Metoclopramide Nasal Spray - Uses, Dosage, Precautions, Side Effects, and Pharmacological Aspects

Overview

Metoclopramide nasal spray is a medication used for the treatment of diabetic gastroparesis (GP), a condition in which stomach emptying is delayed in individuals with diabetes (high blood sugar levels). This innovative nasal spray formulation provides an alternative route of administration, offering benefits for those who may have difficulty with oral medications. The U.S. or United States Food and Drug Administration (FDA) approved Metoclopramide nasal spray for this use in June 2020.

Drug Group

Metoclopramide nasal spray belongs to the drug group known as antiemetics or prokinetic agents, which treat nausea, vomiting, and gastrointestinal motility disorders.

Indications

Metoclopramide nasal spray is used to alleviate symptoms in adults with acute or recurrent diabetic gastroparesis.

Limitations of Use:

Metoclopramide nasal spray is not recommended for:

• Pediatric patients are susceptible to tardive dyskinesia or TD (a condition marked by involuntary, repetitive movements, often due to long-term medication use) risks, other extrapyramidal symptoms, and methemoglobinemia (abnormal hemoglobin in the blood) in neonates.

• Individuals with moderate to severe hepatic (liver) impairment (Child-Pugh B or C) or moderate to severe renal impairment (creatinine clearance below 60 mL (milliliters) per minute), or those using strong CYP2D6 (cytochrome P450 2D6) inhibitors due to increased drug exposure and adverse reactions.

Dosage Forms and Available Strengths

Nasal Spray: Each 70-microliter spray contains 15 mg (milligrams) of Metoclopramide. Metoclopramide nasal spray is an aqueous solution in an amber glass bottle with a metered spray pump.

For Patients

What Is Diabetic Gastroparesis?

Diabetic gastroparesis occurs when the stomach empties slowly because of nerve damage caused by diabetes. This condition occurs when elevated blood sugar levels damage the vagus nerve, which controls the stomach's movements. As a result, the stomach cannot effectively push food into the small intestine. It can range from mild (occasional nausea) to severe (chronic nausea and vomiting). The types are based on severity and underlying issues, such as motor dysfunction (impaired stomach contractions) or neurogenic dysfunction (nerve damage). The condition can lead to difficulties in blood sugar management and nutritional deficiencies, and it often requires careful management of diet and medication to control symptoms and improve stomach function.

How Does the Metoclopramide Nasal Spray Work?

Metoclopramide nasal spray enhances the motility of the upper gastrointestinal tract. It increases the muscle contractions in the stomach and small intestine, which helps with faster gastric emptying and food movement through the digestive system. The nasal spray formulation allows rapid medication absorption through the nasal passages, quickly relieving symptoms.

What Is the Dose of the Metoclopramide Nasal Spray?

The recommended dosage for Metoclopramide nasal spray is as follows:

• Adults: 15 mg administered as one spray into each nostril, four times daily.

• Timing: Use Metoclopramide at least 30 minutes before meals and at bedtime.

• Duration: Do not use it for more than eight weeks at a time. Do not use any Metoclopramide-containing products for more than 12 weeks.

How Is Metoclopramide Nasal Spray Administered?

• Take Metoclopramide exactly as directed by the doctor. Only adjust the dose after consulting them.

• Metoclopramide is supplied as a liquid in a glass bottle with an attached spray pump.

• Do not use Metoclopramide for more than eight weeks at a time.

• Do not use Metoclopramide-containing products, including Metoclopramide, for more than 12 weeks.

• Administer Metoclopramide at least 30 minutes before each meal and at bedtime.

What Are the Side Effects of Metoclopramide Nasal Spray?

Metoclopramide nasal spray may cause serious side effects, including:

Tardive Dyskinesia: This condition involves uncontrollable, abnormal muscle movements, primarily in the face, which may persist even after stopping Metoclopramide nasal spray. The risk of developing tardive dyskinesia would likely increase with:

• Longer duration and higher doses of Metoclopramide nasal spray. It should not be used for more than eight weeks or more than 12 weeks total.

• Age, especially in older individuals.

• Diabetes (high blood sugar levels).

The likelihood of developing tardive dyskinesia cannot be predicted. Contact a healthcare provider immediately if experiencing uncontrollable movements such as:

• Lip smacking, chewing, or puckering.

• Frowning or scowling.

• Sticking out the tongue.

• Blinking or moving the eyes.

• Shaking of the arms or legs.

Treatment with Metoclopramide nasal spray may be discontinued if signs of tardive dyskinesia occur.

What Are the Things to Inform the Doctor Before Taking Metoclopramide Nasal Spray?

Before starting Metoclopramide nasal spray, inform a healthcare provider about all medical conditions, including if:

• Insulin is used for diabetes, as dosage adjustments may be needed.

• The patient had issues with muscle movement control after taking any medication.

• Parkinson’s disease (a progressive neurological disorder).

• Kidney or liver disease.

• Depression or mental illness.

• High blood pressure.

• Heart failure or heart rhythm problems.

• Breast cancer.

• Alcohol consumption.

• Pregnancy is current or planned, as Metoclopramide may harm an unborn baby, especially towards the end of pregnancy. Discuss with a healthcare provider if pregnancy occurs while on Metoclopramide.

• Breastfeeding or planning to breastfeed.

Inform a doctor about all medicines being taken, including prescription, over-the-counter (OTC), vitamins, and herbal supplements. Metoclopramide nasal spray may interact with other medicines and vice versa. Notify a healthcare provider before starting or stopping any medications.

Specifically, mention if taking:

• Other Metoclopramide-containing medications include Metoclopramide orally disintegrating tablets (ODT) or Metoclopramide oral solution.

• Parkinson’s disease medications.

• Blood pressure medications.

• Depression medications, particularly monoamine oxidase inhibitors (MAOIs).

• Antipsychotic medications are used for mental illnesses like schizophrenia (a severe mental disorder marked by delusions).

• Insulin.

• Sedative medications, such as anxiety (excessive worry) treatments, sleep aids, and narcotics.

Maintain a list of all medications to show to healthcare providers and pharmacists when obtaining new prescriptions.

Dietary Considerations

The main dietary consideration while taking Metoclopramide nasal spray is to avoid alcohol, as it can exacerbate certain side effects like drowsiness or dizziness. There are no particular dietary restrictions concerning specific foods or beverages other than alcohol while using Metoclopramide. Still, it is always advisable to follow any dietary advice the healthcare provider gives based on the overall health condition.

Missed Dose

If unsure if the spray entered the nose, skip the dose and take the next scheduled dose as usual. Do not take an extra dose. If a dose is missed, take the next dose at the regular scheduled time. Refrain from double up to make up for a missed dose.

Overdose

Metoclopramide overdosage may cause drowsiness, disorientation, extrapyramidal reactions, other adverse effects (such as methemoglobinemia), and potentially death. Neuroleptic malignant syndrome, or NMS, or neuroleptic malignant syndrome (a rare but severe reaction to certain antipsychotic medications) has also been reported in cases of overdose, especially when combined with other NMS-associated drugs.

Methemoglobinemia can be treated with intravenous (IV) methylene blue administration, but it may cause hemolytic anemia (a condition where red blood cells or RBCs or red blood cells are destroyed faster) in patients with G6PD or glucose-6-phosphate dehydrogenase deficiency. Hemodialysis (medical procedure to remove waste products) and continuous ambulatory peritoneal dialysis (a type of dialysis where a fluid is used to clean the blood inside the abdomen) are not effective in removing significant amounts of Metoclopramide.

Storage and Handling

Metoclopramide nasal spray is provided as a 10 mL solution in a type 1 amber glass bottle equipped with a metered spray pump, protective cap, and safety clip. Each box includes one bottle with FDA-approved patient labeling. Each spray delivers 15 mg of Metoclopramide. A single bottle containing 9.8 mL is adequate for four weeks of use at four times a day.

Store at 20°C or degree Celsius to 25°C (68°F or degrees Fahrenheit to 77°F), with permissible excursions between 15°C to 30°C (59°F to 86°F). Discard Metoclopramide four weeks after opening, even if there is unused medicine remaining.

For Doctors

Description:

Metoclopramide hydrochloride is a dopamine-2 receptor antagonist. It is a white, crystalline, odorless substance that dissolves easily in water. Its chemical name is 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-methoxybenzamide monohydrochloride monohydrate, with the molecular formula C14H22ClN3O2•HCl•H2O and a molecular weight of 354.3.

Warnings and Precautions

• Tardive Dyskinesia: Metoclopramide nasal spray can cause tardive dyskinesia (TD), which involves potentially irreversible, involuntary movements of the face, tongue, or other body parts. The risk increases with more prolonged use and higher doses, particularly in the elderly and those with diabetes. Limit use to 12 weeks and discontinue immediately if TD symptoms occur. TD may improve after stopping Metoclopramide, but the drug can mask it. Avoid use in patients with a history of TD and those on medications that can cause TD.

• Other Extrapyramidal Symptoms: Metoclopramide may cause other movement disorders, such as acute dystonia and Parkinsonian symptoms, particularly in younger adults and pediatric patients. These symptoms can be managed with medications like Diphenhydramine or Benztropine. Avoid Metoclopramide in patients with Parkinson’s disease or those using drugs that can cause extrapyramidal symptoms.

• Neuroleptic Malignant Syndrome (NMS): Metoclopramide can lead to NMS, a potentially fatal condition with symptoms like high fever, muscle rigidity, and altered mental status. Immediate discontinuation of Metoclopramide and other associated drugs is required, along with intensive medical treatment.

• Depression: Depression, including suicidal thoughts, has occurred in some Metoclopramide users. Avoid Metoclopramide in patients with a history of depression.

• Hypertension: Metoclopramide may increase blood pressure and is not recommended for patients with hypertension or pheochromocytoma. It may also interact with monoamine oxidase inhibitors.

• Fluid Retention: Metoclopramide can cause fluid retention in patients with liver disease or heart failure. Discontinue if fluid overload occurs.

• Hyperprolactinemia: Metoclopramide may increase prolactin levels, leading to reproductive issues or, rarely, prolactin-dependent breast cancer.

• Effects on Driving and Machinery: Metoclopramide may impair the ability to drive or operate machinery. Avoid use with other CNS (central nervous system) depressants.

• Renal and Hepatic Impairment: Metoclopramide is advised against patients with severe renal or hepatic impairment or those using potent CYP2D6 (cytochrome P450 2D6) inhibitors due to the increased risk of adverse effects.

What Are the Pharmacological Actions of Metoclopramide Nasal Spray?

Mechanism of Action

Metoclopramide boosts upper gastrointestinal motility without affecting gastric, biliary, or pancreatic secretions. It likely enhances tissue sensitivity to acetylcholine, improving symptoms of gastroesophageal reflux and diabetic gastroparesis. The drug increases gastric and duodenal contractions, relaxes the pyloric sphincter, and speeds up gastric emptying and intestinal transit. It also raises the resting tone of the lower esophageal sphincter, with minimal impact on colon or gallbladder motility.

Pharmacodynamics

In a randomized, double-blind, positive-controlled ECG or electrocardiogram study involving 48 healthy subjects, a single administration of 80 mg of Metoclopramide nasal spray (approximately five times the recommended dose of Metoclopramide) showed no effect on the QTc interval.

Pharmacokinetics

• Absorption: The absolute bioavailability of 10 mg nasal Metoclopramide is 47 percent compared to the same intravenous dose and lower than after oral administration. After a single 15 mg nasal dose, systemic exposure and time to reach Cmax (maximum concentration) were similar to 10 mg oral tablet.

• Distribution: Metoclopramide binds to plasma proteins at around 30 percent and has a high volume of distribution (about 3.5 L/kg or liters per kilogram), suggesting extensive tissue distribution.

• Elimination: The mean elimination half-life of a 15 mg dose of Metoclopramide in individuals with normal renal function is about eight hours. Metoclopramide is metabolized in the liver through oxidation and conjugation (glucuronide and sulfate), with the major metabolite, monodeethylmetoclopramide, primarily formed by the CYP2D6 enzyme, which varies genetically.

• Excretion: Approximately 85 percent of the radioactivity from an oral dose is excreted in urine within 72 hours. After a 10 or 20 mg oral dose, 18 percent and 22 percent of the dose were recovered as free Metoclopramide in the urine within 36 hours.

Non-Clinical Toxicity:

Carcinogenesis: In a 77-week rat study, Metoclopramide at 40 mg/kg/day (milligrams per kilograms per day) increased mammary tumors. In another study, a two-week dose of 260 mg/kg/day enhanced the tumor-promoting effects of a cancer-causing agent.

Mutagenesis: Metoclopramide was mutagenic in the Chinese hamster lung cell assay and clastogenic in the human lymphocyte assay but harmful in other tests.

Impairment of Fertility: Metoclopramide at doses up to 20 mg/kg/day did not affect fertility in rats.

What Are the Contraindications of Metoclopramide Nasal Spray?

Metoclopramide nasal spray is contraindicated:

• In patients with a history of tardive dyskinesia (TD) or a dystonic reaction to Metoclopramide.

• When stimulating, gastrointestinal motility could be hazardous, such as in cases of gastrointestinal bleeding, mechanical obstruction, or perforation.

• In patients with pheochromocytoma or other catecholamine-releasing paragangliomas, due to the risk of a hypertensive or pheochromocytoma crisis from catecholamine release.

• In patients with epilepsy, Metoclopramide may worsen seizure frequency and severity.

• In patients with hypersensitivity to Metoclopramide, which can cause reactions such as laryngeal and glossal angioedema and bronchospasm.

What Are the Drug Interactions of Metoclopramide Nasal Spray?

Metoclopramide nasal spray can interact with various medications, potentially affecting their efficacy and safety:

• Antipsychotics: Increases the risk of tardive dyskinesia (TD), extrapyramidal symptoms (EPS), and neuroleptic malignant syndrome (NMS). Avoid the use of antipsychotics to prevent these risks.

• Strong CYP2D6 Inhibitors: Elevates Metoclopramide levels, raising the risk of EPS. Avoid use with strong CYP2D6 inhibitors such as Quinidine, Bupropion, Fluoxetine, and Paroxetine.

• Monoamine Oxidase Inhibitors: These drugs increase the risk of hypertension. Avoid use to prevent hypertensive effects.

• Central Nervous System (CNS) Depressants: Enhance CNS depression, impairing cognitive and motor functions. Avoid or closely monitor the use of CNS depressants like alcohol, sedatives, and opioids.

• Drugs that Impair Gastrointestinal Motility: May reduce the absorption of Metoclopramide. Monitor for decreased therapeutic effect when used with antiperistaltic antidiarrheals or anticholinergics.

• Dopaminergic Agonists and Dopamine-Increasing Drugs: May reduce Metoclopramide’s effectiveness due to opposing dopamine effects. Monitor for reduced therapeutic effects with drugs like Apomorphine, Bromocriptine, and Levodopa.

• Succinylcholine and Mivacurium: Metoclopramide inhibits plasma cholinesterase, potentially enhancing neuromuscular blockade. Monitor for signs of prolonged neuromuscular blockade.

• Drugs With Altered Absorption Due to Increased GI Motility: Metoclopramide may affect the absorption of other drugs, either increasing or decreasing their levels. Monitor and adjust dosages for drugs with decreased absorption (e.g., Digoxin) or increased absorption (e.g., Sirolimus).

• Insulin: Enhanced gastrointestinal motility may increase blood glucose levels. Monitor blood glucose and adjust insulin doses as necessary.

Clinical Studies

The effectiveness of Metoclopramide has been demonstrated through studies of oral Metoclopramide in relieving symptoms of acute and recurrent diabetic gastroparesis in adults.

Use in Specific Populations

• Pregnancy: No consistent pattern of increased risk for adverse pregnancy outcomes with oral Metoclopramide use. Metoclopramide crosses the placenta and may cause issues like extrapyramidal signs or methemoglobinemia in neonates. Monitor neonates if Metoclopramide is used during delivery.

• Lactation: Metoclopramide is found in human milk in variable amounts. Possible adverse effects in breastfed infants include gastrointestinal discomfort and increased gas. Limited data on its effects on milk production. Monitor breastfed infants for extrapyramidal signs and methemoglobinemia.

• Pediatric Use: Not recommended for children due to risks of tardive dyskinesia, extrapyramidal symptoms, and methemoglobinemia. Safety and effectiveness are not established in this age group.

• Geriatric Use: Elderly patients may have increased sensitivity to Metoclopramide, especially those with impaired renal function. Use a lower starting dose and avoid it as initial therapy.

• Renal Impairment: Decreased clearance and increased exposure in moderate to severe renal impairment. Not recommended for these patients. Adjust dose in mild renal impairment.

• Hepatic Impairment: Reduced clearance in severe hepatic impairment increases the risk of adverse effects. Not recommended for moderate or severe impairment. Adjust dose in mild hepatic impairment.

• NADH-Cytochrome b5 Reductase Deficiency: Increased risk of Methemoglobinemia. Avoid methylene blue treatment in patients with G6PD deficiency due to the potential for hemolytic anemia.

• CYP2D6 Poor Metabolizers: Slower elimination of Metoclopramide in CYP2D6 poor metabolizers may increase the risk of adverse reactions. Not recommended for these patients.