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`reglan® tablets (metoclopramide tablets, USP)
`Rx Only
`WARNING: TARDIVE DYSKINESIA
`Treatment with metoclopramide can cause tardive dyskinesia, a serious movement
`disorder that is often irreversible. The risk of developing tardive dyskinesia increases
`with duration of treatment and total cumulative dose.
`Metoclopramide therapy should be discontinued in patients who develop signs or
`symptoms of tardive dyskinesia. There is no known treatment for tardive dyskinesia. In
`some patients, symptoms may lessen or resolve after metoclopramide treatment is
`stopped.
`Treatment with metoclopramide for longer than 12 weeks should be avoided in all but
`rare cases where therapeutic benefit is thought to outweigh the risk of developing tardive
`dyskinesia.
`See WARNINGS
`DESCRIPTION
`For oral administration, reglan
`® tablets (metoclopramide tablets, USP) 10 mg are white, scored,
`capsule-shaped tablets engraved REGLAN on one side and SP 10 on the opposite side.
`Each tablet contains:
`Metoclopramide base .................................................. 10 mg
`(as the monohydrochloride monohydrate)
`Inactive Ingredients
`Magnesium Stearate, Mannitol, Microcrystalline Cellulose, Stearic Acid.
`reglan
`® tablets (metoclopramide tablets, USP) 5 mg are green, elliptical-shaped tablets
`engraved REGLAN 5 on one side and SP on the opposite side.
`Each tablet contains:
`Metoclopramide base .................................................... 5 mg
`(as the monohydrochloride monohydrate)
`Inactive Ingredients
`Corn starch, D&C Yellow 10 Aluminum Lake, FD&C Blue 1 Aluminum Lake, Lactose,
`Microcrystalline Cellulose, Silicon Dioxide, Stearic Acid.
`Metoclopramide hydrochloride is a white crystalline, odorless substance, freely soluble in water.
`Chemically, it is 4-amino-5- chloro-N-[2-(diethylamino)ethyl]-2-methoxy benzamide
`monohydrochloride monohydrate. Its molecular formula is C
`14H22CIN3O2•HCl•H2O. Its molecular
`weight is 354.3.
`REGLAN® - Package Insert Page 1 of 12
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`HELSINN EXHIBIT 2097
`Azurity Pharmaceuticals, Inc. v. Helsinn Healthcare S.A.
`IPR2025-00948
`Page 1 of 36
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`CLINICAL PHARMACOLOGY
`Metoclopramide stimulates motility of the upper gastrointestinal tract without stimulating gastric,
`biliary, or pancreatic secretions. Its mode of action is unclear. It seems to sensitize tissues to
`the action of acetylcholine. The effect of metoclopramide on motility is not dependent on intact
`vagal innervation, but it can be abolished by anticholinergic drugs.
`Metoclopramide increases the tone and amplitude of gastric (especially antral) contractions,
`relaxes the pyloric sphincter and the duodenal bulb, and increases peristalsis of the duodenum
`and jejunum resulting in accelerated gastric emptying and intestinal transit. It increases the
`resting tone of the lower esophageal sphincter. It has little, if any, effect on the motility of the
`colon or gallbladder.
`In patients with gastroesophageal reflux and low LESP (lower esophageal sphincter pressure),
`single oral doses of metoclopramide produce dose-related increases in LESP. Effects begin at
`about 5 mg and increase through 20 mg (the largest dose tested). The increase in LESP from a
`5 mg dose lasts about 45 minutes and that of 20 mg lasts between 2 and 3 hours. Increased
`rate of stomach emptying has been observed with single oral doses of 10 mg.
`The antiemetic properties of metoclopramide appear to be a result of its antagonism of central
`and peripheral dopamine receptors. Dopamine produces nausea and vomiting by stimulation of
`the medullary chemoreceptor trigger zone (CTZ), and metoclopramide blocks stimulation of the
`CTZ by agents like l-dopa or apomorphine which are known to increase dopamine levels or to
`possess dopamine-like effects. Metoclopramide also abolishes the slowing of gastric emptying
`caused by apomorphine.
`Like the phenothiazines and related drugs, which are also dopamine antagonists,
`metoclopramide produces sedation and may produce extrapyramidal reactions, although these
`are comparatively rare (see WARNINGS). Metoclopramide inhibits the central and peripheral
`effects of apomorphine, induces release of prolactin and causes a transient increase in
`circulating aldosterone levels, which may be associated with transient fluid retention.
`The onset of pharmacological action of metoclopramide is 1 to 3 minutes following an
`intravenous dose, 10 to 15 minutes following intramuscular administration, and 30 to 60 minutes
`following an oral dose; pharmacological effects persist for 1 to 2 hours.
`Pharmacokinetics
`Metoclopramide is rapidly and well absorbed. Relative to an intravenous dose of 20 mg, the
`absolute oral bioavailability of metoclopramide is 80% ± 15.5% as demonstrated in a crossover
`study of 18 subjects. Peak plasma concentrations occur at about 1 to 2 hr after a single oral
`dose. Similar time to peak is observed after individual doses at steady state.
`In a single dose study of 12 subjects, the area under the drug concentration-time curve
`increases linearly with doses from 20 to 100 mg. Peak concentrations increase linearly with
`dose; time to peak concentrations remains the same; whole body clearance is unchanged; and
`the elimination rate remains the same. The average elimination half-life in individuals with
`normal renal function is 5 to 6 hr. Linear kinetic processes adequately describe the absorption
`and elimination of metoclopramide.
`REGLAN® - Package Insert Page 2 of 12
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`Page 2 of 36
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`Approximately 85% of the radioactivity of an orally administered dose appears in the urine within
`72 hr. Of the 85% eliminated in the urine, about half is present as free or conjugated
`metoclopramide.
`The drug is not extensively bound to plasma proteins (about 30%). The whole body volume of
`distribution is high (about 3.5 L/kg) which suggests extensive distribution of drug to the tissues.
`Renal impairment affects the clearance of metoclopramide. In a study with patients with varying
`degrees of renal impairment, a reduction in creatinine clearance was correlated with a reduction
`in plasma clearance, renal clearance, non-renal clearance, and increase in elimination half-life.
`The kinetics of metoclopramide in the presence of renal impairment remained linear however.
`The reduction in clearance as a result of renal impairment suggests that adjustment downward
`of maintenance dosage should be done to avoid drug accumulation.
`Adult Pharmacokinetic Data
`Parameter Value
`Vd (L/kg)
`Plasma Protein Binding
`t
`1/2 (hr)
`Oral Bioavailability
`~ 3.5
`~ 30%
`5 to 6
`80%±15.5%
`In pediatric patients, the pharmacodynamics of metoclopramide following oral and intravenous
`administration are highly variable and a concentration-effect relationship has not been
`established.
`There are insufficient reliable data to conclude whether the pharmacokinetics of metoclopramide
`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
`(GER) or cancer chemotherapy-related nausea and vomiting, its pharmacokinetics have been
`studied in these patient populations.
`In an open-label study, six pediatric patients (age range, 3.5 weeks to 5.4 months) with GER
`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 2-fold (56.8 μg/L) higher
`compared to that observed after the first dose (29 μg/L) indicating drug accumulation with
`repeated dosing. After the tenth dose, 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) of metoclopramide
`were similar to those observed after the first dose. In the youngest patient (age, 3.5 weeks),
`metoclopramide half-life after the first and the tenth dose (23.1 and 10.3 hr, respectively) was
`significantly longer compared to other infants due to reduced clearance. This may be attributed
`to immature hepatic and renal systems at birth.
`Single intravenous doses of metoclopramide 0.22 to 0.46 mg/kg (mean, 0.35 mg/kg) were
`administered over 5 minutes to 9 pediatric cancer patients receiving chemotherapy (mean age,
`11.7 years; range, 7 to 14 yr) for prophylaxis of cytotoxic-induced vomiting. The metoclopramide
`plasma concentrations extrapolated to time zero ranged from 65 to 395 μg/L (mean, 152 μg/L).
`The mean elimination half-life, clearance, and volume of distribution of metoclopramide were 4.4
`hr (range, 1.7 to 8.3 hr), 0.56 L/h/kg (range, 0.12 to 1.20 L/h/kg), and 3.0 L/kg (range, 1.0 to 4.8
`L/kg), respectively.
`In another study, nine pediatric cancer patients (age range, 1 to 9 yr) received 4 to 5
`intravenous infusions (over 30 minutes) of metoclopramide at a dose of 2 mg/kg to control
`emesis. After the last dose, the peak serum concentrations of metoclopramide ranged from
`REGLAN® - Package Insert Page 3 of 12
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`Page 3 of 36
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`1060 to 5680 μg/L. The mean elimination half-life, clearance, and volume of distribution of
`metoclopramide were 4.5 hr (range, 2.0 to 12.5 hr), 0.37 L/h/kg (range, 0.10 to 1.24 L/h/kg), and
`1.93 L/kg (range, 0.95 to 5.50 L/kg), respectively.
`INDICATIONS AND USAGE
`The use of reglan® tablets is recommended for adults only. Therapy should not exceed 12
`weeks in duration.
`Symptomatic Gastroesophageal Reflux
`reglan® tablets are indicated as short-term (4 to 12 weeks) therapy for adults with symptomatic,
`documented gastroesophageal reflux who fail to respond to conventional therapy.
`The principal effect of metoclopramide is on symptoms of postprandial and daytime heartburn
`with less observed effect on nocturnal symptoms. If symptoms are confined to particular
`situations, such as following the evening meal, use of metoclopramide as single doses prior to
`the provocative situation should be considered, rather than using the drug throughout the day.
`Healing of esophageal ulcers and erosions has been endoscopically demonstrated at the end of
`a 12-week trial using doses of 15 mg q.i.d. As there is no documented correlation between
`symptoms and healing of esophageal lesions, patients with documented lesions should be
`monitored endoscopically.
`Diabetic Gastroparesis (Diabetic Gastric Stasis)
`reglan
`® tablets (metoclopramide tablets, USP) is indicated for the relief of symptoms associated
`with acute and recurrent diabetic gastric stasis. The usual manifestations of delayed gastric
`emptying (e.g., nausea, vomiting, heartburn, persistent fullness after meals, and anorexia)
`appear to respond to reglan
`® within different time intervals. Significant relief of nausea occurs
`early and continues to improve over a three-week period. Relief of vomiting and anorexia may
`precede the relief of abdominal fullness by one week or more.
`CONTRAINDICATIONS
`Metoclopramide should not be used whenever stimulation of gastrointestinal motility might be
`dangerous, e.g., in the presence of gastrointestinal hemorrhage, mechanical obstruction, or
`perforation.
`Metoclopramide is contraindicated in patients with pheochromocytoma because the drug may
`cause a hypertensive crisis, probably due to release of catecholamines from the tumor. Such
`hypertensive crises may be controlled by phentolamine.
`Metoclopramide is contraindicated in patients with known sensitivity or intolerance to the drug.
`Metoclopramide should not be used in epileptics or patients receiving other drugs which are
`likely to cause extrapyramidal reactions, since the frequency and severity of seizures or
`extrapyramidal reactions may be increased.
`WARNINGS
`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.
`REGLAN® - Package Insert Page 4 of 12
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`Page 4 of 36
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`Extrapyramidal symptoms, 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 should occur, inject 50 mg diphenhydramine hydrochloride intramuscularly,
`and they usually will subside. Benztropine mesylate, 1 to 2 mg intramuscularly, may also be
`used to reverse these reactions.
`Parkinsonian-like symptoms 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 to 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.
`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.
`Although the risk of TD with metoclopramide has not been extensively studied, one published
`study reported a TD prevalence of 20% among patients treated for at least 12 weeks.
`Treatment with metoclopramide for longer than 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.
`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).
`REGLAN® - Package Insert Page 5 of 12
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`Page 5 of 36
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`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).
`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.
`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.
`Adverse reactions, especially those involving the nervous system, may occur after stopping the
`use of reglan
`®. A small number of patients may experience a withdrawal period after stopping
`reglan® that could include dizziness, nervousness, and/or headaches.
`Information for Patients
`The use of reglan® is recommended for adults only. 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.
`For additional information, patients should be instructed to see the Medication Guide for
`reglan® tablets.
`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).
`REGLAN® - Package Insert Page 6 of 12
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`Page 6 of 36
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`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 I.V., I.M., S.C., 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 (see
`OVERDOSAGE).
`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 b
`5 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
`REGLAN® - Package Insert Page 7 of 12
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`Page 7 of 36
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`are more common in the pediatric population than in adults. (See WARNINGS and
`ADVERSE REACTIONS - Extrapyramidal Reactions.)
`Geriatric Use
`Clinical studies of reglan® 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® that is effective. If
`parkinsonian-like symptoms develop in a geriatric patient receiving reglan®, reglan®
`should generally be discontinued before initiating any specific anti-parkinsonian agents
`(see WARNINGS and DOSAGE AND ADMINISTRATION – For the Relief of
`Symptomatic Gastroesophageal Reflux).
`The elderly may be at greater risk for tardive dyskinesia (see WARNINGS – Tardive
`Dyskinesia).
`Sedation has been reported in reglan® users. Sedation may cause confusion and
`manifest as over-sedation in the elderly (see CLINICAL PHARMACOLOGY,
`PRECAUTIONS – Information for Patients and ADVERSE REACTIONS – CNS
`Effects).
`reglan® 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
`DOSAGE AND ADMINISTRATION – For the Relief of Symptomatic
`Gastroesophageal Reflux and USE IN PATIENTS WITH RENAL OR HEPATIC
`IMPAIRMENT).
`Other Special Populations
`Patients with NADH-cytochrome b
`5 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).
`ADVERSE REACTIONS
`In general, the incidence of adverse reactions correlates with the dose and duration of
`metoclopramide administration. The following reactions have been reported, although in
`most instances, data do not permit an estimate of frequency:
`CNS Effects
`Restlessness, drowsiness, fatigue, and lassitude occur in approximately 10% of patients
`receiving the most commonly prescribed dosage of 10 mg q.i.d. (see PRECAUTIONS).
`Insomnia, headache, confusion, dizziness, or mental depression with suicidal ideation
`REGLAN® - Package Insert Page 8 of 12
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`Page 8 of 36
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`(see WARNINGS) occur less frequently. The incidence of drowsiness is greater at
`higher doses. There are isolated reports of convulsive seizures without clearcut
`relationship to metoclopramide. Rarely, hallucinations have been reported.
`Extrapyramidal Reactions (EPS)
`Acute dystonic reactions, the most common type of EPS associated with
`metoclopramide, occur in approximately 0.2% of patients (1 in 500) treated with 30 to 40
`mg of metoclopramide per day. Symptoms include involuntary movements of limbs,
`facial grimacing, torticollis, oculogyric crisis, rhythmic protrusion of tongue, bulbar type
`of speech, trismus, opisthotonus (tetanus-like reactions), and, rarely, stridor and
`dyspnea possibly due to laryngospasm; ordinarily these symptoms are readily reversed
`by diphenhydramine (see WARNINGS).
`Parkinsonian-like symptoms may include bradykinesia, tremor, cogwheel rigidity, mask­
`like facies (see WARNINGS).
`Tardive dyskinesia most frequently is characterized by involuntary movements of the
`tongue, face, mouth, or jaw, and sometimes by involuntary movements of the trunk
`and/or extremities; movements may be choreoathetotic in appearance (see
`WARNINGS).
`Motor restlessness (akathisia) may consist of feelings of anxiety, agitation, jitteriness,
`and insomnia, as well as inability to sit still, pacing, foot tapping. These symptoms may
`disappear spontaneously or respond to a reduction in dosage.
`Neuroleptic Malignant Syndrome
`Rare occurrences of neuroleptic malignant syndrome (NMS) have been reported. This
`potentially fatal syndrome is comprised of the symptom complex of hyperthermia,
`altered consciousness, muscular rigidity, and autonomic dysfunction (see WARNINGS).
`Endocrine Disturbances
`Galactorrhea, amenorrhea, gynecomastia, impotence secondary to hyperprolactinemia
`(see PRECAUTIONS). Fluid retention secondary to transient elevation of aldosterone
`(see CLINICAL PHARMACOLOGY).
`Cardiovascular
`Hypotension, hypertension, supraventricular tachycardia, bradycardia, fluid retention,
`acute congestive heart failure and possible AV block (see CONTRAINDICATIONS and
`PRECAUTIONS).
`Gastrointestinal
`Nausea and bowel disturbances, primarily diarrhea.
`Hepatic
`Rarely, cases of hepatotoxicity, characterized by such findings as jaundice and altered
`liver function tests, when metoclopramide was administered with other drugs with
`known hepatotoxic potential.
`Renal
`Urinary frequency and incontinence.
`Hematologic
`A few cases of neutropenia, leukopenia, or agranulocytosis, generally without clearcut
`REGLAN® - Package Insert Page 9 of 12
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`Page 9 of 36
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`relationship to metoclopramide. Methemoglobinemia, in adults and especially with
`overdosage in neonates (see OVERDOSAGE). Sulfhemoglobinemia in adults.
`Allergic Reactions
`A few cases of rash, urticaria, or bronchospasm, especially in patients with a history of
`asthma. Rarely, angioneurotic edema, including glossal or laryngeal edema.
`Miscellaneous
`Visual disturbances. Porphyria.
`OVERDOSAGE
`Symptoms of overdosage may include drowsiness, disorientation and extrapyramidal
`reactions. Anticholinergic or antiparkinson drugs or antihistamines with anticholinergic
`properties may be helpful in controlling the extrapyramidal reactions. Symptoms are
`self-limiting and usually disappear within 24 hours.
`Hemodialysis removes relatively little metoclopramide, probably because of the small
`amount of the drug in blood relative to tissues. Similarly, continuous ambulatory
`peritoneal dialysis does not remove significant amounts of drug. It is unlikely that
`dosage would need to be adjusted to compensate for losses through dialysis. Dialysis is
`not likely to be an effective method of drug removal in overdose situations.
`Unintentional overdose due to misadministration has been reported in infants and
`children with the use of metoclopramide oral solution. While there was no consistent
`pattern to the reports associated with these overdoses, events included seizures,
`extrapyramidal reactions, and lethargy.
`Methemoglobinemia has occurred in premature and full-term neonates who were given
`overdoses of metoclopramide (1 to 4 mg/kg/day orally, intramuscularly or intravenously
`for 1 to 3 or more days). Methemoglobinemia can be reversed by the intravenous
`administration of methylene blue. However, methylene blue may cause hemolytic
`anemia in patients with G6PD deficiency, which may be fatal (see PRECAUTIONS –
`Other Special Populations).
`DOSAGE AND ADMINISTRATION
`Therapy with reglan
`® tablets should not exceed 12 weeks in duration.
`For the Relief of Symptomatic Gastroesophageal Reflux
`Administer from 10 mg to 15 mg reglan® (metoclopramide hydrochloride, USP) orally up
`to q.i.d. 30 minutes before each meal and at bedtime, depending upon symptoms being
`treated and clinical response (see CLINICAL PHARMACOLOGY and INDICATIONS
`AND USAGE). If symptoms occur only intermittently or at specific times of the day, use
`of metoclopramide in single doses up to 20 mg prior to the provoking situation may be
`preferred rather than continuous treatment. Occasionally, patients (such as elderly
`patients) who are more sensitive to the therapeutic or adverse effects of
`metoclopramide will require only 5 mg per dose.
`REGLAN® - Package Insert Page 10 of 12
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`Page 10 of 36
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`Experience with esophageal erosions and ulcerations is limited, but healing has thus far
`been documented in one controlled trial using q.i.d. therapy at 15 mg/dose, and this
`regimen should be used when lesions are present, so long as it is tolerated (see
`ADVERSE REACTIONS). Because of the poor correlation between symptoms and
`endoscopic appearance of the esophagus, therapy directed at esophageal lesions is
`best guided by endoscopic evaluation.
`Therapy longer than 12 weeks has not been evaluated and cannot be recommended.
`For the Relief of Symptoms Associated with Diabetic Gastroparesis (Diabetic
`Gastric Stasis)
`Administer 10 mg of metoclopramide 30 minutes before each meal and at bedtime for
`two to eight weeks, depending upon response and the likelihood of continued well-being
`upon drug discontinuation.
`The initial route of administration should be determined by the severity of the presenting
`symptoms. If only the earliest manifestations of diabetic gastric stasis are present, oral
`administration of reglan® may be initiated. However, if severe symptoms are present,
`therapy should begin with metoclopramide injection (consult labeling of the injection
`prior to initiating parenteral administration).
`Administration of metoclopramide injection up to 10 days may be required before
`symptoms subside, at which time oral administration may be instituted. Since diabetic
`gastric stasis is frequently recurrent, reglan
`® therapy should be reinstituted at the
`earliest manifestation.
`USE IN PATIENTS WITH RENAL OR HEPATIC IMPAIRMENT
`Since metoclopramide is excreted principally through the kidneys, in those patients
`whose creatinine clearance is below 40 mL/min, therapy shoul