metoclopramide

INDICATIONS AND USAGE Diabetic Gastroparesis Metoclopramide injection (metoclopramide hydrochloride, USP) is indicated for the relief of symptoms associated with acute and recurrent diabetic gastroparesis in adults. The Prevention of Nausea and Vomiting Associated with Emetogenic Cancer Chemotherapy Metoclopramide injection is indicated for the prophylaxis of vomiting associated with emetogenic cancer chemotherapy in adults. The Prevention of Postoperative Nausea and Vomiting Metoclopramide injection is indicated for the prophylaxis of postoperative nausea and vomiting in those circumstances where nasogastric suction is undesirable in adults. Small Bowel Intubation Metoclopramide injection is indicated to facilitate small bowel intubation in adult and pediatric patients in whom the tube does not pass the pylorus with conventional maneuvers. Radiological Examination Metoclopramide injection is indicated to stimulate gastric emptying and intestinal transit of barium where delayed emptying interferes with radiological examination of the stomach and/or small intestine in adults.

DOSAGE AND ADMINISTRATION For the Relief of Symptoms Associated with Diabetic Gastroparesis If only the earliest manifestations of diabetic gastroparesis are present, oral administration of metoclopramide may be initiated. However, if severe symptoms are present, the recommended dosage of metoclopramide injection in adults is 10 mg administered intramuscularly or intravenously over at least 1- to 2-minutes. Administration of metoclopramide injection up to 10 days may be required before symptoms subside, at which time oral administration of metoclopramide may be instituted. Avoid a total duration of treatment with metoclopramide products, including metoclopramide injection, for longer than 12 weeks. If longer-term use is unavoidable, routinely monitor for signs and symptoms of TD (see WARNINGS – Tardive Dyskinesia ). For the Prevention of Nausea and Vomiting Associated with Emetogenic Cancer Chemotherapy The recommended dosage of metoclopramide injection in adults is 2 mg/kg, with highly emetogenic drugs (e.g., cisplatin or dacarbazine) alone or in combination, and 1 mg/kg, with less emetogenic drugs, infused intravenously over at least 15 minutes, 30 minutes before beginning cancer chemotherapy and repeated every 2 hours for two doses, then every 3 hours for three doses. For doses in excess of 10 mg, metoclopramide injection should be diluted in 50 mL of a parenteral solution. The preferred parenteral solution is Sodium Chloride Injection (normal saline), which when combined with metoclopramide injection, can be stored frozen for up to 4 weeks. Metoclopramide injection is degraded when admixed and frozen with Dextrose-5% in Water. Metoclopramide injection diluted in Sodium Chloride Injection, Dextrose-5% in Water, Dextrose-5% in 0.45% Sodium Chloride, Ringer’s Injection, or Lactated Ringer’s Injection may be stored up to 48 hours (without freezing) after preparation if protected from light. All dilutions may be stored unprotected from light under normal light conditions up to 24 hours after preparation. If acute dystonic reactions should occur, inject 50 mg Benadryl ® (diphenhydramine hydrochloride) intramuscularly, and the symptoms usually will subside. For the Prevention of Postoperative Nausea and Vomiting The recommended dosage of metoclopramide injection in adults is 10 mg or 20 mg as a single intramuscular injection near the end of surgery. To Facilitate Small Bowel Intubation In adult and pediatric patients undergoing small bowel intubation, in whom the tube has not passed the pylorus with conventional maneuvers after 10 minutes, the recommended dosage of metoclopramide injection is a single dose administered (undiluted) by the intravenous route over at least 1 to 2 minutes: Adults and pediatric patients above 14 years of age: 10 mg Pediatric patients 6 to 14 years of age: 2.5 to 5 mg Pediatric patients less than 6 years of age: 0.1 mg/kg To Aid in Radiological Examinations In adult patients where delayed gastric emptying interferes with radiological examination of the stomach and/or small intestine, the recommended dosage of metoclopramide injection is a single 10 mg dose administered (undiluted) by the intravenous route over at least 1- to 2-minutes. Use in Patients with 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. There is no dosage adjustment for patients with mild renal impairment (creatinine clearance greater than 60 mL/minute). For patients with moderate or severe renal impairment (creatinine clearance less than or equal to 60 mL/minute), who are receiving more than a single dose of metoclopramide injection, reduce the metoclopramide injection dosage to one-half the dosage recommended for patients with normal renal function. For patients with End-Stage Renal Disease (ESRD) including those treated with hemodi …

ADMIXTURES COMPATIBILITIES Metoclopramide Injection, USP is compatible for mixing and injection with the following dosage forms to the extent indicated below: Physically and Chemically Compatible up to 48 Hours Cimetidine Hydrochloride (SK&F), Mannitol, USP (Abbott), Potassium Acetate, USP (Invenex), Potassium Phosphate, USP (Invenex). Physically Compatible up to 48 Hours Ascorbic Acid, USP (Abbott), Benztropine Mesylate, USP (MS&D), Cytarabine, USP (Upjohn), Dexamethasone Sodium Phosphate, USP (ESI, MS&D), Diphenhydramine Hydrochloride, USP (Parke-Davis), Doxorubicin Hydrochloride, USP (Adria), Heparin Sodium, USP (ESI), Hydrocortisone Sodium Phosphate (MS&D), Lidocaine Hydrochloride, USP (ESI), Multi-Vitamin Injection (must be refrigerated - USV), Vitamin B Complex with Ascorbic Acid (Roche). Physically Compatible up to 24 Hours (Do not use if precipitation occurs) Clindamycin Phosphate, USP (Upjohn), Cyclophosphamide, USP (Mead-Johnson), Insulin, USP (Lilly). Conditionally Compatible (Use within one hour after mixing or may be infused directly into the same running IV line) Ampicillin Sodium, USP (Bristol), Cisplatin (Bristol), Erythromycin Lactobionate, USP (Abbott), Methotrexate Sodium, USP (Lederle), Penicillin G Potassium, USP (Squibb), Tetracycline Hydrochloride, USP (Lederle). Incompatible (Do Not Mix) Cephalothin Sodium, USP (Lilly), Chloramphenicol Sodium, USP (Parke-Davis), Sodium Bicarbonate, USP (Abbott)

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.

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 may occur in patients receiving the recommended prescribed dosage of metoclopramide injection. Insomnia, headache, confusion, dizziness, or mental depression with suicidal ideation also may occur (see WARNINGS ). In cancer chemotherapy patients being treated with 1-2 mg/kg per dose, incidence of drowsiness is about 70%. There are isolated reports of convulsive seizures without clear-cut relationship to metoclopramide. Rarely, hallucinations have been reported. 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. In cancer chemotherapy patients receiving 1-2 mg/kg per dose, the incidence is 2% in patients over the ages of 30-35, and 25% or higher in pediatric patients and adult patients less than 30 years of age who have not had prophylactic administration of diphenhydramine. 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, 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, muscular rigidity, altered consciousness, and autonomic instability (see WARNINGS ). Endocrine Disturbances Galactorrhea, amenorrhea, gynecomastia, impotence secondary to hyperprolactinemia (see PRECAUTIONS ). Fluid retention secondary to transient elevation of aldosterone (see CLINICAL PHARMACOLOGY ). Cardiovascular Hypotension, hypertension, supraventricular tachycardia, bradycardia, fluid retention, acute congestive heart failure and possible atrioventricular (AV) block (see CONTRAINDICATIONS and PRECAUTIONS ). 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 clear-cut 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. Transient flushing of the face and upper body, without alterations in vital signs, following high doses intravenously. To report SUSPECTED ADVERSE REACTIONS, contact Avenacy at 1-855-283-6229 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

Drug Interactions 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. Strong CYP2D6 Inhibitors, not Included in Antipsychotic Category Above Clinical Impact Increased plasma concentrations of metoclopramide; risk of exacerbation of extrapyramidal symptoms. Intervention Avoid metoclopramide injection. If use is unavoidable, monitor for adverse reactions Examples quinidine, bupropion, fluoxetine, and paroxetine Monoamine Oxidase Inhibitors Clinical Impact Increased risk of hypertension. Intervention Avoid concomitant use. Central Nervous System (CNS) Depressants Clinical Impact Increased risk of CNS depression. Intervention Avoid metoclopramide injection or the interacting drug, depending on the importance of the drug to the patient Examples alcohol, sedatives, hypnotics, opiates and anxiolytics Drugs that Impair Gastrointestinal Motility Clinical Impact Decreased systemic absorption of metoclopramide. Intervention Monitor for reduced therapeutic effect. Examples antiperistaltic antidiarrheal drugs, anticholinergic drugs, and opiates Dopaminergic Agonists and Other Drugs that Increase Dopamine Concentrations Clinical Impact Decreased therapeutic effect of metoclopramide due to opposing effects on dopamine. Intervention Monitor for reduced therapeutic effect. Examples apomorphine, bromocriptine, cabergoline, levodopa, pramipexole, ropinirole, and rotigotine Effects of Metoclopramide on Other Drugs Table 4 displays the effects of metoclopramide on other drugs. Table 4: Effects of Metoclopramide on Other Drugs *Interaction does not apply to posaconazole delayed-release tablets Dopaminergic Agonists and Drugs Increasing Dopamine Concentrations Clinical Impact Opposing effects of metoclopramide and the interacting drug on dopamine. Potential exacerbation of symptoms (e.g., parkinsonian symptoms). Intervention Avoid concomitant use. 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.

DESCRIPTION Metoclopramide hydrochloride is a white or practically white, crystalline, odorless or practically odorless powder. It is very soluble in water, freely soluble in alcohol, sparingly soluble in chloroform, practically insoluble in ether. Chemically it is 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-methoxybenzamide monohydrochloride monohydrate. It has the following structural formula: Molecular formula: C 14 H 22 ClN 3 O 2 • HCl • H 2 O Metoclopramide Injection, USP is a sterile, nonpyrogenic solution of metoclopramide hydrochloride in water for injection. Each milliliter contains metoclopramide base 5 mg (as the hydrochloride monohydrate); 8.5 mg sodium chloride. May contain hydrochloric acid and/or sodium hydroxide for pH adjustment; pH 4.4 (2.5 to 6.5). The solution contains no bacteriostat, antimicrobial agent or added buffer and is intended for use only as a single-dose injection. When smaller doses are required, the unused portion should be discarded. This product is light sensitive. It should be inspected before use and discarded if either color or particulate is observed. Metoclopramide Injection is intended for intravenous or intramuscular administration. structural formula metoclopramide hydrochloride

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 syrup. 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 METOCLOPRAMIDE INJECTION, USP is supplied in the following dosage forms. NDC 51662-1367-1 METOCLOPRAMIDE INJECTION, USP 10 mg/2 Ml (5mg/mL) 2mL SYR HF Acquisition Co LLC, DBA HealthFirst Mukilteo, WA 98275 Also supplied in the following manufacture supplied dosage forms Metoclopramide Injection, USP, 5 mg/mL metoclopramide base (as the monohydrochloride monohydrate) is available as: 10 mg/2 mL (5 mg/mL) in a pre-filled disposable single-use syringe Available in a carton of twenty-four (24) syringes. NDC 76045-101-20 Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature.] Protect from light. Retain in carton until time of use. This product is light sensitive. It should be inspected before use and discarded if either color or particulate is observed. Dilutions may be stored unprotected from light under normal light conditions up to 24 hours after preparation. Discard unused portion. Benadryl® is a registered trademark of McNeil Consumer. Cogentin® is a registered trademark of MS&D. Do not place syringe on a sterile field. Instructions For Use: CAUTION: Certain glass syringes may malfunction, break or clog when connected to some Needleless Luer Access Devices (NLADs) and needles. This syringe has a larger internal syringe tip and an external collar (luer collar). The external collar must remain attached to the syringe. Data show that the syringe achieves acceptable connections with the BD EclipseTM Needle and the Terumo SurGuard2TM Safety Needle and with the following non-center post NLADs: Alaris SMARTSITETM, B-Braun ULTRASITETM, BD-Q SYTETM, Maximum MAX PLUSTM, and B-Braun SAFSITETM. The data also show acceptable connections are achieved to the center post ICU Medical CLAVETM. However, spontaneous disconnection of this glass syringe from needles and NLADs with leakage of drug product may occur. Assure that the needle or NLAD is securely attached before beginning the injection. Visually inspect the glass syringe-needle or glass syringe –NLAD connection before and during drug administration. Do not remove the clear plastic wrap around the external collar. (See Figure 1) Figure 1 Inspect the outer packaging (blister pack) by verifying: - blister integrity - drug name - drug strength - dose volume - route of administration - expiration date to be sure that the drug has not expired - sterile field applicability Do not use if package has been damaged. Peel open the paper (top web) of the outer packaging that displays the product information to access the syringe. Do not pop syringe through. Bend the plastic part of the outer packaging (thermoform) so as to present the plunger rod for syringe removal. (See Figure 2) Figure 2 Perform visual inspection on the syringe by verifying: - absence of syringe damage - absence of external particles - absence of internal particles - proper drug color - expiration date to be sure that the drug has not expired - drug name - drug strength - dose volume - route of administration - integrity of the plastic wrap around the external collar Do not remove plastic wrap around the external collar. Push plunger rod slightly to break the stopper loose while tip cap is still on. Do not remove plastic wrap around the external collar. Remove tip cap by twisting it off. (See Figure 3) Figure 3 Discard the tip cap. Expel air bubble. To use the syringe in pediatric patients or patients who need a dose less than 10 mg, adjust dose into sterile material. Connect the syringe to appropriate injection connection depending on route of administration. Before injection, ensure that the syringe is securely attached to the needle or needleless luer access device (NLAD). Depress plunger rod to deliver medication. Ensure that pressure is maintained on the plunger rod during the entire administration. Remove syringe from NLAD (if applicable) and discard into appropriate receptacle. If delivering medication with a needle, to prevent needle stick injuries, do not recap needle. NOTES: - All steps mus …