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IMPAX GENERICS
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metoclopramide 5 mg tablet

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Uses

Metoclopramide is used in a variety of GI disorders, but principally for the management of GI motility disorders, especially gastric stasis, for the management of gastroesophageal reflux, for the prevention of cancer chemotherapy-induced nausea and vomiting, and for the prevention of postoperative nausea and vomiting when nasogastric suction is considered undesirable. The drug is also used to facilitate intubation of the small intestine and as an adjunct during radiographic examination of the upper GI tract.

Therapy with the drug should not exceed 12 weeks' duration. Metoclopramide oral solution and tablets are recommended for use in adults only.

Diabetic Gastric Stasis

Metoclopramide is used for the symptomatic treatment of acute and recurrent diabetic gastric stasis (gastroparesis). Treatment of diabetic gastric stasis with metoclopramide is not curative. Since diabetic gastric stasis is a chronic, recurrent disease, successful therapy may often require long-term, intermittent use of metoclopramide.

The motility of the stomach is abnormal in patients with diabetic gastric stasis; fundic and antral contractility are markedly diminished and gastric emptying of liquids and solids is delayed. Although a correlation between gastric stasis and autonomic neuropathy has not been shown in diabetics, these patients may have signs of vagal nerve damage.

In patients with diabetic gastric stasis, metoclopramide increases the rate of gastric emptying and decreases usual symptoms of gastric stasis including nausea, vomiting, heartburn, anorexia, persistent postprandial fullness, abdominal pain and distention, and early satiety. Symptoms of delayed gastric emptying appear to respond to metoclopramide within different time intervals. Relief of nausea usually occurs soon after initiating metoclopramide therapy and continues to improve over a 3-week period. Subsequently, relief of vomiting and anorexia may precede relief of abdominal fullness by 1 week or longer.

In most patients with diabetic gastric stasis, metoclopramide-induced reduction of symptoms does not correlate well with improvement in gastric emptying. In some patients, complete relief of symptoms occurs despite minimal increases in the rate of gastric emptying, while in others, symptoms of gastric stasis persist despite a normalization in gastric emptying.

Postsurgical Gastric Stasis

Metoclopramide has been used for the symptomatic treatment of acute and chronic postsurgical gastric stasis following vagotomy and gastric resection or vagotomy and pyloroplasty. The drug has improved gastric emptying and decreased the usual symptoms of gastric stasis in patients with these conditions.

Prevention of Cancer Chemotherapy-induced Emesis

Metoclopramide is used parenterally in high doses for the prevention of nausea and vomiting associated with emetogenic cancer chemotherapy. The drug also has been administered orally for the prevention of chemotherapy-induced nausea and vomiting.

To prevent chemotherapy-induced nausea and vomiting associated with chemotherapy regimens with a high emetic risk (i.e., incidence of emesis exceeds 90% if no antiemetics are administered), the American Society of Clinical Oncology (ASCO) currently recommends a 3-drug antiemetic regimen consisting of a type 3 serotonin (5-HT3) receptor antagonist (e.g., dolasetron, granisetron, ondansetron, palonosetron, tropisetron [not commercially available in the US]), dexamethasone, and aprepitant.

Antiemetic agents with a lower therapeutic index (i.e., less efficacious and generally associated with more frequent adverse effects), including metoclopramide, cannabinoids (e.g., dronabinol, nabilone), butyrophenones, and phenothiazines are not considered by ASCO to be appropriate first-line antiemetics for any group of patients receiving chemotherapy of high emetic risk; ASCO states that these drugs should be reserved for patients unable to tolerate or refractory to first-line agents.

The antiemetic combination of a 5-HT3 receptor antagonist, dexamethasone, and aprepitant also is preferred in patients receiving combination chemotherapy with an anthracycline and cyclophosphamide.

For patients receiving other chemotherapy of moderate emetic risk (i.e., incidence of emesis without antiemetics exceeds 30% but does not exceed 90%), ASCO recommends a 2-drug antiemetic regimen consisting of a 5-HT3 receptor antagonist and dexamethasone.

For patients receiving chemotherapy regimens with a low emetic risk (i.e., incidence of emesis without antiemetics exceeds 10% but does not exceed 30%), ASCO recommends dexamethasone alone on the first day of chemotherapy.

Antiemetics can be prescribed on an as-needed basis in patients receiving chemotherapy with a minimal emetic risk (incidence of emesis is less than 10% without antiemetics).

In patients experiencing vomiting and nausea despite recommended prophylaxis regimens, ASCO recommends that clinicians consider adding a benzodiazepine (e.g., alprazolam, lorazepam) to the regimen, substituting high-dose intravenous metoclopramide for the 5-HT3 receptor antagonist in the regimen, or adding a butyrophenone or phenothiazine to the regimen.

For the prevention of delayed emesis in patients receiving cisplatin or other chemotherapy associated with a high emetic risk, these authorities currently recommend a 2-drug combination of dexamethasone and aprepitant.

Although antihistamines (e.g., diphenhydramine) and benzodiazepines (e.g., alprazolam, lorazepam) may be useful as adjunctive antiemetic agents, they currently are not recommended as monotherapy as antiemetic agents. However, many clinicians find benzodiazepines useful in the management of anticipatory emesis.

Cisplatin

Metoclopramide is used parenterally for the prevention of cisplatin-induced nausea and vomiting. The drug has been used effectively for the prevention of chemotherapy-induced emesis in patients receiving cisplatin alone or in combination with other antineoplastic agents. In patients receiving cisplatin, high-dose metoclopramide (2 mg/kg) reduces the number and duration of vomiting episodes and the volume of emesis. In some patients, cisplatin-induced nausea and vomiting are completely prevented with metoclopramide therapy. Clinical evaluations of metoclopramide in the prevention of cisplatin-induced emesis have shown that the antiemetic effect of metoclopramide is greater than that of placebo, prochlorperazine, or tetrahydrocannabinol (THC). However, it appears that type 3 serotonergic (5-HT3) receptor antagonists (e.g., dolasetron, granisetron, ondansetron, palonosetron, tropisetron [not commercially available in the US]) and aprepitant generally are more effective and better tolerated than metoclopramide, which reportedly is pharmacologically less selective, and therefore, these 5-HT3 receptor antagonists given in combination with dexamethasone and aprepitant may be preferred for the initial prophylaxis of acute emetic effects in many patients; in some cases, these drugs may be effective in treating nausea and emesis that develop despite metoclopramide prophylaxis. Currently available 5-HT3 receptor antagonists (i.e., dolasetron, granisetron, ondansetron, palonosetron, tropisetron [not commercially available in the US]) appear to be comparably effective in preventing acute cisplatin- and other chemotherapy-induced nausea and vomiting. The addition of dexamethasone to monotherapy with a 5-HT3 receptor antagonist or metoclopramide increases the antiemetic efficacy of either drug alone, and such combined therapy may be useful in patients whose nausea and vomiting are refractory to monotherapy. Although addition of diphenhydramine to metoclopramide and dexamethasone therapy may increase the antiemetic efficacy further and decrease metoclopramide-induced adverse effects, combined therapy with a selective 5-HT3 receptor antagonist and dexamethasone appears to be more effective than this triple-drug combination. In addition, some evidence suggests that such combined therapy may be more effective, albeit not optimally, than monotherapy for the prevention and treatment of delayed emesis. Various combinations of antiemetic agents have been used, and comparative efficacy is continually being evaluated.

Remaining most problematic is the management of delayed and anticipatory nausea and vomiting; pending further elucidation of optimal regimens, some clinicians suggest combined regimens of 2 or 3 drugs that include a 5-HT3 receptor antagonist (e.g., dolasetron, granisetron, ondansetron, palonosetron, tropisetron [not commercially available in the US]), aprepitant, a corticosteroid (e.g., dexamethasone), metoclopramide, and/or benzodiazepine (e.g., lorazepam for anxiolytic, amnesic, and possibly antiemetic effects). In several clinical trials, oral metoclopramide has been effective when given in combination with dexamethasone for the prevention of delayed emesis in patients receiving chemotherapy.

Based on limited published data, maximum efficacy of metoclopramide appears to depend greatly on the use of the appropriate dose, route, and schedule during administration of the drug.(See Prevention of Cancer Chemotherapy-induced Emesis, in Dosage and Administration: Dosage.) The efficacy of lower than currently recommended doses and/or alternate administration schedules for metoclopramide in the prevention of cisplatin-induced emesis remains to be clearly established. In one study in patients receiving cisplatin, optimum antiemetic effect was generally associated with serum metoclopramide concentrations greater than 850 ng/mL.

Metoclopramide is more likely to be effective in patients who were not previously exposed to cancer chemotherapy than in patients whose symptoms are refractory to conventional antiemetic agents. The antiemetic efficacy of metoclopramide appears to be maintained during subsequent doses of cisplatin.

Other Antineoplastic Agents

Metoclopramide is used for prevention of nausea and vomiting associated with other antineoplastic agents (e.g., cyclophosphamide, dacarbazine, doxorubicin, methotrexate) and with cancer chemotherapy regimens that do not include cisplatin. Since various antineoplastic agents may induce emesis by different mechanisms, the efficacy of metoclopramide depends on their relative potential and specific pharmacologic pathways for inducing emesis. In patients receiving dacarbazine, high-dose metoclopramide (2 mg/kg) appears to be an effective antiemetic. When oral metoclopramide (10 mg 1-2 hours before chemotherapy and then every 8 hours for a week) was combined with IV dexamethasone (10 mg immediately before initiation of IV chemotherapy) in patients receiving cyclophosphamide, methotrexate, and fluorouracil for breast cancer (a moderately emetogenic regimen), this antiemetic combination appeared to be comparably effective overall to oral ondansetron (8 mg 1-2 hours before chemotherapy and then every 8 hours for a week) in preventing emesis during the 7-day treatment period but was more effective than ondansetron in reducing the frequency of nausea during the first day of chemotherapy. Additional study is needed to further evaluate the role of metoclopramide alone or combined with other antiemetics in the prevention of nausea and vomiting associated with the many different regimens used for cancer chemotherapy.

Intubation of the Small Intestine

Metoclopramide is used parenterally to facilitate intubation of the small intestine in adults and children in whom the tube (e.g., endoscope, biopsy tube) does not pass through the pylorus with conventional maneuvers. The beneficial effect of metoclopramide on intubation of the small intestine is principally related to the pharmacologic action of the drug on GI motility and contractility.(See Pharmacology: GI Effects.) Metoclopramide has little influence on the time required for biopsy capsules to reach the pylorus, but substantially reduces the time required for the capsules to pass through the pylorus.

In several controlled trials in patients with or without GI disease (e.g., inflammatory bowel disease, chronic diarrhea, malabsorption, celiac disease, peptic ulcer) undergoing intubation of the small intestine, IV metoclopramide (10 mg) reduced the time required for intubation and facilitated performance of the procedure; however, administration of the drug generally did not influence patient tolerance of the procedure.

Radiographic Examination of the Upper GI Tract

Metoclopramide is used parenterally to stimulate gastric emptying and intestinal transit of barium in patients in whom delayed emptying interferes with radiographic examination of the stomach and/or small intestine. In patients receiving oral barium, IV metoclopramide increases the rate of gastric emptying and reduces transit time of the barium in the small intestine. Metoclopramide markedly reduces the time required for radiographic examination of the small intestine and is effective in preventing nausea or regurgitation of barium that occurs in some patients with gastric atonia, pylorospasm, or spasm of the duodenal bulb.

Gastroesophageal Reflux

Metoclopramide is used orally for the short-term (up to 12 weeks) relief of symptomatic, documented gastroesophageal reflux in adults who are unresponsive to conventional therapy alone, including changes in lifestyle, habits, and/or diet, which may be contributing or precipitating factors, and weight reduction in obese patients. However, agents that suppress gastric acid secretion (e.g., proton-pump inhibitors, histamine H2-receptor antagonists) currently are considered to be the mainstay of treatment for gastroesophageal reflux disease (GERD).

Metoclopramide produces a dose-related increase in the resting tone of the lower esophageal sphincter in healthy adults and in patients with gastroesophageal reflux. There reportedly is substantial interindividual variation in the effect of metoclopramide on lower esophageal sphincter pressure. In patients with gastroesophageal reflux, metoclopramide increases gastric emptying rate both in those with normal or delayed gastric emptying, and reduces daytime and nocturnal heartburn and regurgitation; however, metoclopramide therapy produces greater reductions in severity and occurrence of daytime and postprandial heartburn and regurgitation than in nocturnal symptoms associated with gastroesophageal reflux. If symptoms are associated with particular situations of precipitating factors (e.g., following the evening meal), administration of a single dose of metoclopramide prior to the provocative situation rather than daily administration of multiple doses of the drug should be considered.

Based on data from a limited number of patients, metoclopramide appears to be more effective than an aluminum hydroxide antacid or placebo and about as effective as cimetidine in improving the symptoms of gastroesophageal reflux. Objective parameters (i.e., endoscopy, lower esophageal sphincter pressure, esophageal contraction amplitude) for response were not consistently improved in these patients following short-term (4-8 weeks) administration of metoclopramide; however, in one unpublished study, endoscopic evidence of healing was observed following administration of metoclopramide (15 mg 4 times daily) for 12 weeks. Since there is no documented correlation between symptoms and healing of esophageal lesions in patients with gastroesophageal reflux, therapy in patients with documented lesions should be accompanied by appropriate endoscopic evaluation. In a study comparing single oral doses of metoclopramide (15 mg) with an aluminum hydroxide antacid (30 mL) or placebo in patients with reflux esophagitis, metoclopramide was reportedly more effective than antacid in reducing the symptoms associated with reflux. Metoclopramide increased the resting tone of the lower esophageal sphincter in all patients for at least 1 hour and prevented gastroesophageal reflux following administration of an intragastric acid load. Although metoclopramide may be effective for the short-term relief of gastroesophageal reflux, safety and efficacy of metoclopramide therapy beyond 12 weeks have not been evaluated and such prolonged use is not recommended.

Although metoclopramide appears to provide symptomatic relief and esophageal healing as effectively as a standard dosage of a histamine H2-receptor antagonist, and improved efficacy has been reported when metoclopramide has been used with a histamine H2-receptor antagonist, the potential risks (e.g., severe and potentially irreversible adverse CNS effects) and benefits of metoclopramide relative to other effective therapies must be considered. The American College of Gastroenterology (ACG) states that the frequent occurrence of adverse CNS effects has appropriately decreased the regular use of metoclopramide for treatment of GERD. Furthermore, the American Gastroenterological Association (AGA) recommends against use of metoclopramide for treatment of GERD because of the drug's adverse effect profile and a lack of high-quality data supporting its use. The ACG and AGA state that proton-pump inhibitors provide greater control of acid reflux than do other currently available agents, including prokinetic agents (e.g., cisapride [no longer commercially available in the US], metoclopramide). Suppression of gastric acid secretion is considered by these experts to be the mainstay of treatment for GERD, and a proton-pump inhibitor or histamine H2-receptor antagonist is used to achieve acid suppression, control symptoms, and prevent complications of the disease. Because GERD is considered to be a chronic disease, many patients with GERD will require long-term, even lifelong, treatment. For further information on the treatment of GERD,

Other Uses

Metoclopramide is used parenterally for the prevention of postoperative nausea and vomiting when nasogastric suction is considered undesirable.

Metoclopramide has been used for the management of migraine. Some experts state that IM metoclopramide may be considered as adjunctive therapy for control of nausea in patients with acute migraine attacks and that the IV drug may be considered as monotherapy for relief of migraine pain. For further information on management and classification of migraine headache,

Metoclopramide has been used in a limited number of patients for the treatment of peptic ulcer. Metoclopramide has also been used as an antiemetic for the prevention of nausea and vomiting associated with drugs other than antineoplastic agents, radiation therapy, and other causes. The drug has also been used for the management of anorexia nervosa, vertigo, and intractable hiccups. Metoclopramide has been used to promote postpartum lactation. Metoclopramide has also been used to empty the stomach of blood prior to endoscopy in patients with upper GI hemorrhage. The safety and efficacy of metoclopramide in these conditions have not been established.

Dosage and Administration

Administration

Metoclopramide is administered orally, by IM or direct IV injection, or by IV infusion.

Therapy with the drug should not exceed 12 weeks' duration. Metoclopramide oral solution and tablets are recommended for adults only.

For IM or direct IV injection, the commercially available metoclopramide injection is used without further dilution. For direct IV injection, each 10 mg of the drug should be administered slowly over 1-2 minutes, since a transient but intense feeling of anxiety and restlessness, followed by drowsiness, may occur with rapid IV injection.

For doses exceeding 10 mg, metoclopramide injection should be diluted in 50 mL of a compatible IV solution.

For IV infusion, metoclopramide hydrochloride injection should be diluted in 50 mL of one of the following IV solutions: 5% dextrose, 0.9% sodium chloride, 5% dextrose and 0.45% sodium chloride, Ringer's, or lactated Ringer's. Because the drug is most stable when diluted in 0.9% sodium chloride injection, the manufacturers state that this is the preferred solution for preparing IV infusions. IV infusions should be given slowly over at least 15 minutes. Other IV solutions flowing through a common administration tubing or site generally should be discontinued while metoclopramide is being infused unless the solutions are known to be compatible and the flow rate is adequately controlled.

Metoclopramide injection and diluted solutions of the drug should be inspected for particulate matter and discoloration prior to administration whenever solution and container permit; the solution should be discarded if particulate matter or discoloration is observed.

Dosage

Although USP currently states that potency of metoclopramide hydrochloride preparations should be expressed both in terms of the salt and the base (''active moiety''), dosage currently is expressed in terms of the base.(See Chemistry and Stability: Chemistry.)

Diabetic Gastric Stasis

For relief of symptoms associated with diabetic gastric stasis in patients who can tolerate oral administration of the drug, the usual adult oral dosage of metoclopramide is 10 mg 4 times daily, given 30 minutes before meals and at bedtime. In patients who have severe symptoms, or when oral administration of metoclopramide is not feasible, the drug should be given by IM or IV injection. The usual adult IM or IV dosage of metoclopramide for symptomatic relief of diabetic gastric stasis is 10 mg 4 times daily, given 30 minutes before meals and at bedtime; parenteral administration of metoclopramide for up 10 days may be required until symptoms subside sufficiently to allow oral administration of the drug.

Oral therapy with metoclopramide is usually continued for 2-8 weeks, depending on patient response and the likelihood of continued well-being if the drug is discontinued. Since diabetic gastric stasis is frequently recurrent, metoclopramide therapy should be reinstituted at the earliest recurrence of symptoms. However, a thorough assessment of the risks and benefits should be made prior to continuing further metoclopramide therapy.

Prevention of Cancer Chemotherapy-induced Emesis

For the prevention of cancer chemotherapy-induced emesis, the manufacturer states that metoclopramide is usually given by IV infusion 30 minutes before administration of cancer chemotherapy, and repeated every 2 hours for 2 additional doses, then every 3 hours for 3 additional doses. For adults, the manufacturer states that the initial 2 doses of metoclopramide should be 2 mg/kg if highly emetogenic drugs (e.g., cisplatin, dacarbazine, dactinomycin) are used alone or in combination, while a metoclopramide dose of 1 mg/kg may be sufficient for less emetogenic drugs or chemotherapy regimens.However, combinations of other antiemetic agents generally are preferred as first-line antiemetic regimens in patients receiving chemotherapy of moderate or high emetic risk (see Uses: Prevention of Cancer Chemotherapy-induced Emesis). If extrapyramidal symptoms occur during these IV metoclopramide dosage regimens, diphenhydramine hydrochloride (e.g., 25-50 mg given IV or IM) may be administered.

Metoclopramide has been administered orally for the prevention of chemotherapy-induced emesis. For prevention of emesis in patients receiving an IV chemotherapy regimen with low emetic risk, some experts state that 10-40 mg of metoclopramide may be administered orally or IV before the chemotherapy dose and then repeated every 4 or 6 hours as needed; these experts state that patients receiving oral chemotherapy requiring only as-needed (''prn'') antiemetic therapy may receive oral metoclopramide (10-40 mg orally before the chemotherapy dose and then every 4 or 6 hours as needed). If dystonic reactions occur, patients may receive diphenhydramine hydrochloride (e.g., 25-50 mg orally or IV every 4 or 6 hours).

Metoclopramide also has been administered orally for the prevention of delayed emesis in patients receiving chemotherapy (i.e., vomiting occurring 24 or more hours after chemotherapy). When given in combination with dexamethasone in clinical trials, oral metoclopramide dosages of 20-40 mg (or 0.5 mg/kg) given 2-4 times daily for 3 or 4 days have been used.

Prevention of Postoperative Nausea and Vomiting

For the prevention of postoperative nausea and vomiting when nasogastric suction is considered undesirable, the manufacturer states that the usual adult IM dose of metoclopramide is 10 mg administered near the end of the surgical procedure, although a 20-mg dose also may be used.

Intubation of the Small Intestine

For patients undergoing intubation of the small intestine in whom the tube has not passed through the pylorus during 10 minutes of conventional maneuvers, the usual dose of metoclopramide to facilitate intubation in adults and children older than 14 years of age is 10 mg, given as a single, direct IV injection. To facilitate intubation in children, the usual single IV dose of metoclopramide is 0.1 mg/kg in children younger than 6 years of age or 2.5-5 mg in children 6-14 years of age.

Radiographic Examination of the Upper GI Tract

For patients in whom delayed gastric emptying interferes with radiographic examination of the stomach and/or small intestine, the usual adult dose of metoclopramide to stimulate gastric emptying and intestinal transit of barium is 10 mg, given as a single, direct IV injection.

Gastroesophageal Reflux

For the symptomatic treatment of gastroesophageal reflux, the usual adult oral dosage of metoclopramide is 10-15 mg given up to 4 times daily 30 minutes before each meal and at bedtime, depending on the symptoms being treated and the patient's clinical response.(See Uses: Gastroesophageal Reflux.) If symptoms occur only intermittently or at specific times of the day, single oral doses up to 20 mg given prior to the provoking situation may be preferred to daily administration of multiple doses of the drug. Some patients (e.g., geriatric patients) who are sensitive to the therapeutic and/or adverse effects of the drug may require individual doses of only 5 mg. Although experience in patients with esophageal erosion and ulceration associated with gastroesophageal reflux is limited, a metoclopramide dosage of 15 mg 4 times daily has been suggested in such patients. Because of the poor correlation between symptoms and endoscopic appearance of the esophagus, therapy in patients with documented esophageal lesions is best guided by endoscopic evaluation. The safety and efficacy of continuing metoclopramide therapy beyond 12 weeks in patients with gastroesophageal reflux have not been established and such prolonged use is not recommended.

Dosage in Renal and Hepatic Impairment

Because metoclopramide is eliminated principally via renal excretion, doses and or frequency of administration of the drug should be modified in response to the degree of impairment in patients with impaired renal function. The manufacturers recommend that patients with creatinine clearances less than 40 mL/minute receive initial metoclopramide dosages that are approximately 50% of the usual recommended dosages. Dosage subsequently should be increased or decreased according to the patient's clinical response and tolerance.

Modification of metoclopramide dosage in patients with impaired hepatic function does not appear to be necessary.

Cautions

Adverse reactions to metoclopramide generally involve the CNS and GI tract and are usually mild, transient, and reversible following discontinuance of the drug. In general, the incidence of metoclopramide-induced adverse effects is related to dosage and duration of therapy.

Nervous System Effects

The most frequent adverse effects of metoclopramide involve the CNS. Restlessness, drowsiness, fatigue, and lassitude have been reported in patients receiving the drug; these effects occur in about 10% of patients receiving a dosage of 10 mg 4 times daily. Insomnia, headache, confusion, dizziness, or depression with suicidal ideation occurs less frequently. The risk of drowsiness is increased at higher doses, occurring in about 70% of patients receiving doses of 1-2 mg/kg. Seizures have been reported rarely, although a causal relationship to metoclopramide has not been established. Hallucinations also have been reported rarely. Feelings of anxiety or agitation also may occur, especially following rapid IV injection of the drug.

Extrapyramidal reactions (e.g., acute dystonic reactions, akathisia) may occur in patients receiving metoclopramide and apparently are mediated via blockade of central dopaminergic receptors involved in motor function. Although extrapyramidal reactions may occur in all age groups and at any dose, they occur more frequently in pediatric patients and adults younger than 30 years of age and following IV administration of high doses of the drug (e.g., those used in prophylaxis of cancer chemotherapy-induced vomiting). Extrapyramidal reactions generally occur within 24-48 hours after starting therapy and usually subside within 24 hours following discontinuance of the drug. Most patients respond rapidly to treatment with diazepam or an agent with central anticholinergic activity such as diphenhydramine or benztropine.

Acute dystonic reactions, which resemble the acute dyskinesias produced by antipsychotic drugs (e.g., phenothiazines, butyrophenones), reportedly occur in less than 1% of adults receiving low dosages of metoclopramide (e.g., 30-40 mg daily) and are not necessarily related to dose. However, dystonic reactions occur in approximately 25% of young adults (i.e., 18-30 years of age) receiving high dosages of metoclopramide (e.g., 2 mg/kg per dose) during cancer chemotherapy; in adults older than 30 years of age who are receiving similar dosages of metoclopramide, the incidence of dystonic reactions is only about 1.8%. Dystonic reactions associated with metoclopramide therapy include involuntary movements of limbs, trismus, torticollis, facial spasms, rhythmic protrusions of the tongue, bulbar type of speech, opisthotonos, and oculogyric crisis. A dystonic reaction resembling tetanus has been reported in at least one patient, and dystonic reactions rarely may present as upper airway obstruction with stridor and dyspnea, possibly secondary to laryngospasm or supraglottic dystonia; cardiorespiratory arrest, which was fatal, also has occurred in at least one patient with an acute dystonic reaction. An acute dystonic reaction combined with myoclonus and asterixis also has been reported.

Akathisia combined with severe dysphoria and anxiety has been reported. Akathisia appears to be related to the peak plasma metoclopramide concentration and usually resolves following a reduction in dosage.

Treatment with metoclopramide may result in tardive dyskinesia, a potentially irreversible disorder manifested 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. Although the risk of tardive dyskinesia with metoclopramide has not been extensively studied, the syndrome has been reported in about 20% of patients receiving the drug for at least 12 weeks. 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. Although the risk of developing tardive dyskinesia in the general population may be increased in geriatric patients, women, and patients with diabetes mellitus, it is not possible to predict which patients will develop metoclopramide-induced tardive dyskinesia. The risk of developing tardive dyskinesia and the likelihood that it will become irreversible increase with increasing duration of therapy and total cumulative dose. Metoclopramide should be discontinued in patients who develop signs or symptoms of tardive dyskinesia. There is no known effective treatment for established cases of tardive dyskinesia, although the syndrome may remit, either partially or completely, in some patients within several weeks to months after metoclopramide is discontinued. Metoclopramide itself may suppress or partially suppress the manifestations of tardive dyskinesia, thereby masking the underlying disease process. Whether this symptomatic suppression affects the long-term course of tardive dyskinesia is unknown. Therefore, metoclopramide should not be used for symptomatic control of tardive dyskinesia.

Rarely, neuroleptic malignant syndrome (NMS) has occurred in patients receiving metoclopramide. NMS is a hypermetabolic reaction to dopamine antagonists, which may be characterized by hyperthermia, varying levels of consciousness, muscular rigidity, and autonomic dysfunction. In patients with clinical manifestations consistent with NMS, it is important to determine whether untreated or inadequately treated extrapyramidal reactions and serious medical illness (e.g., pneumonia, systemic infection) may coexist. Other important considerations in the differential diagnosis of NMS include the possibility of central anticholinergic toxicity, heat stroke, malignant hyperthermia, drug fever, and primary CNS pathology. Treatment of NMS includes immediate discontinuance of metoclopramide therapy and other drugs not considered essential to concurrent therapy, intensive symptomatic treatment and medical monitoring, and treatment of any concomitant serious medical condition for which specific therapies are available. Although drugs such as dantrolene and bromocriptine have been used in the treatment of NMS, their efficacy for this use has not been established and there currently is no specific drug therapy for NMS.

For additional information on tardive dyskinesia and NMS, .

Parkinsonian symptoms, including tremor, rigidity, bradykinesia, and akinesia, rarely occur in patients receiving metoclopramide but may be associated with usual or excessive doses or with decreased renal function. Such symptoms develop more commonly during the first 6 months of metoclopramide therapy but occasionally after longer periods; following discontinuance of the drug, parkinsonian symptoms generally subside within 2-3 months.

Depression has been reported in patients receiving metoclopramide; in some of these patients, there was no history of an underlying depressive disorder. In some patients, depression has been severe and included unprovoked episodes of uncontrollable crying, suicidal ideation, and suicide. In most patients, signs of depression resolved following discontinuance of the drug and, in some, did not recur when metoclopramide was reinstituted at a lower dosage and gradually increased if necessary. Delirium, severe dysphoria, obsessive rumination, and mania have been reported occasionally.

GI Effects

Nausea and bowel disturbances, principally diarrhea but also constipation, have occurred in some patients receiving metoclopramide. Xerostomia also has occurred.

Sensitivity Reactions

Hypersensitivity reactions, including bronchospasm, urticaria, and rash (e.g., maculopapular), have been reported occasionally in patients receiving metoclopramide, especially in patients with a history of asthma. Angioedema, including laryngeal, glossal, or periorbital edema, has been reported rarely.

Hematologic Effects

Agranulocytosis, neutropenia, and leukopenia have been reported rarely in patients receiving metoclopramide, but a causal relationship to the drug has not been established. Methemoglobinemia also has occurred in patients receiving the drug, particularly following overdosage in neonates, but also in adults receiving the drug. Sulfhemoglobinemia has been reported in adults receiving metoclopramide.(See Cautions: Precautions and Contraindications.) One child reportedly developed symptoms of acute intermittent porphyria immediately following IM administration of metoclopramide; the patient had a known history of acute intermittent porphyria exacerbated by various drugs.

Genitourinary Effects

Metoclopramide is a potent stimulator of prolactin secretion in both genders; however, the clinical importance of the drug's effect on prolactin has not been fully determined.(See Cautions: Mutagenicity and Carcinogenicity.) Galactorrhea, gynecomastia, and menstrual disorders (e.g., amenorrhea) may occur in some patients during administration of metoclopramide. Impotence secondary to hyperprolactinemia can occur. Serum prolactin concentration usually returns to normal within 1 week following discontinuance of metoclopramide; adverse effects associated with increased serum prolactin concentration usually subside within a few weeks to months following discontinuance of the drug. Urinary frequency and incontinence also have been reported.

Cardiovascular Effects

The risk of metoclopramide-induced, clinically important adverse cardiovascular effects appears to be low. AV block, hypotension, acute congestive heart failure, and hypertension have been reported. In addition, the drug may cause hypertensive crisis in patients with pheochromocytoma, apparently by causing release of catecholamines from the tumor. Metoclopramide-induced hypertensive crisis in patients with pheochromocytoma may be controlled with phentolamine. Supraventricular tachycardia has been reported rarely following parenteral administration of the drug. Transient flushing of the face and upper body have occurred with large IV doses of the drug. Severe bradycardia has reportedly occurred in one patient immediately following IV administration of 15-17 mg of metoclopramide.

Other Adverse Effects

Visual disturbances have been reported in patients receiving metoclopramide. Fluid retention secondary to transient metoclopramide-induced elevations in serum aldosterone concentration also can occur. Rarely, hepatotoxicity, manifested as jaundice and alterations in liver function test results, has occurred in patients receiving metoclopramide concomitantly with other drugs with hepatotoxic potential.

Precautions and Contraindications

The manufacturer's medication guide should be provided to the patient or caregiver each time metoclopramide is dispensed. The patient or caregiver should be instructed to read the medication guide before initiating therapy and each time the prescription is refilled. The clinician should assist the patient or caregiver in understanding the contents of the medication guide.

Patients should be warned that metoclopramide may impair their ability to perform activities requiring mental alertness or physical coordination (e.g., operating machinery, driving a motor vehicle). Patients also should be warned that metoclopramide may enhance their response to alcohol, barbiturates, or other CNS depressants. Patients should be informed that metoclopramide oral solution and tablets are recommended for use in adults only.

Extrapyramidal reactions may occur during metoclopramide therapy, especially in pediatric patients and adults younger than 30 years of age, or when high doses such as those used for prophylaxis of cancer chemotherapy-induced nausea and vomiting are administered. Because use of metoclopramide may result in tardive dyskinesia, a syndrome of potentially irreversible, involuntary, dyskinetic movements, therapy 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. Metoclopramide should be discontinued in patients who develop signs or symptoms of tardive dyskinesia. Because metoclopramide can exacerbate parkinsonian symptoms, the drug should be used with caution, if at all, in patients with parkinsonian syndrome. Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome requiring immediate discontinuance of the drug and intensive symptomatic treatment, has been reported rarely in patients receiving metoclopramide.(See Cautions: Nervous System Effects.)

Metoclopramide should be used with extreme caution, and only when the anticipated benefits are expected to outweigh the possible risks, in patients with a history of mental depression, especially those with suicidal tendencies.

Because metoclopramide can stimulate GI motility, the drug theoretically could produce increased pressure on suture lines following GI anastomosis or closure. This possibility should be considered and weighed when deciding whether to use metoclopramide or nasogastric suction for the prevention of postoperative nausea and vomiting.

Metoclopramide should be used with caution and in reduced dosage during prolonged therapy in patients with impaired renal function. Because of the potential for transient increases in plasma aldosterone concentrations and sodium retention, the manufacturer and some clinicians state that certain patients (e.g., those with cirrhosis or congestive heart failure) may be at risk of developing fluid retention and volume overload or hypokalemia and should be closely monitored while receiving the drug. The manufacturer states that if fluid retention or volume overload occurs at any time during metoclopramide therapy, the drug should be discontinued. Metoclopramide should be used with caution in patients with hypertension since there is limited evidence that the drug may increase circulating catecholamines in such patients.

Adverse reactions, particularly those involving the CNS, may occur following discontinuance of metoclopramide therapy. A limited number of patients may experience withdrawal symptoms including dizziness, nervousness, and/or headaches following discontinuance.

Patients with cytochrome-b5 reductase deficiency have an increased risk of methemoglobinemia and/or sulfhemoglobinemia when metoclopramide is administered. In patients with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency who experience metoclopramide-induced methemoglobinemia, methylene blue treatment is not recommended.(See Acute Toxicity: Treatment.)

Metoclopramide is contraindicated in patients with a history of sensitivity or intolerance to the drug. Although there are no reports to date, patients allergic to procainamide theoretically may exhibit cross-sensitivity to metoclopramide, since the drugs are structurally similar.

Metoclopramide is contraindicated in patients in whom stimulation of GI motility might be dangerous (e.g., in the presence of mechanical obstruction or perforation). Although the manufacturers state that metoclopramide also is contraindicated in patients with GI hemorrhage, the drug has been used by some clinicians to empty the stomach of blood prior to endoscopy in patients with acute upper GI hemorrhage.

Metoclopramide is contraindicated in patients with pheochromocytoma, since the drug may cause hypertensive crisis in these patients.

Metoclopramide is contraindicated in patients with a history of seizure disorders since the frequency and severity of seizures may be increased by the drug. Metoclopramide is also contraindicated in patients receiving drugs that are likely to cause extrapyramidal reactions (e.g., phenothiazines, butyrophenones), since the frequency and severity of these reactions may be increased by metoclopramide.

Pediatric Precautions

The safety profile of metoclopramide in adults cannot be extrapolated to pediatric patients.

Metoclopramide should be used with caution in pediatric patients, since the incidence of extrapyramidal reactions is increased in these patients.

Following oral or IV administration of metoclopramide in infants and children, pharmacodynamics of the drug are highly variable, and a relationship between drug plasma concentrations and pharmacodynamic effects has not been established. Data are insufficient to determine whether the pharmacokinetics of the drug in children is similar to that in adults.

Metoclopramide should be administered with caution to neonates because decreased clearance may result in increased serum concentrations of the drug.(See Pharmacokinetics: Elimination.) In addition, since neonates have reduced concentrations of cytochrome-b5 reductase, they may be more susceptible to methemoglobinemia.

The manufacturers currently recommend that metoclopramide be used in children only to facilitate intubation of the small intestine. Metoclopramide has been effective for the management of gastric stasis and gastroesophageal reflux in infants and children. The drug has also been used in children for evacuation of the stomach prior to administration of anesthesia for emergency surgery.

Geriatric Precautions

Clinical studies of metoclopramide did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients.

The risk of developing parkinsonian symptoms increases with increasing dosage. Geriatric patients should receive the lowest effective dosage of metoclopramide. If parkinsonian symptoms develop in a geriatric patient receiving metoclopramide, metoclopramide generally should be discontinued before any specific antiparkinsonian therapy is considered. Geriatric patients also may be at increased risk for tardive dyskinesia. Sedation has been reported in patients receiving metoclopramide and may be manifested as confusion and oversedation in geriatric patients.

Metoclopramide is known to be substantially eliminated by the kidneys, and the risk of adverse reactions to the drug may be increased in patients with impaired renal function. In general, dosage should be selected carefully in geriatric patients, usually initiating therapy at the low end of the dosage range; the greater frequency of decreased renal function and of concomitant disease and drug therapy observed in geriatric patients also should be considered.

Mutagenicity and Carcinogenicity

No evidence of metoclopramide-induced mutagenicity was observed in the Ames microbial mutagen test.

Although an increase in mammary neoplasms has been found in rodents following long-term administration of prolactin-stimulating antipsychotic agents (e.g., phenothiazines), no clinical or epidemiologic studies conducted to date have shown an association between long-term administration of prolactin-stimulating drugs and mammary tumorigenesis in humans. Current evidence is considered too limited to be conclusive, and further study is needed to determine the clinical importance in most patients of elevated serum prolactin concentrations associated with metoclopramide administration. Since in vitro tests indicate that approximately one-third of human breast cancers are prolactin-dependent, metoclopramide should be used with caution in patients with previously detected breast cancer.

Pregnancy, Fertility, and Lactation

Pregnancy

Reproduction studies in mice, rats, and rabbits using metoclopramide dosages up to 250 times the usual human dosage have not revealed evidence of harm to the fetus. There are no adequate and controlled studies to date using metoclopramide in pregnant women, and the drug should be used during pregnancy only when clearly needed.

Fertility

It is not known whether metoclopramide affects fertility in humans. Menstrual disturbances have occurred in some individuals during metoclopramide therapy.(See Cautions: Other Adverse Effects.) Reproduction studies in male and female mice, rats, and rabbits using metoclopramide dosages 12-250 times the usual human dosage have not revealed evidence of impaired fertility.

Lactation

Since metoclopramide is distributed into milk, the drug should be used with caution in nursing women.

Drug Interactions

Effects on GI Absorption of Drugs

Because of its pharmacologic effects on transit time in the stomach and small intestine, metoclopramide may alter the absorption of certain drugs. The extent of absorption of drugs that disintegrate, dissolve, and/or are absorbed mainly in the stomach (e.g., digoxin) may be diminished by metoclopramide, whereas the rate and extent of absorption of drugs that are mainly absorbed in the small intestine (e.g., acetaminophen, aspirin, cyclosporine, diazepam, ethanol, levodopa, lithium, tetracycline) may be enhanced. The clinical importance of these effects has not been determined. Metoclopramide reportedly does not affect the absorption of Lanoxin tablets, since these digoxin preparations have a small drug-particle size and are rapidly absorbed.

CNS Depressants

Metoclopramide may be additive with, or may potentiate the action of, other CNS depressants such as opiates or other analgesics, barbiturates or other sedatives, anesthetics, or alcohol. When metoclopramide is used concomitantly with other CNS depressants, caution should be used to avoid excessive sedation.

Insulin

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, potentially resulting in hypoglycemia. Since metoclopramide influences the delivery of food to the intestine and thus the rate of its absorption, adjustment in, or timing of, insulin dosage may be necessary in insulin-controlled diabetics.

Other Drugs

Metoclopramide should not be used in patients receiving drugs that are likely to cause extrapyramidal reactions.(See Cautions: Precautions and Contraindications.)

The effects of metoclopramide on GI motility are antagonized by anticholinergic agents (e.g., atropine) and opiate analgesics.

Acute hypotension reportedly occurred in some patients receiving IV metoclopramide during neurosurgical procedures in which hypotensive anesthetic agents were used; various anesthetic agents, with or without concomitant administration of ganglionic blocking agents, were used. The mechanism and clinical importance of this adverse reaction are not known.

Metoclopramide should be used cautiously, if at all, in patients receiving concomitant therapy with monoamine oxidase (MAO) inhibitors because metoclopramide has been shown to cause release of catecholamines in patients with essential hypertension.

Pharmacokinetics

In all studies described in the Pharmacokinetics section, metoclopramide was administered as the monohydrochloride monohydrate salt; dosages and concentrations of the drug are expressed in terms of metoclopramide.

Absorption

Metoclopramide is rapidly and almost completely absorbed from the GI tract following oral administration; however, absorption may be delayed or diminished in patients with gastric stasis. Considerable interindividual variations (up to fivefold) in peak plasma concentration have been reported with the same oral dose of metoclopramide. This variability apparently results from interindividual differences in first-pass metabolism of the drug. Bioavailability of metoclopramide appears to correlate with the ratio of free:conjugated metoclopramide concentrations in urine. It appears that sulfate conjugation in the GI lumen and/or during first pass through the liver is the principal determinant of bioavailability of orally administered metoclopramide. The absolute bioavailability of orally administered metoclopramide has not been clearly established in humans, but limited data indicate that 30-100% of an oral dose of the drug reaches systemic circulation as unchanged metoclopramide. Following IM administration, the absolute bioavailability of metoclopramide is 74-96%.

Following oral administration of a single 10-mg dose of the drug in healthy, fasting adults in one study, peak plasma metoclopramide concentrations of 32-44 ng/mL occurred at 1-2 hours; following oral administration of a single 20-mg dose, peak plasma metoclopramide concentrations of 72-87 ng/mL occurred at an average of 2 hours. In a study in infants (3.5 weeks-5.4 months of age) with gastroesophageal reflux who received 0.15-mg/kg oral doses of metoclopramide every 6 hours for 10 doses as an oral solution, the mean peak plasma concentration (56.8 ng/mL) of the drug after the 10th dose was twofold higher compared with that after the first dose (29 ng/mL), suggesting that metoclopramide accumulates in plasma following multiple oral dosing in this age group. In these patients, time to reach mean peak plasma concentrations (2.2 hours) was similar after the 10th dose to that occurring after the first dose.

The onset of the principal pharmacologic actions of metoclopramide on the GI tract is 1-3 minutes following IV administration, 10-15 minutes following IM administration, and 30-60 minutes following oral administration. Pharmacologic effects persist for 1-2 hours following administration of a single dose.

The therapeutic range for plasma metoclopramide concentrations and the relationship of plasma concentration to clinical response and toxicity have not been clearly established. In one study, a maximum change in lower esophageal sphincter pressure correlated poorly with peak plasma metoclopramide concentration. Data from patients receiving large IV doses of metoclopramide (8 mg/kg in 4 divided doses) for the prevention of cisplatin-induced nausea and vomiting indicate that serum metoclopramide concentrations greater than 850 ng/mL may be required for optimum antiemetic effect in patients receiving cisplatin. Metoclopramide-induced akathisia is reportedly associated with peak plasma metoclopramide concentrations greater than 120 ng/mL.

Distribution

Distribution of metoclopramide into human body tissues and fluids has not been fully characterized. The apparent volume of distribution of metoclopramide is reportedly 2.2-3.5 L/kg in adults and 1.93-4.4 L/kg in children. Following IM administration of metoclopramide in mice, the drug is rapidly distributed into most body tissues and fluids with high concentrations in the GI mucosa, liver, biliary tract, and salivary glands, and lower concentrations in brain, heart, thymus, adrenals, adipose tissue, and bone marrow. Metoclopramide crosses the blood-brain barrier and enters the CNS in animals, with high concentrations in the area postrema, which contains the chemoreceptor trigger zone (CTZ).

Metoclopramide is weakly bound to plasma proteins; in vitro, metoclopramide is 13-30% protein bound, principally to albumin.

Metoclopramide crosses the placenta and is distributed into milk; concentrations of the drug in milk are higher than those in plasma 2 hours after oral administration.

Elimination

Plasma concentrations of metoclopramide decline in a biphasic manner.

Although limited data from single-dose studies have suggested that elimination of metoclopramide is dose dependent, other studies using oral doses up to 100 mg have not shown a dose-dependent pharmacokinetic profile. In addition, one pharmacokinetic study using high doses of metoclopramide did not demonstrate dose-dependent elimination. In adults, the half-life of metoclopramide in the initial phase (t½α) is about 5 minutes, and the half-life in the terminal phase (t½β) ranges from 2.5-6 hours. In children receiving oral or IV metoclopramide, the elimination half-life of the drug reportedly is 4.1-4.5 hours. Following oral administration of 0.15-mg/kg doses of metoclopramide every 6 hours for 10 doses in an infant (3.5 weeks of age), elimination half-lives of 23.1 and 10.3 hours were observed after the first and 10th dose, respectively, which were substantially longer than those reported in older infants, suggesting a reduced clearance in the neonate possibly being associated with immature renal and hepatic functions present at birth. Total body clearance of metoclopramide is reportedly 10.9-11.7 mL/minute per kg in adults with normal renal function. Plasma metoclopramide concentrations may be higher and the half-life prolonged in patients with impaired renal function. In children receiving oral or IV metoclopramide, clearance of the drug reportedly is 6.16-11.1 mL/minute per kg.

Although the exact metabolic fate of metoclopramide is not clearly established, it appears that metoclopramide is only minimally metabolized. The major metabolite found in urine is 2-[(4-amino-5-chloro-2-methoxybenzoyl)amino]acetic acid; it is not known if this metabolite is pharmacologically active. Metoclopramide is conjugated with sulfuric and/or glucuronic acid.

Metoclopramide and its metabolites are excreted in urine and feces. In a limited number of adults with normal renal function, approximately 85% of an oral dose of radiolabeled metoclopramide was excreted in urine within 72 hours of administration, principally as unchanged drug and glucuronide or sulfate conjugates of metoclopramide. About 5-10% of an oral dose of metoclopramide is excreted in urine as 2-[(4-amino-5-chloro-2-methoxybenzoyl)amino]acetic acid and about 20% is excreted unchanged. Approximately 5% of an oral dose of the drug is excreted in feces via biliary elimination.

Limited evidence indicates that metoclopramide is only minimally removed by hemodialysis or peritoneal dialysis.

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