Included as part of the PRECAUTIONS section.
Metoclopramide can cause tardive dyskinesia (TD), a syndrome of potentially irreversible and disfiguring involuntary movements of the face or tongue, and sometimes of the trunk and/or extremities. Movements may be choreoathetotic in appearance. The risk of developing TD and the likelihood that TD will become irreversible increases with duration of treatment and total cumulative dosage. 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 metoclopramide for longer than 12 weeks. GIMOTI is not recommended in geriatric patients as initial therapy [see DOSAGE AND ADMINISTRATION].
Discontinue GIMOTI immediately in patients who develop signs and symptoms of TD. Consider treatment for established cases of TD, although in some patients TD may remit, partially or completely, within several weeks to months after GIMOTI is withdrawn.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. GIMOTI is contraindicated in patients with a history of TD [see CONTRAINDICATIONS]. Avoid GIMOTI in patients receiving other drugs that are likely to 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 GIMOTI.
- Extrapyramidal symptoms (EPS), such as acute dystonic reactions, occurred in patients treated with oral metoclopramide dosages of 30 mg 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 (GIMOTI 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 GIMOTI in patients receiving other drugs that can cause EPS (e.g., antipsychotics).
- Parkinsonian 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 after discontinuation of metoclopramide. Avoid GIMOTI in patients with Parkinsonâ€™s disease and other patients being treated with antiparkinsonian drugs due to potential exacerbation of symptoms. Avoid treatment with metoclopramide (all dosage forms and routes of administration) for more than 12 weeks [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS].
- 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. Discontinue GIMOTI if these symptoms develop.
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 GIMOTI in patients receiving other drugs associated with NMS, including typical and atypical antipsychotics.
Clinical manifestations of NMS include hyperpyrexia, 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 conditions (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 GIMOTI 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 GIMOTI 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 GIMOTI use in patients with hypertension or in patients taking monoamine oxidase inhibitors [see DRUG INTERACTIONS].
There are also clinical reports of hypertensive crises in patients with undiagnosed pheochromocytoma. GIMOTI is contraindicated in patients with pheochromocytoma or other catecholamine-releasing paragangliomas [see CONTRAINDICATIONS]. Discontinue GIMOTI in any patient with a rapid rise in blood pressure.
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 GIMOTI if any of these adverse reactions occur.
As with other dopamine D2 receptor antagonists, metoclopramide elevates prolactin levels. Hyperprolactinemia may suppress hypothalamic gonadotropin-releasing hormone, 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 metoclopramide.
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 receptor 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 GIMOTI or the interacting drug, depending on the importance of the drug to the patient [see DRUG INTERACTIONS].
Risk Of Adverse Reactions With GIMOTI In Patients With Moderate Or Severe Renal And Hepatic Impairment, CYP2D6 Poor Metabolizers And Patients Taking Strong CYP2D6 Inhibitors
Patients with moderate or severe renal or hepatic impairment, patients who are CYP2D6 poor metabolizers, and patients concurrently using strong CYP2D6 inhibitors have increased exposure to metoclopramide from GIMOTI due to reduced metabolism or excretion which may lead to an increased risk of adverse reactions, including tardive dyskinesia. Use of GIMOTI is not recommended in these patient populations since the dose of GIMOTI cannot be adjusted to reduce exposure [see DRUG INTERACTIONS, Use In Specific Populations].
Patient Counseling Information
Advise the patient or caregiver to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).
Inform the patients or their caregivers that metoclopramide can cause serious adverse reactions. Instruct patients to discontinue GIMOTI and contact a healthcare provider immediately if the following serious reactions occur:
- Tardive dyskinesia and/or 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 the patient or their caregiver that metoclopramide 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].
Inform the 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 GIMOTI.
[see DOSAGE AND ADMINISTRATION]
Advise the patients or their caregiver to read the Instructions for Use on how to appropriately administer GIMOTI:
- Avoid treatment with metoclopramide (all dosage forms and routes of administration) for longer than 12 weeks because of the increased risk of developing TD with longer-term use [see WARNINGS AND PRECAUTIONS].
- One spray in one nostril administers the appropriate dose.
- Before administering the first dose from a bottle, prime the pump by pressing down on the finger flange and releasing 10 sprays in the air.
- Place the spray nozzle tip under one nostril and lean the head slightly forward so the tip of spray nozzle is aimed away from the septum and toward the back of the nose.
- Close the other nostril with the other index finger. Move spray pump upwards so the tip of the nozzle is in the nostril.
- To ensure a full dose, hold the bottle upright while pressing down firmly and completely on finger flange and release while inhaling slowly through the open nostril.
- Remove spray pump nozzle tip from nostril and exhale slowly through the mouth.
- Wipe the spray nozzle with a clean tissue.
Missed Or Incomplete Doses
- If uncertain that the spray entered the nose, do not repeat the dose. Take the next dose at the scheduled time.
- If a dose is missed, take the next dose of GIMOTI at the regularly scheduled time. Do not make up for the missed dose or double the next dose.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
A 77-week study was conducted in rats with oral metoclopramide doses up to 40 mg/kg/day (about 6 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 MRHD 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 in 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 rats.
Use In Specific Populations
Published studies, including retrospective cohort studies, national registry studies, and meta-analyses, do not report a consistent pattern or a consistently increased risk of adverse pregnancy-related outcomes with oral use of metoclopramide during pregnancy. However, available data from a case report of GIMOTI use in pregnancy is insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.
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 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, Use In Specific Populations].
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 was observed.
There are no data on the presence of metoclopramide in human milk following nasal administration; however, published data report the presence of metoclopramide in human milk in variable amounts following oral administration (see Data). Systemic exposure following nasal administration of GIMOTI 15 mg is expected to be similar to oral administration of metoclopramide 10 mg [see CLINICAL PHARMACOLOGY]. Breastfed infants exposed to metoclopramide have experienced gastrointestinal adverse reactions, including intestinal discomfort and increased intestinal gas formation (see Clinical Considerations). 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 motherâ€™s clinical need for GIMOTI and any potential adverse effects on the breastfed child from GIMOTI or from the underlying maternal condition.
Monitor breastfeeding neonates because metoclopramide may cause extrapyramidal signs (dystonias) and methemoglobinemia [see WARNINGS AND PRECAUTIONS, Use In Specific Populations].
In published clinical studies, the estimated amount of metoclopramide received by the breastfed infant was less than 10% of the maternal weight-adjusted oral 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.
Metoclopramide 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 GIMOTI in pediatric patients have not been established.
Dystonias and other extrapyramidal symptoms associated with metoclopramide are more common in pediatric patients than in adults [see INDICATIONS AND USAGE, WARNINGS AND PRECAUTIONS]. In addition, neonates have reduced levels of NADH-cytochrome b5 reductase, making them more susceptible to methemoglobinemia, a possible adverse reaction of metoclopramide use in neonates [see Use In Specific Populations].
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 WARNINGS AND PRECAUTIONS, Use In Specific Populations, CLINICAL PHARMACOLOGY]. Elderly patients are more likely to have decreased renal function and may be more sensitive to the adverse effects of metoclopramide, especially elderly women, and require a lower starting dosage. GIMOTI is not recommended in geriatric patients as initial therapy. Geriatric patients receiving an alternative metoclopramide product at a stable dosage of 10 mg four times daily can be switched to GIMOTI [see DOSAGE AND ADMINISTRATION].
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 [see CLINICAL PHARMACOLOGY]. GIMOTI is not recommended in patients with moderate and severe renal impairment (creatinine clearance less than 60 mL/minute), including those receiving hemodialysis and continuous ambulatory peritoneal dialysis [see WARNINGS AND PRECAUTIONS] Use the recommended dosage of GIMOTI in patients with mild renal impairment (creatinine clearance 60 mL/minute or greater) [see DOSAGE AND ADMINISTRATION].
Patients with severe hepatic impairment (Child-Pugh C) have reduced systemic metoclopramide clearance (by approximately 50%) compared to patients with normal hepatic function [see CLINICAL PHARMACOLOGY]. 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). GIMOTI is not recommended in patients with moderate or severe (Child-Pugh B or C) hepatic impairment [see WARNINGS AND PRECAUTIONS]. Use the recommended dosage of GIMOTI in patients with mild hepatic impairment (Child-Pugh A) [see DOSAGE AND ADMINISTRATION].
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 with 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 OVERDOSAGE].
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 metoclopramide [see CLINICAL PHARMACOLOGY]. GIMOTI is not recommended in patients who are CYP2D6 poor metabolizers [see WARNINGS AND PRECAUTIONS].