Review of the Gastrointestinal Drug Metoclopramide (GIMOTI, REGLAN)

Metoclopramide belongs to the group of medications know as dopamine antagonists. The drug increases the tone of the muscle at the junction of the stomach and the esophagus (the tube connecting the mouth to the stomach) and increases stomach contractions. It is available in tablet form under the brand name REGLAN[1] and in multiple generic versions, and a nasal-spray version sold under the brand name GIMOTI,[2] as well as injectable versions used in the hospital or clinic setting.

Reglan and Gimoti are approved by the Food and Drug Administration (FDA) to relieve symptoms such as nausea, vomiting, loss of appetite, heartburn and a feeling of fullness after meals in adults with diabetes who have a condition in which the stomach takes too long to empty — a condition called diabetic gastroparesis.[3],[4] Reglan also is approved to treat adults with gastroesophageal reflux, a condition in which the stomach contents flow backward into the esophagus, causing heartburn.[5]

Public Citizen’s Health Research Group has designated metoclopramide as a Limited Use drug given its numerous serious risks, which are discussed below.

Important warnings[6]

Tardive dyskinesia

The product labeling for metoclopramide includes an FDA-required black-box warning — the agency’s most prominent warning — about the risk of tardive dyskinesia, a serious drug-induced movement disorder that is often irreversible (see text box, below).

Tardive dyskinesia most commonly involves abnormal, involuntary movements of the jaw, lips and tongue, such as sticking out and twisting the tongue, lip smacking and chewing movements. It also can cause involuntary movements of the limbs and trunk.[7]

Use of metoclopramide should be limited to no more than 12 weeks because of the risk of tardive dyskinesia.

FDA-Required Black-Box Warning for Metoclopramide

• Reglan can cause tardive dyskinesia, a serious movement disorder that is often irreversible. There is no known treatment for tardive dyskinesia. The risk of developing tardive dyskinesia increases with duration of treatment and total cumulative dosage.
• Metoclopramide should be discontinued in patients who develop signs or symptoms of tardive dyskinesia. In some patients, symptoms may lessen or resolve after the drug is stopped.
• Avoid treatment with metoclopramide for longer than 12 weeks because of the increased risk of developing tardive dyskinesia with longer-term use.

Other movement disorders

In addition to tardive dyskinesia, metoclopramide may cause other neurologic movement-disorder symptoms, including the following:

• Extrapyramidal symptoms, such as acute dystonic reactions (sudden involuntary muscle contractions in head, neck or back). Such reactions occurred more frequently in adults younger than 30 years of age and with higher-than-recommended dosages of metoclopramide.
• Parkinson’s disease-like symptoms, including bradykinesia (slowness of movements), tremor, rigidity and expressionless or masklike face
• Motor restlessness, consisting of feelings of anxiety, agitation, jitteriness and insomnia, as well as inability to sit still, pacing and foot tapping

Neuroleptic malignant syndrome

Metoclopramide can cause neuroleptic malignant syndrome (NMS), particularly if overdosed or taken concomitantly with other medications that cause NMS, such as antipsychotic drugs. NMS is a life-threatening neurological disorder requiring immediate medical attention. Signs and symptoms of NMS include high fever; excessive sweating; stupor (impaired consciousness and markedly decreased responsiveness); muscle rigidity or stiffness; unstable blood pressure, which may lead to dizziness and fainting upon standing; and irregular heart rate or pulse.

Depression

Depression has occurred in metoclopramide-treated patients with and without a history of depression. Symptoms have included suicidal thoughts and behavior. Metoclopramide should be avoided in patients with a history of depression.

Hypertension

Metoclopramide may increase blood pressure. The drug should be avoided in patients with hypertension or those taking monoamine oxidase inhibitors.

Increased prolactin

Metoclopramide increases levels of the hormone prolactin. This may lead to galactorrhea (a milky nipple discharge unrelated to the normal milk production of breast-feeding), amenorrhea (absence of menstruation), gynecomastia (breast enlargement) and erectile dysfunction.

Impaired driving

Metoclopramide may impair the mental or physical abilities required for the performance of hazardous tasks such as driving a motor vehicle or operating machinery. Concomitant use of central nervous system depressants or drugs associated with extrapyramidal symptoms (for example, alcohol, benzodiazepines and opioids) may increase this effect.

Fluid retention

Patients with cirrhosis (late-stage scarring of the liver) or heart failure who take metoclopramide may develop fluid retention and volume overload, which can lead to swelling in feet, legs, hands and face and shortness of breath due to fluid buildup in the lungs.

Limits on use

Reglan should be used only temporarily to treat severe gastroesophageal reflux disease that has not responded to acid-suppressing medications, such as histamine-2 blockers (for example, cimetidine [TAGAMET HB] and famotidine [PEPCID AC]) or proton pump inhibitors (for example, esomeprazole [NEXIUM] and omeprazole [PRILOSEC]).

Patients older than 60 generally should take less than the usual adult dose because older adults often do not tolerate metoclopramide well.

Removal of metoclopramide from the body is impaired in patients with moderate-to-severe impairment of kidney function and in patients with severe liver disease. The product labeling for Reglan advises that the dosage for the drug be reduced in patients with moderate or severe kidney- or liver-function impairment,[8] and the product labeling for Gimoti advises that the drug not be used in such patients.[9]

The product labeling for metoclopramide also advises that the drug should not be used in children due to the risk of tardive dyskinesia and other neurologic movement disorders.[10]

This drug should not be used to treat motion sickness or vertigo (dizziness and the sensation that you are spinning or that the world is spinning around you), a use not approved by the FDA.

What You Can Do

Before taking metoclopramide, discuss with your doctor alternative treatments for your gastroparesis or gastroesophageal reflux and tell your doctor about all of your medical conditions, including whether you

• have diabetes (your insulin dose may need to be adjusted during metoclopramide therapy);
• had problems controlling your muscle movements after taking any medication;
• have high blood pressure, heart failure or abnormal heart rhythms;
• have kidney or liver disease;
• have breast cancer;
• have or had depression;
• have Parkinson’s disease;
• are pregnant or plan to become pregnant or are breast-feeding or plan to breast feed; or
• drink alcohol.

You should not take metoclopramide for more than 12 weeks. When taking the drug, do not drink alcohol or use other drugs that can cause drowsiness. Until you know how you react to metoclopramide, do not drive or perform other activities requiring alertness.

When taking metoclopramide, call your doctor immediately if you experience

• signs of tardive dyskinesia, such as lip smacking; chewing movements; puffing of cheeks; rapid, darting tongue movements; uncontrolled movements of arms or legs; or unusual twisting movements of body;
• signs of parkinsonism, such as difficulty speaking or swallowing, loss of balance, masklike face, stiffness of arms or legs, trembling and shaking, or shuffling walk;
• increased blood pressure;
• depression or suicidal thoughts;
• fever or uncontrolled sweating;
• muscle stiffness;
• confusion;
• restlessness or nervousness;
• severe or persistent headache;
• heartbeat that is fast, slow or irregular;
• difficulty breathing; or
• vision problems.

References

[1] ANI Pharmaceuticals, Inc. Label: metoclopramide (REGLAN). August 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/017854s062lbl.pdf. Accessed January 12, 2022.

[2] Evoke Pharma, Inc. Label: metoclopramide (GIMOTI). January 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/209388s001lbl.pdf. Accessed January 12, 2022.

[3] ANI Pharmaceuticals, Inc. Label: metoclopramide (REGLAN). August 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/017854s062lbl.pdf. Accessed January 12, 2022.

[4] Evoke Pharma, Inc. Label: metoclopramide (GIMOTI). January 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/209388s001lbl.pdf. Accessed January 12, 2022.

[5] ANI Pharmaceuticals, Inc. Label: metoclopramide (REGLAN). August 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/017854s062lbl.pdf. Accessed January 12, 2022.

[6] Ibid.

[7] Deik A, Tarsy D. Tardive dyskinesia: Etiology, risk factors, clinical features, and diagnosis. UpToDate. July 30, 2020.

[8] ANI Pharmaceuticals, Inc. Label: metoclopramide (REGLAN). August 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/017854s062lbl.pdf. Accessed January 12, 2022.

[9] Evoke Pharma, Inc. Label: metoclopramide (GIMOTI). January 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/209388s001lbl.pdf. Accessed January 12, 2022.

[10] ANI Pharmaceuticals, Inc. Label: metoclopramide (REGLAN). August 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/017854s062lbl.pdf. Accessed January 12, 2022.