CLINICAL PHARMACOLOGY
CLINICAL PHARMACOLOGY
Metoclopramide stimulates motility of the upper gastrointestinal tract without stimulating gastric, biliary, or pancreatic secretions. Its mode of action is unclear. It seems to sensitize tissues to the action of acetylcholine. The effect of metoclopramide on motility is not dependent on intact vagal innervation, but it can be abolished by anticholinergic drugs.
Metoclopramide increases the tone and amplitude of gastric (especially antral) contractions, relaxes the pyloric sphincter and the duodenal bulb, and increases peristalsis of the duodenum and jejunum resulting in accelerated gastric emptying and intestinal transit. It increases the resting tone of the lower esophageal sphincter. It has little, if any, effect on the motility of the colon or gallbladder.
In patients with gastroesophageal reflux and low LESP (lower esophageal sphincter pressure), single oral doses of metoclopramide produce dose-related increases in LESP. Effects begin at about 5 mg and increase through 20 mg (the largest dose tested). The increase in LESP from a 5 mg dose lasts about 45 minutes and that of 20 mg lasts between 2 and 3 hours. Increased rate of stomach emptying has been observed with single oral doses of 10 mg.
The antiemetic properties of metoclopramide appear to be a result of its antagonism of central and peripheral dopamine receptors. Dopamine produces nausea and vomiting by stimulation of the medullary chemoreceptor trigger zone (CTZ), and metoclopramide blocks stimulation of the CTZ by agents like l-dopa or apomorphine which are known to increase dopamine levels or to possess dopamine-like effects. Metoclopramide also abolishes the slowing of gastric emptying caused by apomorphine.
Like the phenothiazines and related drugs, which are also dopamine antagonists, metoclopramide produces sedation and may produce extrapyramidal reactions, although these are comparatively rare (see WARNINGS). Metoclopramide inhibits the central and peripheral effects of apomorphine, induces release of prolactin and causes a transient increase in circulating aldosterone levels, which may be associated with transient fluid retention.
The onset of pharmacological action of metoclopramide is 1 to 3 minutes following an intravenous dose, 10 to 15 minutes following intramuscular administration, and 30 to 60 minutes following an oral dose, pharmacological effects persist for 1 to 2 hours.
Pharmacokinetics
Metoclopramide is rapidly and well absorbed. Relative to an intravenous dose of 20 mg, the absolute oral bioavailability of metoclopramide is 80% ± 15.5% as demonstrated in a crossover study of 18 subjects. Peak plasma concentrations occur at about 1 to 2 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 increases linearly with doses from 20 to 100 mg. Peak concentrations increase linearly with dose; time to peak concentrations remains the same; whole body clearance is unchanged; and the elimination rate remains the same. The average elimination half-life in individuals with normal renal function is 5 to 6 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.
Parameter | Value |
Vd (L/kg) | ~3.5 |
Plasma Protein Binding | ~30% |
t1/2 (hr) | 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 mcg/L) higher compared to that observed after the first dose (29 mcg/L) indicating drug accumulation with repeated dosing. After the tenth dose, the mean time to reach peak concentrations (2.2 hrs), half-life (4.1 hrs), 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 hrs, 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 nine pediatric cancer patients receiving chemotherapy (mean age, 11.7 years; range, 7 to 14 yrs) 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 hrs (range, 1.7 to 8.3 hrs), 0.56 L/h/kg (range, 0.12 to 1.20 L/h/kg), and 3.0 L/kg (range, 1.0 to 4.8 L/kg), respectively.
In another study, nine pediatric cancer patients (age range, 1 to 9 yrs) 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 hrs (range, 2.0 to 12.5 hrs), 0.37 L/h/kg (range, 0.10 to 1.24 L/h/kg), and 1.93 L/kg (range, 0.95 to 5.50 L/kg), respectively.
| a SEM not available. 1. Bateman, DN, et al. Br J Clin Pharmac 15:557-559, 1983. 2. Ford, C. Clin Pharmac Ther 43:196, 1988. | |||||
Reference | Dose, Route | t1/2 (hr) | CI (L/hr/kg) | Vd (L/kg) | Cmax (mcg/L) |
1. | 0.35 mg/kg IV over 5 min | 4.4 ± 0.56 | 0.56 ± 0.10 | 3.0 ± 0.38 (Dose/Cp0) | 152 ± 31 |
2. | 2 mg/kg 30 min IV infusion 4 to 5 times within 9.5 hours | 4.5a | 0.37a | 1.93a | 1060 to 5680a |
MEDICATION GUIDE
MEDICATION GUIDE
Metoclopramide (met” oh kloe’ pra mide) Injection, USP
You or your caregiver should read the Medication Guide before you start receiving metoclopramide injection and before you get another dose of metoclopramide injection. There may be new information. If you take another product that contains metoclopramide (such as metoclopramide tablets, metoclopramide orally disintegrating tablets, or metoclopramide oral solution), you should read the Medication Guide that comes with that product. Some of the information may be different. This Medication Guide does not take the place of talking to your doctor about your medical condition or your treatment.
What is the most important information I should know about metoclopramide?
Metoclopramide can cause serious side effects, including:
Abnormal muscle movements called tardive dyskinesia (TD). These movements happen mostly in the face muscles. You can not control these movements. They may not go away even after stopping metoclopramide. There is no treatment for TD, but symptoms may lessen or go away over time after you stop taking metoclopramide.
Your chances for getting TD go up:
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- the longer you take metoclopramide and the more metoclopramide you take. You should not take metoclopramide for more than 12 weeks.
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- if you are older, especially if you are a woman
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- if you have diabetes
It is not possible for your doctor to know if you will get TD if you take metoclopramide.
Call your doctor right away if you get movements you can not stop or control, such as:
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- lip smacking, chewing, or puckering up your mouth
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- frowning or scowling
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- sticking out your tongue
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- blinking and moving your eyes
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- shaking of your arms and legs
See the section "What are the possible side effects of metoclopramide?" for more information about side effects.
What is metoclopramide?
Metoclopramide is a prescription medicine used to:
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- relieve symptoms of slow stomach emptying in people with diabetes
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- prevent nausea and vomiting that can happen with cancer chemotherapy
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- prevent nausea and vomiting that may happen after surgery, if your doctor decides that you should not be treated with a stomach tube and suction
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- help make it easier to insert a tube into the small intestine in both adults and children, if the tube does not pass into the stomach normally.
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- to help empty stomach contents or to help barium move through your intestine, when you get an X-ray examination of the stomach or small intestine. It is not known if metoclopramide is safe and works in children except when used to help insert a tube into the small intestine.
Who should not receive metoclopramide?
Do not receive metoclopramide if you:
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- have stomach or intestine problems that could get worse with metoclopramide, such as bleeding, blockage or a tear in your stomach or bowel wall
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- have an adrenal gland tumor called pheochromocytoma
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- are allergic to metoclopramide or anything in it. See the end of this Medication Guide for a list of ingredients in metoclopramide.
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- take medicines that can cause uncontrolled movements, such as medicines for mental illness
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- have seizures
What should I tell my doctor before receiving metoclopramide?
Tell your doctor about all of your medical conditions, including if you have:
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- depression
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- Parkinson's disease
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- high blood pressure
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- kidney problems. Your doctor may start with a lower dose.
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- liver problems or heart failure. Metoclopramide may cause your body to hold fluids.
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- diabetes. Your dose of insulin may need to be changed.
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- breast cancer
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- you are pregnant or plan to become pregnant. It is not known if metoclopramide will harm your unborn child.
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- you are breastfeeding. Metoclopramide is passed into human milk and may harm your baby. Talk with your doctor about the best way to feed your baby if you take metoclopramide.
Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. Metoclopramide and some other medicines can affect each other and may not work as well, or cause possible side effects. Do not start any new medicines while receiving metoclopramide until you talk with your doctor.
Especially tell your doctor if you take:
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- another medicine that contains metoclopramide, such as metoclopramide tablets, metoclopramide orally disintegrating tablets, or metoclopramide oral solution
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- a blood pressure medicine
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- a medicine for depression, especially a Monoamine Oxidase Inhibitor (MAOI)
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- insulin
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- 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.
How will I receive metoclopramide?
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- Metoclopramide will be given to you by intravenous (IV) infusion into your vein or by intramuscular (IM) injection into a large muscle. Where and how you receive your metoclopramide injection (IV or IM) will depend on why you are receiving it.
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- Certain side effects can happen if metoclopramide is given too fast. See the section "What are the possible side effects of metoclopramide?"
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- You should not take or receive metoclopramide for more than 12 weeks.
What should I avoid while receiving metoclopramide?
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- Do not drink alcohol while receiving metoclopramide. Alcohol may make some side effects of metoclopramide worse, such as feeling sleepy.
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- Do not drive, work with machines, or do dangerous tasks until you know how metoclopramide affects you. Metoclopramide may cause sleepiness.
What are the possible side effects of metoclopramide?
Metoclopramide can cause serious side effects, including:
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- Abnormal muscle movements. See the section "What is the most important information I should know about metoclopramide?"
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- Uncontrolled spasms of your face and neck muscles, or muscles of your body, arms, and legs (dystonia). These muscle spasms can cause abnormal movements and body positions. These spasms usually start within the first 2 days of treatment. These spasms happen more often in children and adults under age 30.
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- Depression, thoughts about suicide, and suicide. Some people who take metoclopramide become depressed. You may have thoughts about hurting or killing yourself. Some people who take metoclopramide have ended their own lives (suicide).
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- Neuroleptic Malignant Syndrome (NMS). NMS is a very rare but very serious condition that can happen with metoclopramide. NMS can cause death and must be treated in a hospital. Symptoms of NMS include: high fever, stiff muscles, problems thinking, very fast or uneven heartbeat, and increased sweating.
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- Parkinsonism. Symptoms include slight shaking, body stiffness, trouble moving or keeping your balance. If you already have Parkinson's disease, your symptoms may become worse while you are receiving metoclopramide.
Call your doctor and get medical help right away if you:
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- feel depressed or have thoughts about hurting or killing yourself
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- have high fever, stiff muscles, problems thinking, very fast or uneven heartbeat, and increased sweating
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- have muscle movements you can not stop or control
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- have muscle movements that are new or unusual
Common side effects of metoclopramide include:
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- feeling restless, sleepy, tired, dizzy, or exhausted
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- headache
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- confusion
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- trouble sleeping
Infusion related side effects can happen if metoclopramide is given too fast. You may feel very anxious and restless for a short time, and then become sleepy while you are receiving a dose of metoclopramide. Tell your doctor or nurse right away if this happens.
You may have more side effects the longer you take metoclopramide and the more metoclopramide you take.
Tell your doctor about any side effects that bother you or do not go away. These are not all the possible side effects of metoclopramide.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
General information about metoclopramide
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.
This Medication Guide summarizes the most important information about metoclopramide. If you would like more information about metoclopramide, talk with your doctor. You can ask your doctor or pharmacist for information about metoclopramide that is written for healthcare professionals. For more information go to www.hospira.com or call 1-800-615-0187.
What are the ingredients in metoclopramide?
Active ingredient: metoclopramide
Inactive ingredients: sodium chloride, water, hydrochloric acid or sodium hydroxide
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Distributed by Hospira, Inc., Lake Forest, IL 60045 USA
LAB-1291-2.0
Revised: 09/2023
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