after starting
metoclopramide, more commonly within the first 6 months, but also after longer periods. Symptoms generally
have subsided within 2 to 3 months following discontinuation of metoclopramide. Avoid METOZOLV ODT in
patients with Parkinson's disease and other patients being treated with antiparkinsonian drugs due to potential
exacerbation of symptoms. Avoid treatment with METOZOLV ODT for more than 12 weeks [see DOSAGE AND ADMINISTRATION, Tardive Dyskinesia].
- Motor restlessness (akathisia) has developed and consisted of feelings of anxiety, agitation, jitteriness, and
insomnia, as well as inability to sit still, pacing, and foot tapping. If symptoms resolve, consider restarting at a
Neuroleptic Malignant Syndrome
Metoclopramide may cause a potentially fatal symptom complex called Neuroleptic Malignant Syndrome (NMS). NMS
has been reported in association with metoclopramide overdosage and concomitant treatment with another drug associated
with NMS. Avoid METOZOLV ODT in patients receiving other drugs associated with NMS, including typical and
Clinical manifestations of NMS include hyperthermia, muscle rigidity, altered mental status, and manifestations of
autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac arrhythmias). Additional
signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. Patients
with such symptoms should be evaluated immediately.
In the diagnostic evaluation, consider the presence of other serious medical illness (e.g., pneumonia, systemic infection)
and untreated or inadequately treated extrapyramidal signs and symptoms. Other important considerations in the
differential diagnosis include central anticholinergic toxicity, heat stroke, malignant hyperthermia, drug fever, serotonin
syndrome and primary central nervous system pathology.
Management of NMS includes:
- Immediate discontinuation of METOZOLV ODT and other drugs not essential to concurrent therapy [see DRUG INTERACTIONS].
- Intensive symptomatic treatment and medical monitoring.
- Treatment of any concomitant serious medical problems for which specific treatments are available.
Depression has occurred in metoclopramide-treated patients with and without a history of depression. Symptoms have
included suicidal ideation and suicide. Avoid METOZOLV ODT use in patients with a history of depression.
Metoclopramide may elevate blood pressure. In one study in hypertensive patients, intravenously administered
metoclopramide was shown to release catecholamines; hence, avoid use in patients with hypertension or in patients taking
monoamine oxidase inhibitors [see DRUG INTERACTIONS].
There are also clinical reports of hypertensive crises in some patients with undiagnosed pheochromocytoma.
METOZOLV ODT is contraindicated in patients with pheochromocytoma or other catecholamine-releasing
paragangliomas [see CONTRAINDICATIONS]. Discontinue METOZOLV ODT in any patient with a rapid rise in blood
Because metoclopramide produces a transient increase in plasma aldosterone, patients with cirrhosis or congestive heart
failure may be at risk of developing fluid retention and volume overload. Discontinue METOZOLV ODT if any of these
adverse reactions occur.
As with other dopamine D2 antagonists, metoclopramide elevates prolactin levels.
Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion. This, in
turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients.
Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported with prolactin-elevating drugs, including
Hyperprolactinemia may potentially stimulate prolactin-dependent breast cancer. However, some clinical studies and
epidemiology studies have not shown an association between administration of dopamine D2 antagonists and
tumorigenesis in humans [see Nonclinical Toxicology].
Effects On The Ability To Drive And Operate Machinery
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. Concomitant use of central nervous system (CNS) depressants or drugs
associated with EPS may increase this effect (e.g., alcohol, sedatives, hypnotics, opiates, and anxiolytics). Avoid
METOZOLV ODT or the interacting drug, depending on the importance of the drug to the patient [see DRUG INTERACTIONS].
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Inform patients or their caregivers that METOZOLV ODT can cause serious adverse reactions. Instruct patients to
discontinue METOZOLV ODT and contact a healthcare provider immediately if the following serious reactions
- Tardive dyskinesia and other extrapyramidal reactions [see WARNINGS AND PRECAUTIONS]
- Neuroleptic malignant syndrome [see WARNINGS AND PRECAUTIONS]
- Depression and/or possible suicidal ideation [see WARNINGS AND PRECAUTIONS]
Inform patients or their caregivers that concomitant treatment with numerous other medications can precipitate or
worsen serious adverse reactions such as tardive dyskinesia or other extrapyramidal reactions, neuroleptic malignant
syndrome, and CNS depression [see DRUG INTERACTIONS]. Explain that the prescriber of any other medication
must be made aware that the patient is taking METOZOLV ODT.
Inform patients or their caregivers that METOZOLV ODT can cause drowsiness or dizziness, or otherwise impair the
mental and/or physical abilities required for the performance of hazardous tasks such as operating machinery or
driving a motor vehicle [see WARNINGS AND PRECAUTIONS].
Instruct patients to:
- Take on an empty stomach at least 30 minutes before eating. Do not repeat dose if inadvertently taken with food.
- Remove each dose from the packaging just prior to taking. Handle the tablet with dry hands and place on the
tongue. If the tablet should break or crumble while handling, discard and remove a new tablet.
- Place the tablet on the tongue and allow it to disintegrate (takes approximately one minute) and swallow the
granules without water [see DOSAGE AND ADMINISTRATION].
Carcinogenesis, Mutagenesis, Impairment Of Fertility
A 77-week study was conducted in rats with oral metoclopramide doses up to 40 mg/kg/day (about six times the
maximum recommended human dose on body surface area basis). Metoclopramide elevated prolactin levels and the
elevation persisted during chronic administration. An increase in mammary neoplasms was found in rodents after chronic
administration of metoclopramide [see WARNINGS AND PRECAUTIONS]. In a rat model for assessing the tumor promotion
potential, a 2-week oral treatment with metoclopramide at a dose of 260 mg/kg/day (about 35 times the maximum
recommended human dose based on body surface area) enhanced the tumorigenic effect of N-nitrosodiethylamine.
Metoclopramide was positive in the in vitro Chinese hamster lung cell / HGPRT forward mutation assay for mutagenic
effects and the in vitro human lymphocyte chromosome aberration assay for clastogenic effects. It was negative in the in
vitro Ames mutation assay, the in vitro unscheduled DNA synthesis assay with rat and human hepatocytes and the in vivo rat micronucleus assay.
Impairment Of Fertility
Metoclopramide at intramuscular doses up to 20 mg/kg/day (about 3 times the maximum recommended human dose
based on body surface area) was found to have no effect on fertility and reproductive performance of male and female
Use In Specific Populations
Published studies, including retrospective cohort studies, national registry studies, and meta-analyses, do not report an
increased risk of adverse pregnancy-related outcomes with use of metoclopramide during pregnancy.
There are potential risks to the neonate following exposure in utero to metoclopramide during delivery (see Clinical
Considerations). In animal reproduction studies, no adverse developmental effects were observed with oral administration
of metoclopramide to pregnant rats and rabbits at exposures about 6 and 12 times the maximum recommended human
dose (MRHD) (see Data).
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All
pregnancies have a background risk of birth defects, loss or other adverse outcomes. In the U.S. general population, the
estimated background risk of major birth defects and miscarriage in the clinically recognized pregnancies is 2 to 4% and
15 to 20%, respectively.
Fetal/Neonatal Adverse Reactions
Metoclopramide crosses the placental barrier and may cause extrapyramidal signs and methemoglobinemia in neonates
with maternal administration during delivery. Monitor neonates for extrapyramidal signs [see WARNINGS AND PRECAUTIONS , Pediatric Use].
Reproduction studies have been performed following administration of oral metoclopramide during organogenesis in
pregnant rats at about 6 times the MRHD calculated on body surface area and in pregnant rabbits at about 12 times the
MRHD calculated on body surface area. No evidence of adverse developmental effects due to metoclopramide were
Limited published data report the presence of metoclopramide in human milk in variable amounts. Breastfed infants
exposed to metoclopramide have experienced gastrointestinal adverse reactions, including intestinal discomfort and
increased intestinal gas formation (see Data). Metoclopramide elevates prolactin levels [see WARNINGS AND PRECAUTIONS]; however, the published data are not adequate to support drug effects on milk production. The developmental and
health benefits of breastfeeding should be considered along with the mother’s clinical need for METOZOLV ODT and any
potential adverse effects on the breastfed child from METOZOLV ODT or from the underlying maternal condition.
Monitor breastfeeding neonates because metoclopramide may cause extrapyramidal signs (dystonias) and
methemoglobinemia [see WARNINGS AND PRECAUTIONS , Pediatric Use].
In published clinical studies, the estimated amount of metoclopramide received by the breastfed infant was less than 10%
of the maternal weight-adjusted dose. In one study, the estimated daily amount of metoclopramide received by infants
from breast milk ranged from 6 to 24 mcg/kg/day in early puerperium (3 to 9 days postpartum) and from 1 to 13
mcg/kg/day at 8 to 12 weeks postpartum.
METOZOLV ODT is not recommended for use in pediatric patients due to the risk of tardive dyskinesia (TD) and other
extrapyramidal symptoms as well as the risk of methemoglobinemia in neonates. The safety and effectiveness of
METOZOLV ODT in pediatric patients have not been established.
Dystonias and other extrapyramidal reactions associated with metoclopramide are more common in the pediatric patients
than in adults [see WARNINGS AND PRECAUTIONS]. In addition, neonates have reduced levels of NADH-cytochrome
b5 reductase, making them more susceptible to methemoglobinemia, a possible side effect of metoclopramide use in
neonates [see NADH-Cytochrome b5 Reductase Deficiency].
Metoclopramide is known to be substantially excreted by the kidney, and the risk of adverse reactions, including tardive
dyskinesia (TD), may be greater in patients with impaired renal function [see Use In Specific Populations , CLINICAL PHARMACOLOGY]. Elderly patients are more likely to have decreased renal function and may be more sensitive to the
therapeutic or adverse effects of metoclopramide; therefore, consider a reduced dosage of METOZOLOV ODT in elderly
patients [see DOSAGE AND ADMINISTRATION , WARNINGS AND PRECAUTIONS].
The clearance of metoclopramide is decreased and the systemic exposure is increased in patients with moderate to severe
renal impairment compared to patients with normal renal function, which may increase the risk of adverse reactions.
Reduce the METOZOLV ODT dosage in patients with moderate and severe renal impairment (creatinine clearance less
than or equal to 60 mL/minute), including those receiving hemodialysis and continuous ambulatory peritoneal dialysis
[see DOSAGE AND ADMINISTRATION , CLINICAL PHARMACOLOGY].
Patients with severe hepatic impairment (Child-Pugh C) have reduced systemic metoclopramide clearance (by
approximately 50%) compared to patients with normal hepatic function. The resulting increase in metoclopramide blood
concentrations increases the risk of adverse reactions. There are no pharmacokinetic data in patients with moderate
hepatic impairment (Child-Pugh B). Reduce METOZOLV ODT dosage in patients with moderate or severe (Child-Pugh
B or C) hepatic impairment [see DOSAGE AND ADMINISTRATION]. There is no dosage adjustment required for
patients with mild hepatic impairment (Child-Pugh A).
In addition, metoclopramide, by producing a transient increase in plasma aldosterone, may increase the risk of fluid
retention in patients with hepatic impairment [see WARNINGS AND PRECAUTIONS].
Monitor patients with hepatic impairment for the occurrence of fluid retention and volume overload.
NADH-Cytochrome b5 Reductase Deficiency
Metoclopramide-treated patients with NADH-cytochrome b5 reductase deficiency are at an increased risk of developing
methemoglobinemia and/or sulfhemoglobinemia. For patients with glucose-6-phosphate dehydrogenase (G6PD)
deficiency the metoclopramide-induced methemoglobinemia, methylene blue treatment is not recommended. Methylene
blue may cause hemolytic anemia in patients with G6PD deficiency, which may be fatal [see OVERDOSE].
CYP2D6 Poor Metabolizers
Metoclopramide is a substrate of CYP2D6. The elimination of metoclopramide may be slowed in patients who are
CYP2D6 poor metabolizers (compared to patients who are CYP2D6 intermediate, extensive, or ultra-rapid metabolizers);
possibly increasing the risk of dystonic and other adverse reactions to METOZOLV ODT [see CLINICAL PHARMACOLOGY]. Reduce the METOZOLV ODT dosage in patients who are poor CYP2D6 metabolizers [see DOSAGE AND ADMINISTRATION].