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Metozolv

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Metozolv ODT

Metozolv ODT

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

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in some patients, TD may remit, partially or completely, within several weeks to months after metoclopramide is withdrawn.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.

Acute Dystonic Reactions, Drug-induced Parkinsonism, and Other Extrapyramidal Symptoms

Extrapyramidal symptoms (EPS), manifested primarily as acute dystonic reactions, occur in approximately 1 in 500 patients treated with the usual adult dosages of 30 to 40 mg/day of metoclopramide. These usually are seen during the first 24 to 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 higher doses. 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 occur, inject 50 mg diphenhydramine hydrochloride intramuscularly. Benztropine mesylate, 1 to 2 mg intramuscularly, may also be used to reverse these reactions.

Drug-induced Parkinsonism can occur during metoclopramide therapy, more commonly within the first 6 months after beginning treatment, but also after longer periods. Parkinsonian symptoms generally subside within 2 to 3 months following discontinuation of metoclopramide. Patients with a history of Parkinson's disease should be given metoclopramide cautiously, if at all, since such patients can experience exacerbation of Parkinsonian symptoms when taking metoclopramide.

Neuroleptic Malignant Syndrome

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) 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 immediate discontinuation of metoclopramide and other drugs not essential to concurrent therapy; intensive symptomatic treatment and medical monitoring; and, 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 has not been established [see ADVERSE REACTIONS].

Depression

Depression associated with metoclopramide use has occurred in patients with and without a history of depression. Symptoms ranged from mild to severe and included suicidal ideation and suicide. For those patients with a prior history of depression, metoclopramide should only be given if the expected benefits outweigh the potential risks.

Hypertension

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. There are also clinical reports of hypertensive crises in some patients with undiagnosed pheochromocytoma, thus any rapid rise in blood pressure associated with METOZOLV ODT use should result in immediate cessation of metoclopramide use in those patients [see CONTRAINDICATIONS].

Congestive Heart Failure and Ventricular Arrhythmia

Since 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. If these side effects occur at any time in any patients during metoclopramide therapy, the drug should be discontinued.

Withdrawal from Metoclopramide

Adverse reactions, especially those involving the nervous system, may occur after stopping the use of METOZOLV ODT. A small number of patients may experience withdrawal symptoms after stopping that could include dizziness, nervousness, and/or headaches.

Patient Counseling Information

  • Instruct patients to take METOZOLV ODT at least 30 minutes before eating and at bedtime.
  • A patient Medication Guide is available for METOZOLV ODT and printed at the end of the prescribing information. Instruct patients, families, and caregivers to read the Medication Guide and assist them in understanding its contents.
  • Inform patients or their caregivers of serious potential issues associated with metoclopramide use such as tardive dyskinesia, extrapyramidal symptoms, and neuroleptic malignant syndrome. Advise patients to inform their physician if symptoms associated with these disorders occur during or after treatment with METOZOLV ODT.
  • Inform patients that METOZOLV ODT may cause drowsiness, dizziness, or otherwise impair mental alertness or physical abilities required for the performance of hazardous tasks such as operating machinery or driving a motor vehicle. Sedation may be more pronounced in the elderly.
  • Inform patients that the most common adverse reactions in patients treated with METOZOLV ODT or other metoclopramide-containing products are headache, nausea, vomiting, tiredness, sleepiness, dizziness, and restlessness.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

A 77-week study was conducted in rats with oral doses up to 40 mg/kg/day (about 5 times the maximum recommended human dose on surface area basis). 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.

In a rat model for assessing the tumor promotion potential, a two-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 (UDS) assay with rat and human hepatocytes and the in vivo rat micronucleus assay.

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

Pregnancy

Teratogenic Effects: Pregnancy Category B

Reproduction studies have been performed in rats at oral doses about 6 times the maximum recommended human dose calculated on the basis of surface area, and in rabbits at oral doses about 12 times the maximum recommended human dose calculated on the basis of surface area, and have revealed no evidence of impaired fertility or 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.

Labor and Delivery

The use of metoclopramide in labor and delivery has not been studied.

Nursing Mothers

Metoclopramide is excreted in human milk. Caution should be exercised when metoclopramide is administered to a nursing mother. Because of the potential for serious adverse reactions from metoclopramide in nursing infants and because of the potential for tumorigenicity (including tumor promoting potential in rats), a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

The safety and effectiveness of METOZOLV ODT in pediatric patients have not been established.

The safety profile of METOZOLV ODT 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. 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.

Pediatric PK

The pharmacodynamics of metoclopramide following oral and intravenous administration in pediatric populations are highly variable and a concentration-effect relationship has not been established. Thus, there are insufficient data to conclude whether the pharmacokinetics of METOZOLV ODT in adults and the pediatric population are similar. Although there are insufficient data to support the efficacy of metoclopramide in pediatric patients with symptomatic gastroesophageal reflux disease (GERD) or cancer chemotherapy-related nausea and vomiting, the pharmacokinetics of metoclopramide have been studied in these patient populations and are summarized as follows.

In an open-label study, six pediatric patients (ranging in age from 3.5 weeks to 5.4 months) with GERD received metoclopramide 0.15 mg/kg oral solution every 6 hours for 10 doses. The mean peak plasma concentration of metoclopramide after the tenth dose was twice the level (56.8 mcg/L) compared to after the first dose (29 mcg/L) indicating drug accumulation with repeated dosing. However, the PK parameters after the tenth dose were comparable to those observed after the first dose for the mean time to reach peak concentrations (2.2 hr); half-life (4.1 hr); clearance (0.67 L/h/kg); and volume of distribution (4.4 L/kg). The youngest patient (3.5 weeks) showed a significantly longer half-life after the first dose (23.1 hr) compared to after the tenth dose (10.3 hr), suggesting the reduced clearance observed at birth may be a reflection of the immature hepatic and renal systems.

Geriatric Use

Clinical studies of metoclopramide 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 drug-induced Parkinsonism due to metoclopramide is dose-related. Geriatric patients should receive the lowest dose that is effective. If drug-induced Parkinsonism symptoms develop in a geriatric patient, METOZOLV ODT should be discontinued. The elderly may be at greater risk for tardive dyskinesia [see WARNINGS AND PRECAUTIONS].

Sedation is a potential adverse event associated with metoclopramide use in the elderly.

Metoclopramide 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. For these reasons, dose selection for an elderly patient should be cautious, starting at the low end of the dosing range, due to the greater frequency of decreased renal function, concomitant disease, or other drug therapy in the elderly, [see WARNINGS AND PRECAUTIONS].

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.

Since metoclopramide is excreted principally through the kidneys, therapy should be initiated at approximately one-half the recommended dose in those patients whose creatinine clearance is below 40 mL/min. Depending upon clinical efficacy and safety considerations, the dosage may be increased or decreased as appropriate. Metoclopramide has been safely used in patients with advanced liver disease whose renal function was normal.

Last reviewed on RxList: 10/17/2011
This monograph has been modified to include the generic and brand name in many instances.

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