METOCLOPRAMIDE- metoclopramide hydrochloride solution
For Healthcare Providers >

1. Patient Information
2. Your Chances For Getting Tardive Dyskinesia Go Up:
3. Call Your Doctor Right Away If You Get Movements You Cannot Stop Or Control, Such As:
4. Metoclopramide Is A Prescription Medicine Used:
5. Do Not Take Metoclopramide If You:
6. Especially Tell Your Doctor If You Take:
7. Metoclopramide Can Cause Serious Side Effects, Including:
8. What Are The Ingredients In Metoclopramide?
9. Inform Patients Or Their Caregivers That Metoclopramide Can Cause Serious Adverse Reactions. Instruct Patients To Discontinue Metoclopramide And Contact A Healthcare Provider Immediately If The Following Serious Reactions Occur:
10. Before Taking Metoclopramide, Tell Your Healthcare Provider About All Of Your Medical Conditions, Including If You:
11. Tell Your Healthcare Provider About All The Medicines You Take, Including Prescription And Over-the-counter Medicines, Vitamins, And Herbal Supplements.metoclopramide May Affect The Way Other Medicines Work, And Other Medicines May Affect How Metoclopramide Works. Tell Your Healthcare Provider Before You Start Or Stop Other Medicines.especially Tell Your Healthcare Provider If You Take:
12. How Should I Take Metoclopramide?
13. What Should I Avoid While Taking Metoclopramide?
14. What Are The Possible Side Effects Of Metoclopramide?
15. What Are The Ingredients In Metoclopramide?active Ingredient:
16. Inactive Ingredients:

Patient Information ⮝

Metoclopramide (met-o-KLO-pra-mide) Oral Solution USP

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

Your Chances For Getting Tardive Dyskinesia Go Up: ⮝

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

It is not possible for your doctor to know if you will get tardive dyskinesia if you take Metoclopramide.

Call Your Doctor 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

Your doctor may decide to stop Metoclopramide.

Metoclopramide Is A Prescription Medicine Used: ⮝

• in adults for 4 to 12 weeks to relieve heartburn symptoms with gastroesophageal reflux disease (GERD) when certain other treatments do not work. Metoclopramide relieves daytime heartburn and heartburn after meals. It also helps ulcers in the esophagus to heal.
• to relieve symptoms of slow stomach emptying in people with diabetes. Metoclopramide helps treat symptoms such as nausea, vomiting, heartburn, feeling full long after a meal, and loss of appetite. All these symptoms do not get better at the same time.

It is not known if Metoclopramide is safe and works in children.

Do Not Take Metoclopramide If You: ⮝

• have stomach or intestine problems that could get worse with Metoclopramide, such as bleeding, blockage or a tear in the stomach or bowel wall
• have an adrenal gland tumor called a pheochromocytoma
• are allergic to Metoclopramide or anything in it.

  , including if you have:Tell your doctor about all your medical conditions

  • depression
  • Parkinson's disease
  • high blood pressure
  • kidney problems. Your doctor may start with a lower dose.
  • liver problems or heart failure. Metoclopramide may cause your body to hold fluids.
  • diabetes. Your dose of insulin may need to be changed.
  • breast cancer
  • you are pregnant or plan to become pregnant. It is not known if Metoclopramide will harm your unborn baby.
  • you are breast-feeding. Metoclopramide can pass into breast milk and may harm your baby. Talk with your doctor about the best way to feed your baby if you take Metoclopramide.

  Metoclopramide and some other medicines may interact with each other and may not work as well, or cause possible side effects. Do not start any new medicines while taking Metoclopramide until you talk with your doctor.Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.

Especially Tell Your Doctor If You Take: ⮝

• another medicine that contains Metoclopramide, such as REGLAN tablets, REGLAN ODT.
• a blood pressure medicine
• a medicine for depression, especially a Monoamine Oxidase Inhibitor (MAOI)
• insulin
• a medicine that can make you sleepy, such as anti-anxiety medicine, sleep medicines, and narcotics.

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

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

Metoclopramide Can Cause Serious Side Effects, Including: ⮝

• • Keep Metoclopramide at room temperature between 68 F to 77 F (20 C to 25 C).
  • Keep Metoclopramide in the bottle it comes in. Keep the bottle closed tightly.

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

  General information about Metoclopramide

  Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Metoclopramide for a condition for which it was not prescribed. Do not give Metoclopramide to other people, even if they have the same symptoms that you have. It may harm them.

  This Medication Guide summarizes the most important information about Metoclopramide. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Metoclopramide that is written for health professionals. For more information, go to www.paipharma.com or call 1-800-845-8210.

What Are The Ingredients In Metoclopramide? ⮝

Active ingredient: Metoclopramide

Inactive ingredients: citric acid, FD&C Yellow No. 6 (Sunset Yellow), flavoring, glycerin, methylparaben, propylparaben, purified water, and sorbitol solution.

Greenville, SC 29605 www.paipharma.comPharmaceutical Associates, Inc.

R10/12

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Inform Patients Or Their Caregivers That Metoclopramide Can Cause Serious Adverse Reactions. Instruct Patients To Discontinue Metoclopramide And Contact A Healthcare Provider Immediately If The Following Serious Reactions Occur: ⮝

• Tardive dyskinesia and other extrapyramidal reactions[
  Metoclopramide 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 Metoclopramide. There is no treatment for tardive dyskinesia, but symptoms may decrease or go away over time after you stop taking Metoclopramide.
  Your chances for getting tardive dyskinesia increase:
  • the longer you take Metoclopramide and the more Metoclopramide you take. You should not take Metoclopramide 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 ifyouwill get tardive dyskinesia if you take Metoclopramide. 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
  
  Metoclopramide 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.
  Metoclopramide is not recommended for use in children.

Before Taking Metoclopramide, 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 (pheochromocytoma).
• 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. Metoclopramide may harm your unborn baby if taken during the end of pregnancy. Talk to your healthcare provider if you become pregnant while taking Metoclopramide.
• are breastfeeding or plan to breastfeed. Metoclopramide can pass into your breast milk and may harm your baby. You and your healthcare provider should decide if you will take Metoclopramide or breastfeed.

Tell Your Healthcare Provider About All The Medicines You Take, Including Prescription And Over-the-counter Medicines, Vitamins, And Herbal Supplements.metoclopramide May Affect The Way Other Medicines Work, And Other Medicines May Affect How Metoclopramide 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 Metoclopramide? ⮝

• Take Metoclopramide exactly as your healthcare provider tells you. Do not change your dose unless your healthcare provider tells you to.
• You should not take Metoclopramide for more than 12 weeks.
• Take Metoclopramide at least 30 minutes before each meal and at bedtime.
• If you take too much Metoclopramide, 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 Metoclopramide? ⮝

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

What Are The Possible Side Effects Of Metoclopramide? ⮝

• Tardive dyskinesia (abnormal muscle movements).
  • Store Metoclopramide at room temperature between 68 F to 77 F (20 C to 25 C).
  • Keep Metoclopramide in the bottle it comes in and away from light. Keep the bottle closed tightly.
  Keep Metoclopramide and all medicines out of the reach of children.General information about the safe and effective use of Metoclopramide.
  Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Metoclopramide for a condition for which it was not prescribed. Do not give Metoclopramide 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 Metoclopramide that is written for health professionals.

What Are The Ingredients In Metoclopramide?active Ingredient: ⮝

metoclopramide

Inactive Ingredients: ⮝

Citric acid, FD&C Yellow No. 6 (Sunset Yellow), flavoring, glycerin, methylparaben, propylparaben, purified water and sorbitol solution.
MANUFACTURED BY
Pharmaceutical
Associates, Inc.
Greenville, SC 29605
www.paipharma.com
R09/17

1. Highlights Of Prescribing Information
2. Warning: Tardive Dyskinesia
3. See Full Prescribing Information For Complete Boxed Warning.
4. Recent Major Changes
5. Indications And Usage
6. Dosage And Administration
7. Dosage Forms And Strengths
8. Contraindications
9. Warnings And Precautions
10. Adverse Reactions
11. Drug Interactions
12. 1 Indications And Usage
13. 2 Dosage And Administration
14. 3 Dosage Forms And Strengths
15. 4 Contraindications
16. 5 Warnings And Precautions
17. 6 Adverse Reactions
18. 7 Drug Interactions
19. 8 Use In Specific Populations
20. 10 Overdosage
21. 11 Description
22. 12 Clinical Pharmacology
23. 13 Nonclinical Toxicology
24. 16 How Supplied/storage And Handling
25. Principal Display Panel - 473 Ml Bottle Label
26. Principal Display Panel - 10 Ml Cup Label
27. Description
28. Clinical Pharmacology
29. Warnings
30. Precautions
31. Overdosage
32. How Supplied
33. Nystatin Suspension
34. Metoclopramide (metoclopramide Hydrochloride) Solution
35. Metoclopramide Oral Solution Usp
36. Propranolol Hydrochloride Solution

Highlights Of Prescribing Information ⮝

These highlights do not include all the information needed to use Metoclopramide Oral Solution USP safely and effectively. See full prescribing information for Metoclopramide Oral Solution USP.



Metoclopramide Oral Solution USP, for oral use Initial U.S. Approval: 1979

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.

SeeWARNINGS

See Full Prescribing Information For Complete Boxed Warning.  ⮝

• Metoclopramide can cause tardive dyskinesia (TD), a serious movement disorder that is often irreversible. There is no known treatment for TD. The risk of developing TD increases with duration of treatment and total cumulative dosage ( 5.1)
• Discontinue metoclopramide in patients who develop signs or symptoms of TD ( 5.1)
• Avoid treatment with metoclopramide for longer than 12 weeks because of the risk of developing TD with longer-term use ( 5.1, 2.1, 2.2, 2.3)

Recent Major Changes ⮝

Boxed Warning	8/2017
Indications and Usage ( 1)	8/2017
Dosage and Administration, Dosage for Gastroesophageal Reflux ( 2.2)	8/2017
Dosage and Administration, Dosage for Acute and Recurrent Diabetic Gastroparesis ( 2.3)	8/2017
Contraindications ( 4)	8/2017
Warnings and Precautions, Tardive Dyskinesia ( 5.1)	8/2017
Warnings and Precautions, Other Extrapyramidal Symptoms ( 5.2)	8/2017
Warnings and Precautions, Neuroleptic Malignant Syndrome ( 5.3)	8/2017
Warnings and Precautions, Hyperprolactinemia ( 5.7)	8/2017

Indications And Usage ⮝

The use of Metoclopramide Oral Solution is recommended for adults only. Therapy should not exceed 12 weeks in duration.

Symptomatic Gastroesophageal Reflux

Metoclopramide Oral Solution USP is 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)

Metoclopramide 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 metoclopramide 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.

Dosage And Administration ⮝

Therapy with metoclopramide oral solution should not exceed 12 weeks in duration.

For the Relief of Symptomatic Gastroesophageal Reflux

Administer from 10 mg to 15 mg Metoclopramide Oral Solution USP (orally) up to q.i.d. 30 minutes before each meal and at bedtime, depending upon symptoms being treated and clinical response (see and ). 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. CLINICAL PHARMACOLOGYINDICATIONS AND USAGE

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 ). Because of the poor correlation between symptoms and endoscopic appearance of the esophagus, therapy directed at esophageal lesions is best guided by endoscopic evaluation. ADVERSE REACTIONS

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 metoclopramide 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 the 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, metoclopramide 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 should be initiated at approximately one-half the recommended dosage. Depending upon clinical efficacy and safety considerations, the dosage may be increased or decreased as appropriate.

See section for information regarding dialysis. OVERDOSAGE

Metoclopramide undergoes minimal hepatic metabolism, except for simple conjugation. Its safe use has been described in patients with advanced liver disease whose renal function was normal.

Dosage Forms And Strengths ⮝

Oral Solution: 10 mg/10 mL metoclopramide ( 3)

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 And Precautions ⮝

• Tardive Dyskinesia (TD), Other Extrapyramidal Symptoms (EPS), and Neuroleptic Malignant Syndrome (NMS): Avoid concomitant use of other drugs known to cause TD/EPS/NMS and avoid use in patients with Parkinson's Disease. If symptoms occur, discontinue metoclopramide and seek immediate medical attention. ( 5.1, 5.2, 5.3, 7.1, 7.2)
• Depression and suicidal ideation/suicide: Avoid use. ( 5.4)

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 ). Insomnia, headache, confusion, dizziness or mental depression with suicidal ideation (see ) 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. PRECAUTIONSWARNINGS

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 and 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 ). Fluid retention secondary to transient elevation of aldosterone (see ). PRECAUTIONSCLINICAL PHARMACOLOGY

Cardiovascular

Hypotension, hypertension, supraventricular tachycardia, bradycardia, fluid retention, acute congestive heart failure and possible AV block (see and ). CONTRAINDICATIONSPRECAUTIONS

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 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.

Drug Interactions ⮝

• Antipsychotics: Potential for additive effects, including TD, EPS, and NMS; avoid concomitant use. ( 7.1)
• CNS depressants: Increased risk of CNS depression. Avoid concomitant use and monitor for adverse reactions. ( 7.1)
• Strong CYP2D6 inhibitors (e.g., quinidine, bupropion, fluoxetine, and paroxetine): See Full Prescribing Information for recommended dosage reductions. ( 2.2, 2.3, 7.1)
• MAO inhibitors: Increased risk of hypertension; avoid concomitant use. ( 5.5, 7.1)
• Additional drug interactions: See Full Prescribing Information. ( 7.1, 7.2)

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

Revised: 9/2017

1 Indications And Usage ⮝

Metoclopramide is 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:

Metoclopramide is 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 (8.4)].

2 Dosage And Administration ⮝

2.1 Important Administration Instructions

Avoid treatment with metoclopramide for longer than 12 weeks because of the increased risk of developing TD with longer-term use [see Dosage and Administration (2.2, 2.3), Warnings and Precautions (5.1)].

2.2 Dosage for Gastroesophageal Reflux

Metoclopramide 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 metoclopramide 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 metoclopramide 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 Metoclopramide Dosage in Patients with Gastroesophageal Reflux

	Recommended Dosage	Maximum Recommended Daily Dosage
* Elderly patients may be more sensitive to the therapeutic or adverse effects of metoclopramide; 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.
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 (8.5)]	5 mg * 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 (8.7)]	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 (8.9)]
Concomitant use with strong CYP2D6 inhibitors (e.g., quinidine, bupropion, fluoxetine, and paroxetine) [see Drug Interactions (7.1)]
Moderate or severe renal impairment (creatinine clearance less than or equal to 60 mL/minute) [see Use in Specific Populations (8.6)]
Patients with End-Stage Renal Disease (ESRD) including those treated with hemodialysis and continuous ambulatory peritoneal dialysis [see Use in Specific Populations (8.6)]	5 mg four times daily (thirty minutes before each meal and at bedtime) or 10 mg twice daily	20 mg

2.3 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 metoclopramide treatment for greater than 12 weeks [see Warnings and Precautions (5.1)]. 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.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 metoclopramide, consider starting therapy with metoclopramide injection given intramuscularly or intravenously for up to 10 days (see the prescribing information for metoclopramide injection).If patients with diabetic gastroparesis have severe nausea or vomiting and are unable to take metoclopramide, consider starting therapy with metoclopramide injection given intramuscularly or intravenously for up to 10 days (see the prescribing information for metoclopramide injection).

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

	Recommended Dosage	Maximum Recommended Daily Dosage
* Elderly patients may be more sensitive to the therapeutic or adverse effects of metoclopramide; 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.
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 (8.5)]	5 mg * 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 (8.7)]	5 mg four times daily (30 minutes before each meal and at bedtime)	20 mg
CYP2D6 poor metabolizers [see Use in Specific Populations (8.9)]
Concomitant use with strong CYP2D6 inhibitors (e.g., quinidine, bupropion, fluoxetine, and paroxetine) [see Drug Interactions (7.1)]
Moderate or severe renal impairment (creatinine clearance less than 60 mL/minute) [see Use in Specific Populations (8.6)]
Patients with End-Stage Renal Disease (ESRD ) including those treated with hemodialysis and continuous ambulatory peritoneal dialysis [see Use in Specific Populations (8.6)]	5 mg twice daily	10 mg

3 Dosage Forms And Strengths ⮝

Oral Solution: 10 mg/10 mL metoclopramide

4 Contraindications ⮝

Metoclopramide is contraindicated:

• In patients with a history of tardive dyskinesia (TD) or a dystonic reaction to metoclopramide [see Warnings and Precautions (5.1, 5.2)] .
• 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.

  Metoclopramide may cause a hypertensive/pheochromocytoma crisis, probably due to release of catecholamines from the tumor . Metoclopramide may cause a hypertensive/pheochromocytoma crisis, probably due to release of catecholamines from the tumor [see Warnings and Precautions (5.5)] .

• In patients with epilepsy. Metoclopramide may increase the frequency and severity of seizures [see Adverse Reactions (6)] .
• In patients with hypersensitivity to metoclopramide. Reactions have included laryngeal and glossal angioedema and bronchospasm [see Adverse Reactions (6)] .

5 Warnings And Precautions ⮝

5.1 Tardive Dyskinesia

Metoclopramide can cause tardive dyskinesia (TD), a syndrome of potentially irreversible and disfiguring involuntary movements of the face or tongue, and sometimes of the trunk and/or extremities. Movements may be choreoathetotic in appearance. The risk of developing TD and the likelihood that TD will become irreversible increases with duration of treatment and total cumulative dosage. Additionally, the risk of developing TD is increased among the elderly, especially elderly women [see Use in Specific Populations (8.5)] , and in patients with diabetes mellitus. Due to the risk of developing TD, avoid treatment with metoclopramide for longer than 12 weeks and reduce the dosage in elderly patients [see Dosage and Administration (2.2, 2.3)].

Discontinue metoclopramide immediately in patients who develop signs and symptoms of TD. There is no known effective treatment for established cases of TD, although in some patients TD may remit, partially or completely, within several weeks to months after metoclopramide is withdrawn.Discontinue metoclopramide immediately in patients who develop signs and symptoms of TD. There is no known effective treatment for established cases of TD, although in some patients TD may remit, partially or completely, within several weeks to months after 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. Metoclopramide is contraindicated in patients with a history of TD Avoid metoclopramide in patients receiving other drugs that are likely to cause TD (e.g., antipsychotics). 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. Metoclopramide is contraindicated in patients with a history of TD [see Contraindications (4)]. Avoid metoclopramide in patients receiving other drugs that are likely to cause TD (e.g., antipsychotics).

5.2 Other Extrapyramidal Symptoms

In addition to TD, metoclopramide may cause other extrapyramidal symptoms (EPS), parkinsonian symptoms, and motor restlessness. Advise patients to seek immediate medical attention if such symptoms occur and to discontinue metoclopramide.

• Extrapyramidal symptoms (EPS), such as acute dystonic reactions, occurred in patients treated with metoclopramide dosages of 30 mg to 40 mg daily. Such reactions occurred more frequently in adults less than 30 years of age and at higher than recommended dosages. EPS occurred more frequently in pediatric patients compared to adults (metoclopramide is not approved for use in pediatric patients) . Symptoms can occur in the first 24 to 48 hours after starting metoclopramide. Symptoms included involuntary movements of limbs and facial grimacing, torticollis, oculogyric crisis, rhythmic protrusion of tongue, bulbar type of speech, trismus, or dystonic reactions resembling tetanus. Rarely, dystonic reactions were present as stridor and dyspnea, possibly due to laryngospasm. Diphenhydramine hydrochloride or benztropine mesylate may be used to treat these adverse reactions. Avoid metoclopramide in patients receiving other drugs that can cause EPS (e.g., antipsychotics).
• Parkinsonian symptoms (bradykinesia, tremor, cogwheel rigidity, mask-like facies) have occurred after starting metoclopramide, more commonly within the first 6 months, but also after longer periods. Symptoms generally have subsided within 2 to 3 months after discontinuation of metoclopramide. Avoid metoclopramide in patients with Parkinson's disease and other patients being treated with antiparkinsonian drugs due to potential exacerbation of symptoms. Avoid treatment with metoclopramide for more than 12 weeks [see Dosage and Administration (2.2, 2.3), Warnings and Precautions (5.1)] .
• Motor restlessness (akathisia) has developed and consisted of feelings of anxiety, agitation, jitteriness, and insomnia, as well as inability to sit still, pacing, and foot tapping. If symptoms resolve, consider restarting at a lower dosage.

5.3 Neuroleptic Malignant Syndrome

Metoclopramide may cause a potentially fatal symptom complex called neuroleptic malignant syndrome (NMS). NMS has been reported in association with metoclopramide overdosage and concomitant treatment with another drug associated with NMS. Avoid metoclopramide in patients receiving other drugs associated with NMS, including typical and atypical antipsychotics.

Clinical manifestations of NMS include hyperpyrexia, muscle rigidity, altered mental status, and manifestations of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac arrhythmias). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. Patients with such symptoms should be evaluated immediately.Clinical manifestations of NMS include hyperpyrexia, muscle rigidity, altered mental status, and manifestations of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac arrhythmias). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. Patients with such symptoms should be evaluated immediately.

In the diagnostic evaluation, consider the presence of other serious medical conditions (e.g., pneumonia, systemic infection) and untreated or inadequately treated extrapyramidal signs and symptoms. Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, malignant hyperthermia, drug fever, serotonin syndrome, and primary central nervous system pathology.In the diagnostic evaluation, consider the presence of other serious medical conditions (e.g., pneumonia, systemic infection) and untreated or inadequately treated extrapyramidal signs and symptoms. Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, malignant hyperthermia, drug fever, serotonin syndrome, and primary central nervous system pathology.

Management of NMS includes:Management of NMS includes:

• Immediate discontinuation of metoclopramide and other drugs not essential to concurrent therapy [see Drug Interactions (7.1)] .
• Intensive symptomatic treatment and medical monitoring.
• Treatment of any concomitant serious medical problems for which specific treatments are available.

5.4 Depression

Depression has occurred in metoclopramide-treated patients with and without a history of depression. Symptoms have included suicidal ideation and suicide. Avoid metoclopramide use in patients with a history of depression.

5.5 Hypertension

Metoclopramide may elevate blood pressure. In one study in hypertensive patients, intravenously administered metoclopramide was shown to release catecholamines; hence, avoid use in patients with hypertension or in patients taking monoamine oxidase inhibitors [see Drug Interactions (7.1)] .

There are also clinical reports of hypertensive crises in patients with undiagnosed pheochromocytoma. Metoclopramide is contraindicated in patients with pheochromocytoma or other catecholamine-releasing paragangliomas [see Contraindications (4)]. Discontinue metoclopramide in any patient with a rapid rise in blood pressure.

5.6 Fluid Retention

Because metoclopramide produces a transient increase in plasma aldosterone, patients with cirrhosis or congestive heart failure may be at risk of developing fluid retention and volume overload. Discontinue metoclopramide if any of these adverse reactions occur.

5.7 Hyperprolactinemia

As with other dopamine D 2 receptor antagonists, metoclopramide elevates prolactin levels.

Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported with prolactin-elevating drugs, including metoclopramide.Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported with prolactin-elevating drugs, including metoclopramide.

Hyperprolactinemia may potentially stimulate prolactin-dependent breast cancer. However, some clinical studies and epidemiology studies have not shown an association between administration of dopamine D2 receptor antagonists and tumorigenesis in humans Hyperprolactinemia may potentially stimulate prolactin-dependent breast cancer. However, some clinical studies and epidemiology studies have not shown an association between administration of dopamine D2 receptor antagonists and tumorigenesis in humans [see Nonclinical Toxicology (13.1)].

5.8 Effects on the Ability to Drive and Operate Machinery

Metoclopramide may impair the mental and/or physical abilities required for the performance of hazardous tasks such as operating machinery or driving a motor vehicle. Concomitant use of central nervous system (CNS) depressants or drugs associated with EPS may increase this effect (e.g., alcohol, sedatives, hypnotics, opiates, and anxiolytics). Avoid metoclopramide or the interacting drug, depending on the importance of the drug to the patient [see Drug Interactions (7.1)].

6 Adverse Reactions ⮝

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

• Tardive dyskinesia [see Boxed Warning and Warnings and Precautions (5.1)]
• Other extrapyramidal effects [see Warnings and Precautions (5.2)]
• Neuroleptic malignant syndrome [see Warnings and Precautions (5.3)]
• Depression [see Warnings and Precautions (5.4)]
• Hypertension [see Warnings and Precautions (5.5)]
• Fluid retention [see Warnings and Precautions (5.6)]
• Hyperprolactinemia [see Warnings and Precautions (5.7)]
• Effects on the ability to drive and operate machinery [see Warnings and Precautions (5.8)]

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

7 Drug Interactions ⮝

7.1 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 (5.1, 5.2, 5.3)].
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 (12.3)].
Intervention	Reduce the metoclopramide dosage [see Dosage and Administration (2.2, 2.3)].
Examples	quinidine, bupropion, fluoxetine, and paroxetine
Monoamine Oxidase Inhibitors
Clinical Impact	Increased risk of hypertension [see Warnings and Precautions (5.5)].
Intervention	Avoid concomitant use.
Central Nervous System (CNS) Depressants
Clinical Impact	Increased risk of CNS depression [see Warnings and Precautions (5.8)].
Intervention	Avoid metoclopramide 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

7.2 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
* Interaction does not apply to posaconazole delayed-release tablets
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 (5.2)] .
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.

8 Use In Specific Populations ⮝

8.1 Pregnancy

Risk Summary

Published studies, including retrospective cohort studies, national registry studies, and meta- analyses, do not report an increased risk of adverse pregnancy-related outcomes with use of metoclopramide during pregnancy.

There are potential risks to the neonate following exposure in utero to metoclopramide during delivery [see Clinical Considerations]. In animal reproduction studies, no adverse developmental effects were observed with oral administration of metoclopramide to pregnant rats and rabbits at exposures about 6 and 12 times the maximum recommended human dose (MRHD) [see Data] .

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in the clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Metoclopramide crosses the placental barrier and may cause extrapyramidal signs and methemoglobinemia in neonates with maternal administration during delivery. Monitor neonates for extrapyramidal signs [see Warnings and Precautions (5.1, 5.2), Use in Specific Populations (8.4)] .

Data

Animal Data

Reproduction studies have been performed following administration of oral metoclopramide during organogenesis in pregnant rats at about 6 times the MRHD calculated on body surface area and in pregnant rabbits at about 12 times the MRHD calculated on body surface area. No evidence of adverse developmental effects due to metoclopramide were observed.

8.2 Lactation

Risk Summary

Limited published data report the presence of metoclopramide in human milk in variable amounts. Breastfed infants exposed to metoclopramide have experienced gastrointestinal adverse reactions, including intestinal discomfort and increased intestinal gas formation [see Data] . Metoclopramide elevates prolactin levels [see Warnings and Precautions (5.7)] ; however, the published data are not adequate to support drug effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for metoclopramide and any potential adverse effects on the breastfed child from metoclopramide or from the underlying maternal condition.

Clinical Considerations

Monitor breastfeeding neonates because metoclopramide may cause extrapyramidal signs (dystonias) and methemoglobinemia [see Warnings and Precautions (5.1, 5.2), Use in Specific Populations (8.4)] .

Data

In published clinical studies, the estimated amount of metoclopramide received by the breastfed infant was less than 10% of the maternal weight-adjusted dose. In one study, the estimated daily amount of metoclopramide received by infants from breast milk ranged from 6 to 24 mcg/kg/day in early puerperium (3 to 9 days postpartum) and from 1 to 13 mcg/kg/day at 8 to 12 weeks postpartum.

8.4 Pediatric Use

Metoclopramide is not recommended for use in pediatric patients due to the risk of tardive dyskinesia (TD) and other extrapyramidal symptoms as well as the risk of methemoglobinemia in neonates. The safety and effectiveness of metoclopramide in pediatric patients have not been established.

Dystonias and other extrapyramidal symptoms associated with metoclopramide are more common in pediatric patients than in adults [see Warnings and Precautions (5.1, 5.2)] . In addition, neonates have reduced levels of NADH-cytochrome b5 reductase, making them more susceptible to methemoglobinemia, a possible adverse reaction of metoclopramide use in neonates [see Use in Specific Populations (8.8)] .

8.5 Geriatric Use

Metoclopramide is known to be substantially excreted by the kidney, and the risk of adverse reactions, including tardive dyskinesia (TD), may be greater in patients with impaired renal function [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)] . Elderly patients are more likely to have decreased renal function and may be more sensitive to the therapeutic or adverse effects of metoclopramide; therefore, consider a reduced dosage of metoclopramide in elderly patients [see Boxed Warning, Dosage and Administration (2.2, 2.3), Warnings and Precautions (5.1)].

8.6 Renal Impairment

The clearance of metoclopramide is decreased and the systemic exposure is increased in patients with moderate to severe renal impairment compared to patients with normal renal function, which may increase the risk of adverse reactions. Reduce the metoclopramide dosage in patients with moderate and severe renal impairment (creatinine clearance less than or equal to 60 mL/minute), including those receiving hemodialysis and continuous ambulatory peritoneal dialysis [see Dosage and Administration (2.2, 2.3), Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

Patients with severe hepatic impairment (Child-Pugh C) have reduced systemic metoclopramide clearance (by approximately 50%) compared to patients with normal hepatic function. The resulting increase in metoclopramide blood concentrations increases the risk of adverse reactions. There is no pharmacokinetic data in patients with moderate hepatic impairment (Child-Pugh B). Reduce metoclopramide dosage in patients with moderate or severe (Child-Pugh B or C) hepatic impairment [see Dosage and Administration (2.2, 2.3)] . There is no dosage adjustment required for patients with mild hepatic impairment (Child-Pugh A).

In addition, metoclopramide, by producing a transient increase in plasma aldosterone, may increase the risk of fluid retention in patients with hepatic impairment [see Warnings and Precautions (5.6)] .

Monitor patients with hepatic impairment for the occurrence of fluid retention and volume overload.

8.8 NADH-Cytochrome b5 Reductase Deficiency

Metoclopramide-treated patients with NADH-cytochrome b5 reductase deficiency are at an increased risk of developing methemoglobinemia and/or sulfhemoglobinemia. For patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency with metoclopramide-induced methemoglobinemia, methylene blue treatment is not recommended. Methylene blue may cause hemolytic anemia in patients with G6PD deficiency, which may be fatal [see Overdosage (10)].

8.9 CYP2D6 Poor Metabolizers

Metoclopramide is a substrate of CYP2D6. The elimination of metoclopramide may be slowed in patients who are CYP2D6 poor metabolizers (compared to patients who are CYP2D6 intermediate, extensive, or ultra-rapid metabolizers); possibly increasing the risk of dystonic and other adverse reactions to metoclopramide [see Clinical Pharmacology (12.3)]. Reduce the metoclopramide dosage in patients who are poor CYP2D6 metabolizers [see Dosage and Administration (2.2, 2.3)].

10 Overdosage ⮝

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 (5.1, 5.2, 5.3)].

There are no specific antidotes for metoclopramide 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.

11 Description ⮝

Metoclopramide, is a dopamine-2 receptor antagonist. Metoclopramide hydrochloride (metoclopramide monohydrochloride monohydrate) is a white crystalline, odorless substance, freely soluble in water. Its chemical name is 4-amino 5-chloro-N-[2-(diethylamino)ethyl]-2-methoxy benzamide monohydrochloride monohydrate.

The molecular formula is C 14H 22ClN 3O 2 HCl H 2O. Its molecular weight is 354.3. The structural formula is:

Metoclopramide Oral Solution USP is an orange-colored, berry-citrus flavored liquid for oral administration and is available in 10 mg/10 mL oral solution.

• Each 5 mL (teaspoonful) for oral administration contains: Metoclopramide base (as the monohydrochloride monohydrate) 5 mg. Inactive ingredients: Citric acid, FD&C Yellow No. 6 (Sunset Yellow), flavoring, glycerin, methylparaben, propylparaben, purified water, and sorbitol solution.

12 Clinical Pharmacology ⮝

12.1 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.

12.2 Pharmacodynamics

Gastroesophageal Reflux

In patients with gastroesophageal reflux and low lower esophageal sphincter pressure (LESP), single oral doses of metoclopramide 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.

12.3 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 (2.2, 2.3), Use in Specific Populations (8.9)] .

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 (2.2, 2.3) and Use in Specific Populations (8.6)].

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 (2.2, 2.3) and Use in Specific Populations (8.7)].

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 C max and AUC 0- , respectively, compared to patients who received metoclopramide alone (see Table 5) [see Drug Interactions (7.1)] .

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

Parameter	Metoclopramide alone (mean SD)	Metoclopramide with fluoxetine (mean SD)
C max (ng/mL)	44 15	62.7 9.2
AUC 0- (ng h/mL)	313 113	591 140
t 1/2 (h)	5.5 1.1	8.5 2.2

13 Nonclinical Toxicology ⮝

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

A 77-week study was conducted in rats with oral metoclopramide doses up to 40 mg/kg/day (about six times the maximum recommended human dose on body surface area basis). Metoclopramide elevated prolactin levels and the elevation persisted during chronic administration. An increase in mammary neoplasms was found in rodents after chronic administration of metoclopramide [see Warnings and Precautions (5.7)]. In a rat model for assessing the tumor promotion potential, a 2-week oral treatment with metoclopramide at a dose of 260 mg/kg/day (about 35 times the maximum recommended human dose based on body surface area) enhanced the tumorigenic effect of N-nitrosodiethylamine.

Mutagenesis

Metoclopramide was positive in the in vitro Chinese hamster lung cell/HGPRT forward mutation assay for mutagenic effects and in the in vitro human lymphocyte chromosome aberration assay for clastogenic effects. It was negative in the in vitro Ames mutation assay, the in vitro unscheduled DNA synthesis assay with rat and human hepatocytes, and the in vivo rat micronucleus assay.

Impairment of Fertility

Metoclopramide at intramuscular doses up to 20 mg/kg/day (about three 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.

16 How Supplied/storage And Handling ⮝

Metoclopramide Oral Solution USP, 5 mg metoclopramide base (as the monohydrochloride monohydrate) per 5 mL (teaspoonful) is available as an orange-colored, berry-citrus flavored, sugar-free solution and is supplied in the following oral dosage forms:

NDC 0121-0576-16:	16 fl oz (473 mL) bottle
NDC 0121-1576-10:	10 mL unit dose cup. Case contains 100 unit dose cups of 10 mL packaged in 10 trays of 10 unit dose cups each.

STORAGE

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

Principal Display Panel - 473 Ml Bottle Label ⮝

NDC 0121-0576-16

Metoclopramide
Oral Solution USP

5 mg/5 mL*

*Each 5 mL (1 teaspoonful) contains:
Metoclopramide 5 mg
(present as the hydrochloride)

PHARMACIST: Dispense the accompanying
Medication Guide to each patient.

Rx ONLY

16 fl oz (473 mL)

Pharmaceutical
Associates, Inc.
Greenville, SC 29605

Principal Display Panel - 10 Ml Cup Label ⮝

Delivers 10 mL
NDC 0121-1576-10

M ETOCLOPRAMIDE
O RAL S OLUTION USP
10 mg/10 mL
(present as the hydrochloride)

FOR INSTITUTIONAL USE ONLY
Rx ONLY
PHARMACEUTICAL ASSOCIATES, INC.
GREENVILLE, SC 29605
SEE INSERT

A15761001

METOCLOPRAMIDE metoclopramide hydrochloride solution

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0121-0576 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength METOCLOPRAMIDE HYDROCHLORIDE (UNII: W1792A2RVD) (METOCLOPRAMIDE - UNII:L4YEB44I46) METOCLOPRAMIDE 5 mg in 5 mL

Inactive Ingredients Ingredient Name Strength CITRIC ACID MONOHYDRATE (UNII: 2968PHW8QP) FD&C YELLOW NO. 6 (UNII: H77VEI93A8) GLYCERIN (UNII: PDC6A3C0OX) METHYLPARABEN (UNII: A2I8C7HI9T) PROPYLPARABEN (UNII: Z8IX2SC1OH) WATER (UNII: 059QF0KO0R) SORBITOL (UNII: 506T60A25R)

Product Characteristics Color orange Score Shape Size Flavor BERRY (BERRY CITRIS) Imprint Code Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0121-0576-16 473 mL in 1 BOTTLE; Type 0: Not a Combination Product 06/01/1991

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA072744 06/01/1991

METOCLOPRAMIDE metoclopramide hydrochloride solution

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0121-1576 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength METOCLOPRAMIDE HYDROCHLORIDE (UNII: W1792A2RVD) (METOCLOPRAMIDE - UNII:L4YEB44I46) METOCLOPRAMIDE 5 mg in 5 mL

Inactive Ingredients Ingredient Name Strength CITRIC ACID MONOHYDRATE (UNII: 2968PHW8QP) FD&C YELLOW NO. 6 (UNII: H77VEI93A8) GLYCERIN (UNII: PDC6A3C0OX) METHYLPARABEN (UNII: A2I8C7HI9T) PROPYLPARABEN (UNII: Z8IX2SC1OH) WATER (UNII: 059QF0KO0R) SORBITOL (UNII: 506T60A25R)

Product Characteristics Color orange Score Shape Size Flavor BERRY (BERRY CITRIS) Imprint Code Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0121-1576-10 10 in 1 CASE 06/01/1991 1 10 in 1 TRAY 1 10 mL in 1 CUP, UNIT-DOSE; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA072744 06/01/1991

Labeler - Pharmaceutical Associates, Inc. (044940096)

Establishment
Name	Address	ID/FEI	Business Operations
Pharmaceutical Associates, Inc.		097630693	manufacture(0121-0576, 0121-1576)

Revised: 12/2017 Document Id: 602b2124-a88a-0bd0-e053-2a91aa0a7acc 34391-3 Set id: 3cc8ca5b-8b71-4c77-a181-9ce154597b9a Version: 11 Effective Time: 20171212 Pharmaceutical Associates, Inc.

Description ⮝

Metoclopramide Oral Solution USP is an orange-colored, berry-citrus flavored liquid for oral administration.

Each 5 mL (teaspoonful) for oral administration contains: Metoclopramide base (as the monohydrochloride monohydrate) 5 mg.

Citric acid, FD&C Yellow No. 6 (Sunset Yellow), flavoring, glycerin, methylparaben, propylparaben, purified water, and sorbitol solution. Inactive ingredients:

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 H ClN O HCl H O. Molecular weight: 354.3. Its structural formula is: 1422322

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 ). 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. WARNINGS

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 hours 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 increased 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 hours. Linear kinetic processes adequately describe the absorption and elimination of metoclopramide.

Approximately 85% of the radioactivity of an orally administered dose appears in the urine within 72 hours. 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)	~3.5
Plasma Protein Binding	~30%
t (hr) 1/2	5 to 6
Oral Bioavailability	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 g/L) higher compared to that observed after the first dose (29 g/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 mcg/L (mean, 152 mcg/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 L/kg (range, 1 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 1060 to 5680 mcg/L. The mean elimination half-life, clearance, and volume of distribution of metoclopramide were 4.5 hr (range, 2 to 12.5 hr), 0.37 L/h/kg (range, 0.1 to 1.24 L/h/kg), and 1.93 L/kg (range, 0.95 to 5.5 L/kg), respectively.

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.

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 the 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, 50 mg of diphenhydramine hydrochloride injection should be given 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 pre-existing 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. 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.

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, 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 metoclopramide. A small number of patients may experience a withdrawal period after stopping metoclopramide that could include dizziness, nervousness, and/or headaches.

Information for Patients

The use of metoclopramide oral solution 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.

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).

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 , 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 vitro

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 ). In addition, neonates have reduced levels of NADH-cytochrome b reductase, which, in combination with the aforementioned pharmacokinetic factors, make neonates more susceptible to methemoglobinemia (see ). CLINICAL PHARMACOLOGY Pharmacokinetics5OVERDOSAGE

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. (See and .) WARNINGSADVERSE REACTIONS Extrapyramidal 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 metoclopramide that is effective. If parkinsonian-like symptoms develop in a geriatric patient receiving metoclopramide, metoclopramide should generally be discontinued before initiating any specific antiparkinsonian agents (see and ). WARNINGSDOSAGE 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 metoclopramide users. Sedation may cause confusion and manifest as over-sedation in the elderly (see and ). , CLINICAL PHARMACOLOGYPRECAUTIONS - Information for PatientsADVERSE REACTIONS - CNS Effects

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 - 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 functions, concomitant disease, or other drug therapy in the elderly (see and ). DOSAGE AND ADMINISTRATION - For the Relief of Symptomatic Gastroesophageal RefluxUSE IN PATIENTS WITH RENAL OR HEPATIC IMPAIRMENT

Other Special Populations

Patients with NADH-cytochrome b 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 ). 5OVERDOSAGE

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

How Supplied ⮝

NDC:17856-3727-5 in a CUP of 5 SOLUTIONS

Store at 20 to 25 C (68 to 77 F). [See USP Controlled Room Temperature.]

Manufactured By:

Greenville, SC 29605 www.paipharma.com Pharmaceutical Associates, Inc.

R10/12

Nystatin Suspension ⮝

METOCLOPRAMIDE metoclopramide hydrochloride solution

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:17856-0537(NDC:0121-0576) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Metoclopramide Hydrochloride (UNII: W1792A2RVD) (Metoclopramide - UNII:L4YEB44I46) Metoclopramide 5 mg in 5 mL

Inactive Ingredients Ingredient Name Strength citric acid monohydrate (UNII: 2968PHW8QP) FD&C Yellow No. 6 (UNII: H77VEI93A8) glycerin (UNII: PDC6A3C0OX) methylparaben (UNII: A2I8C7HI9T) propylparaben (UNII: Z8IX2SC1OH) water (UNII: 059QF0KO0R) sorbitol (UNII: 506T60A25R)

Product Characteristics Color ORANGE Score Shape Size Flavor BERRY (BERRY CITRIS) Imprint Code Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:17856-0537-5 5 mL in 1 CUP; Type 0: Not a Combination Product 10/24/2019

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA072744 06/01/1991

Labeler - Atlantic Biologicals Corps (047437707)

Registrant - Atlantic Biologicals Corps (047437707)

Establishment
Name	Address	ID/FEI	Business Operations
Atlantic Biologicals Corps		047437707	RELABEL(17856-0537) , REPACK(17856-0537)

Revised: 10/2019 Document Id: be2acd81-78bd-48d6-b5ea-0fb0e0a9d051 34391-3 Set id: 8d1f052d-e31d-4a60-9c3c-04a477e6f768 Version: 3 Effective Time: 20191024 Atlantic Biologicals Corps

Metoclopramide (metoclopramide Hydrochloride) Solution ⮝

METOCLOPRAMIDE metoclopramide hydrochloride solution

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:17856-0576(NDC:0121-0576) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Metoclopramide Hydrochloride (UNII: W1792A2RVD) (Metoclopramide - UNII:L4YEB44I46) Metoclopramide 5 mg in 5 mL

Inactive Ingredients Ingredient Name Strength citric acid monohydrate (UNII: 2968PHW8QP) FD&C Yellow No. 6 (UNII: H77VEI93A8) glycerin (UNII: PDC6A3C0OX) methylparaben (UNII: A2I8C7HI9T) propylparaben (UNII: Z8IX2SC1OH) water (UNII: 059QF0KO0R) sorbitol (UNII: 506T60A25R)

Product Characteristics Color ORANGE Score Shape Size Flavor BERRY (BERRY CITRIS) Imprint Code Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:17856-0576-5 5 mL in 1 CUP; Type 0: Not a Combination Product 05/04/2016 2 NDC:17856-0576-3 1 mL in 1 SYRINGE; Type 0: Not a Combination Product 09/01/2016 3 NDC:17856-0576-4 1 mL in 1 SYRINGE; Type 0: Not a Combination Product 03/10/2017 4 NDC:17856-0576-6 60 in 1 BOX 08/27/2018 4 0.5 mL in 1 SYRINGE; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA072744 06/01/1991

Labeler - Atlantic Biologicals Corps (047437707)

Registrant - Atlantic Biologicals Corps (047437707)

Establishment
Name	Address	ID/FEI	Business Operations
Atlantic Biologicals Corps		047437707	RELABEL(17856-0576) , REPACK(17856-0576)

Revised: 8/2018 Document Id: bb46cac4-a09e-4cc7-90ff-742413a55949 34391-3 Set id: 3cd4b274-6176-4e5b-9765-4f50763bd58f Version: 5 Effective Time: 20180827 Atlantic Biologicals Corps

Metoclopramide Oral Solution Usp ⮝

Rx ONLY

Propranolol Hydrochloride Solution ⮝

METOCLOPRAMIDE metoclopramide hydrochloride solution

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:17856-3727(NDC:0121-0576) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Metoclopramide Hydrochloride (UNII: W1792A2RVD) (Metoclopramide - UNII:L4YEB44I46) Metoclopramide 5 mg in 5 mL

Inactive Ingredients Ingredient Name Strength citric acid monohydrate (UNII: 2968PHW8QP) FD&C Yellow No. 6 (UNII: H77VEI93A8) glycerin (UNII: PDC6A3C0OX) methylparaben (UNII: A2I8C7HI9T) propylparaben (UNII: Z8IX2SC1OH) water (UNII: 059QF0KO0R) sorbitol (UNII: 506T60A25R)

Product Characteristics Color ORANGE Score Shape Size Flavor BERRY (BERRY CITRIS) Imprint Code Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:17856-3727-5 5 mL in 1 CUP; Type 0: Not a Combination Product 05/04/2015

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA072744 06/01/1991

Labeler - Atlantic Biologicals Corps (047437707)

Registrant - Atlantic Biologicals Corps (047437707)

Establishment
Name	Address	ID/FEI	Business Operations
Atlantic Biologicals Corps		047437707	RELABEL(17856-3727) , REPACK(17856-3727)

Revised: 5/2016 Document Id: 46e61d3f-323b-49e3-9c28-a5ddace56457 34391-3 Set id: c6384f37-1d85-42fa-ab7c-7d912abe9ce4 Version: 2 Effective Time: 20160504 Atlantic Biologicals Corps