Reglan ODT

Patient Information

REGLAN^®
(REG-lan)
(metoclopramide) tablets, oral use

Read this Medication Guide before you start taking REGLAN and each time you get a refill. There may be new information. If you take another product that contains metoclopramide (such as REGLAN injection, metoclopramide orally disintegrating tablets, or metoclopramide oral solution), you should read the Medication Guide that comes with that product. Some of the information may be different. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment.

What is the most important information I should know about REGLAN?

REGLAN can cause serious side effects, including:

Tardive dyskinesia (abnormal muscle movements). These movements happen mostly in the face muscles. You cannot control these movements. They may not go away even after stopping REGLAN. There is no treatment for tardive dyskinesia, but symptoms may lessen or go away over time after you stop taking REGLAN. Your chances for getting tardive dyskinesia increase:

• the longer you take REGLAN and the more REGLAN you take. You should not take REGLAN for more than 12 weeks.
• if you are older, especially if you are an older woman.
• if you have diabetes.

It is not possible for your healthcare provider to know if you will get tardive dyskinesia if you take REGLAN.

Call your healthcare provider right away if you get movements you cannot stop or control, such as:

• lip smacking, chewing, or puckering up your mouth
• frowning or scowling
• sticking out your tongue
• blinking and moving your eyes
• shaking of your arms and legs

See the section “What are the possible side effects of REGLAN?” for more information about side effects.

What is REGLAN?

REGLAN is a prescription medicine used in adults:

• for 4 to 12 weeks to relieve heartburn symptoms with gastroesophageal reflux when certain other treatments do not work.
• to relieve the symptoms of slow stomach emptying in people with diabetes.

Reglan is not recommended for use in children.

Do not take REGLAN if you:

• have a history of tardive dyskinesia or have a problem controlling your muscles and movements after taking REGLAN or a medicine that works like REGLAN.
• have stomach or intestine problems that could get worse with REGLAN, such as bleeding, blockage or a tear in the stomach or bowel wall.
• have a type of tumor that can cause high blood pressure such as pheochromocytoma.
• have epilepsy (seizures). REGLAN can increase your chance for seizures and make them worse.
• are allergic to metoclopramide. REGLAN can cause serious allergic reactions. Stop taking REGLAN right away and get emergency help if you have any of these symptoms:
  • swelling of your tongue, throat, lips, eyes or face.
  • trouble swallowing or breathing.
  • skin rash, hives, sores in your mouth, or skin blisters.

Before taking REGLAN, tell your healthcare provider about all of your medical conditions, including if you:

• have diabetes. Your dose of insulin may need to be changed.
• had problems controlling your muscle movements after taking any medicine.
• have Parkinson’s disease.
• have a type of tumor that can cause high blood pressure (pheochromoctyoma).
• have kidney or liver disease.
• have or had depression or mental illness.
• have high blood pressure.
• have heart failure or heart rhythm problems.
• have breast cancer.
• drink alcohol.
• have seizures
• are pregnant or plan to become pregnant. REGLAN may harm your unborn baby if taken during the end of pregnancy. Talk to your healthcare provider if you become pregnant while taking REGLAN.
• are breastfeeding or plan to breastfeed. REGLAN can pass into your breast milk and may harm your baby. You and your healthcare provider should decide if you will take REGLAN or breastfeed.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

REGLAN may affect the way other medicines work, and other medicines may affect how REGLAN works.

Tell your healthcare provider before you start or stop other medicines.

Especially tell your healthcare provider if you take:

• another medicine that contains metoclopramide, such as REGLAN injection or metoclopramide oral solution
• a medicine for Parkinson’s disease
• a blood pressure medicine
• a medicine for depression, especially a Monoamine Oxidase Inhibitor (MAOI)
• an anti-psychotic medicine, used to treat mental illness such as schizophrenia
• insulin
• medicines that can make you sleepy, such as anti-anxiety medicines, sleep medicines, and narcotics

If you are not sure if your medicine is one listed above, ask your healthcare provider or pharmacist.

Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.

How should I take REGLAN?

• Take REGLAN exactly as your healthcare provider tells you. Do not change your dose unless your healthcare provider tells you to.
• REGLAN comes as a tablet you take by mouth.
• You should not take REGLAN for more than 12 weeks.
• Take REGLAN at least 30 minutes before each meal and at bedtime.
• If you take too much REGLAN, call your poison control center at 1-800-222-1222 or go to the nearest emergency room right away.

What should I avoid while taking REGLAN?

• Do not drink alcohol while taking REGLAN. Alcohol may make some side effects of REGLAN worse, such as feeling sleepy.
• Do not drive, operate machinery, or do other dangerous activities until you know how REGLAN affects you. REGLAN may cause sleepiness or dizziness.

What are the possible side effects of REGLAN?

• Tardive dyskinesia (abnormal muscle movements). See “What is the most important information I need to know about REGLAN?”
• Other changes in muscle control and movement, such as:
  • Uncontrolled spasms of your face and neck muscles, or muscles of your body, arms, and legs (dystonia). These muscle spasms can cause abnormal movements and body positions, and speech problems. These spasms usually start within the first 2 days of treatment. Rarely, these muscle spasms may cause trouble breathing. These spasms happen more often in adults less than 30 years of age.
  • Parkinsonism. Symptoms include slight shaking, body stiffness, trouble moving or keeping your balance. If you already have Parkinson’s Disease, your symptoms may become worse while you are taking REGLAN.
  • Being unable to sit still or feeling you need to move your hands, feet, or body (akathisia). Symptoms can include feeling jittery, anxious, irritated or unable to sleep (insomnia), feeling the need to walk around (pacing) and tapping your feet.
• Neuroleptic Malignant Syndrome (NMS). NMS is a very rare but very serious condition that can happen with REGLAN. NMS can cause death and must be treated in a hospital. Symptoms of NMS include: high fever, stiff muscles, problems thinking, very fast or uneven heartbeat, and increased sweating.
• Depression, thoughts about suicide, and suicide. Some people who take REGLAN become depressed, even if they have no history of despression. You may have thoughts about hurting or killing yourself. Some people who have taken REGLAN have ended their own lives (suicide).
• High blood pressure. REGLAN can cause your blood pressure to increase.
• Too much body water. People who have certain liver problems or heart failure and take REGLAN may hold too much water in their body (fluid retention). Tell your doctor right away if you have sudden weight gain, or swelling of your hands, legs, or feet.
• Increased prolactin. Tell your doctor if your menstrual periods stop, your breasts get larger and make milk, or you cannot have sex (impotence). These symptoms go away when you stop taking REGLAN.

Call your healthcare provider and get medical help right away if you:

• feel depressed or have thoughts about hurting or killing yourself
• have high fever, stiff muscles, problems thinking, very fast or uneven heartbeat, and increased sweating
• have muscle movements you cannot stop or control
• have muscle movements that are new or unusual

The most common side effects of REGLAN include:

• restlessness
• drowsiness
• tiredness
• lack of energy

You may have more side effects the longer you take REGLAN and the more REGLAN you take.

You may still have side effects after stopping REGLAN. You may have symptoms from stopping REGLAN such as headaches, and feeling dizzy or nervous.

Tell your healthcare provider about any side effect that bothers you or that does not go away. These are not all the possible side effects of REGLAN. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store REGLAN?

• Store REGLAN at room temperature between 68°F to 77°F (20°C to 25°C).
• Keep REGLAN in the bottle it comes in and away from light. Keep the bottle closed tightly.

Keep REGLAN and all medicines out of the reach of children.

General information about the safe and effective use of REGLAN.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use REGLAN for a condition for which it was not prescribed.

Do not give REGLAN to other people, even if they have the same symptoms that you have. It may harm them.

You can ask your pharmacist or healthcare provider for information about REGLAN that is written for health professionals.

What are the ingredients in REGLAN?

Active ingredient: metoclopramide

Inactive ingredients:

REGLAN 5 mg tablets: corn starch, D&C yellow 10 aluminum lake, FD&C blue 1 aluminum lake, lactose, microcrystalline cellulose, silicon dioxide, stearic acid

REGLAN 10 mg tablets: magnesium stearate, mannitol, microcrystalline cellulose, stearic acid

Description

REGLAN ODT™ (metoclopramide orally disintegrating tablets) is an orally administered formulation of metoclopramide which disintegrates on the tongue.

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 C₁₄H₂₂ClN₃O₂•HCl•H₂O. Its molecular weight is 354.3.

 

 

Each orally disintegrating tablet contains either 5 mg or 10 mg of metoclopramide base (as the monohydrochloride monohydrate) and the following inactive ingredients: aspartame, colloidal silicon dioxide, crospovidone, magnesium stearate, mannitol, aminoalkyl methacrylate copolymer, microcrystalline cellulose, natural and artificial orange flavor and povidone.

Reglan tablets are indicated for the:

• Treatment for 4 to 12 weeks of symptomatic, documented gastroesophageal reflux in adults who fail to respond to conventional therapy.
• Relief of symptoms in adults with acute and recurrent diabetic gastroparesis.

Limitations Of Use

Reglan tablets are not recommended for use in pediatric patients due to the risk of developing tardive dyskinesia (TD) and other extrapyramidal symptoms as well as the risk of methemoglobinemia in neonates [see Use In Specific Populations].

Dosage And Admintisration

Important Administration Instructions

Avoid treatment with Reglan for longer than 12 weeks because of the increased risk of developing TD with longer-term use [see Dosage for Gastroesophageal Reflux, Dosage For Acute And Recurrent Diabetic Gastroparesis, WARNINGS AND PRECAUTIONS].

Dosage For Gastroesophageal Reflux

Reglan tablets may be administered continuously or intermittently in patients with symptomatic gastroesophageal reflux who fail to respond to conventional therapy:

Continuous Dosing

The recommended adult dosage of Reglan is 10 to 15 mg four times daily for 4 to 12 weeks. The treatment duration is determined by endoscopic response. Administer the dosage thirty minutes before each meal and at bedtime. The maximum recommended daily dosage is 60 mg.

Table 1 displays the recommended daily dosage and maximum daily dosage for adults and dosage adjustments for patients with moderate or severe hepatic impairment (Child-Pugh B or C), in patients with creatinine clearance less than 60 mL/minute, in cytochrome P450 2D6 (CYP2D6) poor metabolizers, and with concomitant use with strong CYP2D6 inhibitors.

Intermittent Dosing

If symptoms only occur intermittently or at specific times of the day, administer Reglan in single dose up to 20 mg prior to the provoking situation. Consider dosage reductions for the populations and situations in Table 1.

Table 1. Recommended Reglan Tablet Dosage in Patients with Gastroesophageal Reflux>

	Recommended Dosage	Maximum Recommended Daily Dosage
Adult patients	10 to 15 mg four times daily (thirty minutes before each meal and at bedtime)	60 mg
Mild hepatic impairment (Child-Pugh A)
Elderly patients [see Use In Specific Populations]	5 mg1 four times daily (thirty minutes before each meal and at bedtime)
Moderate or severe hepatic impairment (Child-Pugh B or C) [see Use In Specific Populations]	5 mg four times daily (thirty minutes before each meal and at bedtime), or 10 mg taken three times daily	30 mg
CYP2D6 poor metabolizers [see Use In Specific Populations]
Concomitant use with strong CYP2D6 inhibitors (e.g., quinidine, bupropion, fluoxetine, and paroxetine) [see DRUG INTERACTIONS]
Moderate or severe renal impairment (creatinine clearance less than or equal to 60 mL/minute) [see Use In Specific Populations]
Patients with End-Stage Renal Disease (ESRD) including those treated with hemodialysis and continuous ambulatory peritoneal dialysis [see Use In Specific Populations]	5 mg four times daily (thirty minutes before each meal and at bedtime) or 10 mg twice daily	20 mg
1 Elderly patients may be more sensitive to the therapeutic or adverse effects of Reglan; therefore, consider a lower starting dosage of 5 mg four times daily with titration to the recommended adult dosage of 10 to 15 mg four times daily based upon response and tolerability.

 

Dosage For Acute And Recurrent Diabetic Gastroparesis

The recommended adult dosage for the treatment of acute and recurrent diabetic gastroparesis is 10 mg four times daily for 2 to 8 weeks, depending on symptomatic response. Avoid Reglan treatment for greater than 12 weeks [see WARNINGS AND PRECAUTIONS]. Administer the dosage thirty minutes before each meal and at bedtime. The maximum recommended daily dosage is 40 mg.

Table 2 displays the recommended daily dosage and maximum daily dosage for adults and dosage adjustments for patients with moderate or severe hepatic impairment (Child-Pugh B or C), in patients with creatinine clearance less than 60 mL/minute, in cytochrome P450 2D6 (CYP2D6) poor metabolizers, and with concomitant use with strong CYP2D6 inhibitors.

If patients with diabetic gastroparesis have severe nausea or vomiting and are unable to take oral Reglan tablets, consider starting therapy with metoclopramide injection given intramuscularly or intravenously for up to 10 days (see the prescribing information for metoclopramide injection). After patients are able to take oral therapy, switch to Reglan tablets.

Table 2. Recommended Reglan Tablet Dosage in Patients with Acute and Recurrent Diabetic Gastroparesis

	Recommended Dosage	Maximum Recommended Daily Dosage
Adult Patients	10 mg four times daily (30 minutes before each meal and at bedtime)	40 mg
Mild hepatic impairment (Child-Pugh A)
Elderly patients [see Use In Specific Populations]	5 mg1 four times daily (30 minutes before each meal and at bedtime)
Moderate or severe hepatic impairment (Child-Pugh B or C) [see Use In Specific Populations]	5 mg four times daily (30 minutes before each meal and at bedtime)	20 mg
CYP2D6 poor metabolizers [see Use In Specific Populations]
Concomitant use with strong CYP2D6 inhibitors (e.g., quinidine). Avoid use with bupropion, fluoxetine, and paroxetine [see DRUG INTERACTIONS]
Moderate or severe renal impairment (creatinine clearance less than 60 mL/minute) [see Use In Specific Populations]
Patients with End-Stage Renal Disease (ESRD) including those treated with hemodialysis and continuous ambulatory peritoneal dialysis [see Use In Specific Populations]	5 mg twice daily	10 mg
1 Elderly patients may be more sensitive to the therapeutic or adverse effects of Reglan; therefore, consider a lower dosage of 5 mg four times daily with titration to the recommended adult dosage of 10 mg four times daily based upon response and tolerability.

 

How Supplied

Dosage Forms And Strengths

Tablets:

• 5 mg metoclopramide: green, elliptical-shaped, debossed “REGLAN” over “5” on one side and “ANI” on the opposite side
• 10 mg metoclopramide: white, double edge scored, capsule-shaped, debossed “REGLAN” on one side and “ANI 10” on the opposite side

Storage And Handling

Each green, elliptical-shaped Reglan tablet contains 5 mg metoclopramide. The tablet is debossed “REGLAN” over “5” on one side and “ANI” on the opposite side. Available in bottles of 100 tablets (NDC 62559-165-01)

Each white, double edge scored, capsule-shaped Reglan tablet contains 10 mg metoclopramide. The tablet is debossed “REGLAN” on one side and “ANI 10” on the opposite side. Available in bottles of 100 tablets (NDC 62559-166-01)

Dispense tablets in tight, light-resistant container. Store tablets at controlled room temperature between 20°C and 25°C (68°F and 77°F).

Manufactured by: ANI Pharmaceuticals, Inc., Baudette, MN 56623. Revised: Aug 2017

The following adverse reactions are described, or described in greater detail, in other sections of the labeling:

• Tardive dyskinesia [see BOX WARNING and WARNINGS AND PRECAUTIONS]
• Other extrapyramidal effects [see WARNINGS AND PRECAUTIONS]
• Neuroleptic malignant syndrome [see WARNINGS AND PRECAUTIONS]
• Depression [see WARNINGS AND PRECAUTIONS]
• Hypertension [see WARNINGS AND PRECAUTIONS]
• Fluid retention [see WARNINGS AND PRECAUTIONS]
• Hyperprolactinemia [see WARNINGS AND PRECAUTIONS]
• Effects on the ability to drive and operate machinery [see WARNINGS AND PRECAUTIONS]

The following adverse reactions have been identified from clinical studies or postmarketing reports of metoclopramide. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The most common adverse reactions (in approximately 10% of patients receiving 10 mg of metoclopramide four times daily) were restlessness, drowsiness, fatigue, and lassitude. In general, the incidence of adverse reactions correlated with the dosage and duration of metoclopramide administration.

Adverse reactions, especially those involving the nervous system, occurred after stopping metoclopramide including dizziness, nervousness, and headaches.

Central Nervous System Disorders

• Tardive dyskinesia, acute dystonic reactions, drug-induced parkinsonism, akathisia, and other extrapyramidal symptoms
• Convulsive seizures
• Hallucinations
• Restlessness, drowsiness, fatigue, and lassitude occurred in approximately 10% of patients who received 10 mg four times daily. Insomnia, headache, confusion, dizziness, or depression with suicidal ideation occurred less frequently.
• Neuroleptic malignant syndrome, serotonin syndrome (in combination with serotonergic agents)

Endocrine Disorders

Fluid retention secondary to transient elevation of aldosterone. Galactorrhea, amenorrhea, gynecomastia, impotence secondary to hyperprolactinemia

Cardiovascular Disorders

Acute congestive heart failure, possible atrioventricular block, hypotension, hypertension, supraventricular tachycardia, bradycardia, fluid retention

Gastrointestinal Disorders

Nausea, bowel disturbances (primarily diarrhea)

Hepatic Disorders

Hepatotoxicity, characterized by, e.g., jaundice and altered liver function tests, when metoclopramide was administered with other drugs with known hepatotoxic potential

Renal And Urinary Disorders

Urinary frequency, urinary incontinence

Hematologic Disorders

Agranulocytosis, neutropenia, leukopenia, methemoglobinemia, sulfhemoglobinemia

Hypersensitivity Reactions

Bronchospasm (especially in patients with a history of asthma), urticaria; rash; angioedema, including glossal or laryngeal edema

Eye Disorders

Visual disturbances

Metabolism Disorders

Porphyria

Effects Of Other Drugs On Metoclopramide

Table 3 displays the effects of other drugs on metoclopramide

Table 3. Effects of Other Drugs on Metoclopramide

Antipsychotics
Clinical Impact	Potential for additive effects, including increased frequency and severity of tardive dyskinesia (TD), other extrapyramidal symptoms (EPS), and neuroleptic malignant syndrome (NMS).
Intervention	Avoid concomitant use [see WARNINGS AND PRECAUTIONS].
Strong CYP2D6 Inhibitors, not Included in Antipsychotic Category Above
Clinical Impact	Increased plasma concentrations of metoclopramide; risk of exacerbation of extrapyramidal symptoms [see CLINICAL PHARMACOLOGY].
Intervention	Reduce the Reglan dosage [see DOSAGE AND ADMINISTRATION].
Examples	quinidine, bupropion, fluoxetine, and paroxetine
Monoamine Oxidase Inhibitors
Clinical Impact	Increased risk of hypertension [see WARNINGS AND PRECAUTIONS].
Intervention	Avoid concomitant use.
Central Nervous System (CNS) Depressants
Clinical Impact	Increased risk of CNS depression [see WARNINGS AND PRECAUTIONS].
Intervention	Avoid Reglan or the interacting drug, depending on the importance of the drug to the patient.
Examples	alcohol, sedatives, hypnotics, opiates and anxiolytics
Drugs that Impair Gastrointestinal Motility
Clinical Impact	Decreased systemic absorption of metoclopramide.
Intervention	Monitor for reduced therapeutic effect.
Examples	antiperistaltic antidiarrheal drugs, anticholinergic drugs, and opiates
Dopaminergic Agonists and Other Drugs that Increase Dopamine Concentrations
Clinical Impact	Decreased therapeutic effect of metoclopramide due to opposing effects on dopamine.
Intervention	Monitor for reduced therapeutic effect.
Examples	apomorphine, bromocriptine, cabergoline, levodopa, pramipexole, ropinirole, and rotigotine

 

Effects Of Metoclopramide On Other Drugs

Table 4 displays the effects of Metoclopramide on other drugs.

Table 4. Effects of Metoclopramide on Other Drugs

Dopaminergic Agonists and Drugs Increasing Dopamine Concentrations
Clinical Impact	Opposing effects of metoclopramide and the interacting drug on dopamine. Potential exacerbation of symptoms (e.g., parkinsonian symptoms).
Intervention	Avoid concomitant use [see WARNINGS AND PRECAUTIONS].
Examples	Apomorphine, bromocriptine, cabergoline, levodopa, pramipexole, ropinirole, rotigotine
Succinylcholine, Mivacurium
Clinical Impact	Metoclopramide inhibits plasma cholinesterase leading to enhanced neuromuscular blockade.
Intervention	Monitor for signs and symptoms of prolonged neuromuscular blockade.
Drugs with Absorption Altered due to Increased Gastrointestinal Motility
Clinical Impact	The effect of metoclopramide on other drugs is variable. Increased gastrointestinal (GI) motility by metoclopramide may impact absorption of other drugs leading to decreased or increased drug exposure.
Intervention	Drugs with Decreased Absorption (e.g., digoxin, atovaquone, posaconazole oral suspension*, fosfomycin): Monitor for reduced therapeutic effect of the interacting drug. For digoxin monitor therapeutic drug concentrations and increase the digoxin dose as needed (see prescribing information for digoxin). Drugs with Increased Absorption (e.g., sirolimus, tacrolimus, cyclosporine): Monitor therapeutic drug concentrations and adjust the dose as needed. See prescribing information for the interacting drug.
Insulin
Clinical Impact	Increased GI motility by metoclopramide may increase delivery of food to the intestines and increase blood glucose.
Intervention	Monitor blood glucose and adjust insulin dosage regimen as needed.
* Interaction does not apply to posaconazole delayed-release tablets

 

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, 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. 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.

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].

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.

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 REGLAN ODT™ use should result in immediate cessation of metoclopramide use in those patients [see CONTRAINDICATIONS].

Congestive Heart Failure and Ventricular Arrhythmia

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.

Withdrawal from Metoclopramide

Adverse reactions, especially those involving the nervous system, may occur after stopping the use of REGLAN ODT™ (metoclopramide orally disintegrating tablets) . A small number of patients may experience a withdrawal period after stopping REGLAN ODT™ (metoclopramide orally disintegrating tablets) that could include dizziness, nervousness, and/or headaches.

Patient Counseling Information

[See Medication Guide]

Instruct patients to take REGLAN ODT™ (metoclopramide orally disintegrating tablets) at least 30 minutes before eating and at bedtime.

Instruct patients not to remove REGLAN ODT™ (metoclopramide orally disintegrating tablets) orally disintegrating tablets from the packaging until just prior to dosing. With dry hands, the patient should remove the tablet from the package and immediately place the tablet on the tongue to disintegrate and be swallowed with the saliva. The tablet typically disintegrates in about one and one-half minutes. Administration with liquid is not necessary.

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 REGLAN ODT™ .

Inform patients that metoclopramide may cause drowsiness, 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. Sedation may be more pronounced in the elderly. The ambulatory patient should be cautioned accordingly.

Inform patients that the most common adverse reactions in patients treated with REGLAN ODT™ or other metoclopramide-containing products are headache, nausea, vomiting, tiredness, sleepiness, dizziness, and restlessness.

Phenylketonuric patients should be informed that REGLAN ODT™ (metoclopramide orally disintegrating tablets) contains phenylalanine 4.2 mg per 5 mg orally disintegrating tablet and 8.3 mg per 10 mg orally disintegrating tablet.

For additional information, patients should be instructed to see the Medication Guide for REGLAN ODT™ (metoclopramide orally disintegrating tablets) .

Nonclinical Toxicology

Carcinogenesls, Mutagenesis, and Impairment of Fertility

A 77-week study was conducted in rats with oral doses of metoclopramide 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 on surface area basis) enhanced the tumorigenic effect of N-nitrosodiethylamine.

Metoclopramide was positive in the 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 in male and female rats (about 3 times the maximum recommended human dose on surface area basis) was found to have no effect on fertility and reproductive performance.

Use In Specific Populations

Pregnancy

Teratogenic Effects: Pregnancy Category B. Teratology studies have been performed in rats at oral doses up to 45 mg/kg/day (about 6 times the maximum recommended human dose on surface area basis), and in rabbits at oral doses up to 45 mg/kg/day (about 12 times the maximum recommended human dose on surface area basis) 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 in nursing infants from metoclopramide and because of the potential for tumorigenicity and tumor promoting potential shown for metoclopramide 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

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]. 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, a possible side effect of metoclopramide use in neonates [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, [seeWARNINGS AND PRECAUTIONS and ADVERSE REACTIONS]

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 parkinsonian-like side effects increases with ascending dose. Geriatric patients should receive the lowest dose of REGLAN ODT™ (metoclopramide orally disintegrating tablets) that is effective. If parkinsonian-like symptoms develop in a geriatric patient receiving REGLAN ODT™ (metoclopramide orally disintegrating tablets) , REGLAN ODT™ (metoclopramide orally disintegrating tablets) should be discontinued before initiating any specific anti-parkinsonian agents [see WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION].

The elderly may be at greater risk for tardive dyskinesia [see WARNINGS AND PRECAUTIONS].

Sedation has been reported in metoclopramide users. Sedation may cause confusion and manifest as over-sedation in the elderly [see CLINICAL PHARMACOLOGY, ADVERSE REACTIONS, and PATIENT INFORMATION].

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 [see DOSAGE AND ADMINISTRATION].

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].

Hepatic Insufficiency

Metoclopramide has been safely used in patients with advanced liver disease whose renal function was normal.

Renal Insufficiency

Renally impaired patients whose creatinine clearance is below 40 mL/min may be more sensitive to the therapeutic dose or the adverse effects of metoclopramide. Therefore, these patients should start therapy at a lower dose (approximately half the recommended dosage) and the dose should be titrated according to their overall clinical response and/or adverse event profile. Dialysis is not likely to be an effective method of drug removal in overdose situations. (See DOSAGE AND ADMINISTRATION)

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].

Overdose

Manifestations of metoclopramide overdosage included drowsiness, disorientation, extrapyramidal reactions, other adverse reactions associated with metoclopramide use (including, e.g., methemoglobinemia), and sometimes death. Neuroleptic malignant syndrome (NMS) has been reported in association with metoclopramide overdose and concomitant treatment with another drug associated with NMS [see WARNINGS AND PRECAUTIONS].

There are no specific antidotes for Reglan overdosage. If over-exposure occurs, call your Poison Control Center at 1-800-222-1222 for current information on the management of poisoning or overdosage.

Methemoglobinemia can be reversed by the intravenous administration of methylene blue. However, methylene blue may cause hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, which may be fatal.

Hemodialysis and continuous ambulatory peritoneal dialysis do not remove significant amounts of metoclopramide.

Contraindications

Reglan is contraindicated:

• In patients with a history of tardive dyskinesia (TD) or a dystonic reaction to metoclopramide [see WARNINGS AND PRECAUTIONS].
• When stimulation of gastrointestinal motility might be dangerous (e.g., in the presence of gastrointestinal hemorrhage, mechanical obstruction, or perforation).
• In patients with pheochromocytoma or other catecholamine-releasing paragangliomas. Reglan may cause a hypertensive/pheochromocytoma crisis, probably due to release of catecholamines from the tumor [see WARNINGS AND PRECAUTIONS].
• In patients with epilepsy. Reglan may increase the frequency and severity of seizures [see ADVERSE REACTIONS].
• In patients with hypersensitivity to metoclopramide. Reactions have included laryngeal and glossal angioedema and bronchospasm [see ADVERSE REACTIONS].

Mechanism Of Action

Metoclopramide stimulates motility of the upper gastrointestinal tract without stimulating gastric, biliary, or pancreatic secretions. The exact mechanism of action of metoclopramide in the treatment of gastroesophageal reflux and acute and recurrent diabetic gastroparesis has not been fully established. 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.

Pharmacodynamics

Gastroesophageal Reflux

In patients with gastroesophageal reflux and low lower esophageal sphincter pressure (LESP), single oral doses of Reglan produced dose-related increases in LESP. Effects began at about 5 mg and increased through 20 mg. The increase in LESP from a 5 mg dose lasted about 45 minutes and that of 20 mg lasted between 2 and 3 hours. Increased rate of stomach emptying was observed with single oral doses of 10 mg.

Pharmacokinetics

Absorption

Relative to an intravenous dose of 20 mg, the absolute bioavailability of oral metoclopramide is 80% ± 15.5% as demonstrated in a crossover study of 18 subjects. Peak plasma concentrations occurred at about 1 to 2 hours after a single oral dose. Similar time to peak was observed after individual doses at steady state.

In a single dose study of 12 subjects, the area under the drug concentration-time curve increased linearly with doses from 20 to 100 mg (5 times the maximum recommended single dose). Peak concentrations increased linearly with dose; time to peak concentrations remained the same; whole body clearance was unchanged; and the elimination rate remained the same. The mean elimination half-life in subjects with normal renal function was 5 to 6 hours. Linear kinetic processes adequately describe the absorption and elimination of metoclopramide.

Distribution

Metoclopramide 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.

Elimination

Metabolism

Metoclopramide undergoes enzymatic metabolism via oxidation as well as glucuronide and sulfate conjugation reactions in the liver.

Monodeethylmetoclopramide, a major oxidative metabolite, is formed primarily by CYP2D6, an enzyme subject to genetic variability [see DOSAGE AND ADMINISTRATION, Use In Specific Populations].

Excretion

Approximately 85% of the radioactivity of an orally administered dose appeared in the urine within 72 hours. After oral administration of 10 or 20 mg, a mean of 18% and 22% of the dose, respectively, was recovered as free metoclopramide in urine within 36 hours.

Specific Populations

Patients With Renal Impairment

In a study of 24 patients with varying degrees of renal impairment (moderate, severe, and end-stage renal disease (ESRD) requiring dialysis), the systemic exposure (AUC) of metoclopramide in patients with moderate to severe renal impairment was about 2-fold the AUC in subjects with normal renal function. The AUC of metoclopramide in patients with ESRD on dialysis was about 3.5-fold the AUC in subjects with normal renal function [see DOSAGE AND ADMINISTRATION and Use In Specific Populations].

Patients With Hepatic Impairment

In a group of 8 patients with severe hepatic impairment (Child-Pugh C), the average metoclopramide clearance was reduced by approximately 50% compared to patients with normal hepatic function [see DOSAGE AND ADMINISTRATION and Use In Specific Populations].

Drug Interaction Studies

Effect Of Metoclopramide On CYP2D6 Substrates

Although in vitro studies suggest that metoclopramide can inhibit CYP2D6, metoclopramide is unlikely to interact with CYP2D6 substrates in vivo at therapeutically relevant concentrations.

Effect Of CYP2D6 Inhibitors On Metoclopramide

In healthy subjects, 20 mg of metoclopramide and 60 mg of fluoxetine (a strong CYP2D6 inhibitor) were administered, following prior exposure to 60 mg fluoxetine orally for 8 days. The patients who received concomitant metoclopramide and fluoxetine had a 40% and 90% increase in metoclopramide Cmax and AUC0-∞, respectively, compared to patients who received metoclopramide alone (see Table 5) [see DRUG INTERACTIONS].

Table 5. Metoclopramide Pharmacokinetic Parameters in Healthy Subjects with and without Fluoxetine

Parameter	Metoclopramide alone (mean ± SD)	Metoclopramide with fluoxetine (mean ± SD)
Cmax (ng/mL)	44 ±15	62.7 ± 9.2
AUC0-∞ (ng·h/mL)	313 ± 113	591 ± 140
t1/2 (h)	5.5 ± 1.1	8.5 ± 2.2