iological examination of the stomach and/or small intestine.

include 1) immediate discontinuation of metoclopramide and other drugs not essential to concurrent therapy, 2) intensive symptomatic treatment and medical monitoring, and 3) treatment of any concomitant serious medical problems for which specific treatments are available. bromocriptine and dantrolene sodium have been used in treatment of nms, but their effectiveness have not been established (see adverse reactions ). extrapyramidal symptoms (eps) acute dystonic reactions acute dystonic reactions occur in approximately 1 in 500 patients treated with the usual adult dosages of 30 to 40 mg/day of metoclopramide. these usually are seen during the first 24 to 48 hours of treatment with metoclopramide, occur more frequently in pediatric patients and adult patients less than 30 years of age and are even more frequent at the higher doses used in prophylaxis of vomiting due to cancer chemotherapy. these symptoms may include involuntary movements of limbs and facial grimacing, torticollis, oculogyric crisis, rhythmic protrusion of tongue, bulbar type of speech, trismus, or dystonic reactions resembling tetanus. rarely, dystonic reactions may present as stridor and dyspnea, possibly due to laryngospasm. if these symptoms should occur, inject 50 mg benadryl ® (diphenhydramine hydrochloride) intramuscularly, and they usually will subside. cogentin ® (benztropine mesylate), 1 to 2 mg intramuscularly, may also be used to reverse these reactions. tardive dyskinesia (see boxed warnings ) treatment with metoclopramide can cause tardive dyskinesia (td), a potentially irreversible and disfiguring disorder characterized by involuntary movements of the face, tongue, or extremities. the risk of tardive dyskinesia increases with the duration of treatment and the total cumulative dose. an analysis of utilization patterns showed that about 20% of patients who used metoclopramide took it longer than 12 weeks. treatment with metoclopramide for longer than the recommended 12 weeks should be avoided in all but rare cases where therapeutic benefit is thought to outweigh the risk of developing td. although the risk of developing td in the general population may be increased among the elderly, women, and diabetics, it is not possible to predict which patients will develop metoclopramide-induced td. both the risk of developing td and the likelihood that td will become irreversible increase with duration of treatment and total cumulative dose. metoclopramide should be discontinued in patients who develop signs or symptoms of td. there is no known effective treatment for established cases of td, although in some patients, td may remit, partially or completely, within several weeks to months after metoclopramide is withdrawn. metoclopramide itself may suppress, or partially suppress, the signs of td, thereby masking the underlying disease process. the effect of this symptomatic suppression upon the long-term course of td is unknown. therefore, metoclopramide should not be used for the symptomatic control of td. parkinsonian-like symptoms parkinsonian-like symptoms, including bradykinesia, tremor, cogwheel rigidity, or mask-like facies, have occurred, more commonly within the first 6 months after beginning treatment with metoclopramide, but occasionally after longer periods. these symptoms generally subside within 2 to 3 months following discontinuance of metoclopramide. patients with pre-existing parkinson's disease should be given metoclopramide cautiously, if at all, since such patients may experience exacerbation of parkinsonian symptoms when taking metoclopramide. depression mental depression has occurred in patients with and without prior history of depression. symptoms have ranged from mild to severe and have included suicidal ideation and suicide. metoclopramide should be given to patients with a prior history of depression only if the expected benefits outweigh the potential risks.

urs for two doses, then every 3 hours for three doses. the initial two doses should be 2 mg/kg if highly emetogenic drugs such as cisplatin or dacarbazine are used alone or in combination. for less emetogenic regimens, 1 mg/kg per dose may be adequate. for doses in excess of 10 mg, metoclopramide injection, usp 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, usp, can be stored frozen for up to 4 weeks. metoclopramide injection, usp is degraded when admixed and frozen with dextrose-5% in water. metoclopramide injection, usp 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 metoclopramide injection, usp should be given intramuscularly near the end of surgery. the usual adult dose is 10 mg; however, doses of 20 mg may be used. to facilitate small bowel intubation if the tube has not passed the pylorus with conventional maneuvers in 10 minutes, a single dose (undiluted) may be administered slowly by the intravenous route over a 1 to 2 minute period. the recommended single use is: pediatric patients above 14 years of age and adults – 10 mg metoclopramide base. pediatric patients (6 to 14 years of age) – 2.5 to 5 mg metoclopramide base; (under 6 years of age) – 0.1 mg/kg metoclopramide base. to aid in radiological examinations in patients where delayed gastric emptying interferes with radiological examination of the stomach and/or small intestine, a single use may be administered slowly by the intravenous route over a 1 to 2 minute period. for dosage, see intubation, above. use in patients with renal or hepatic impairment since metoclopramide is excreted principally through the kidneys, in those patients whose creatinine clearance is below 40 ml/min, therapy should be initiated at approximately one-half the recommended dosage. depending upon clinical efficacy and safety considerations, the dosage may be increased or decreased as appropriate. see overdosage section for information regarding dialysis. metoclopramide undergoes minimal hepatic metabolism, except for simple conjugation. its safe use has been described in patients with advanced liver disease whose renal function was normal. note: parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. admixture 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 (hospira), potassium acetate, usp (invenex), potassium phosphate, usp (invenex). physically compatible up to 48 hours ascorbic acid, usp (hospira), 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 infusion (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 (hospira), 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 (hospira).

ay. in cancer chemotherapy patients receiving 1 to 2 mg/kg per dose, the incidence is 2% in patients over the ages of 30 to 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, and 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 a 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.

se through 20 mg (the largest dose tested). the increase in lesp from a 5 mg dose lasts about 45 minutes and that of 20 mg lasts between 2 and 3 hours. increased rate of stomach emptying has been observed with single oral doses of 10 mg. the antiemetic properties of metoclopramide appear to be a result of its antagonism of central and peripheral dopamine receptors. dopamine produces nausea and vomiting by stimulation of the medullary chemoreceptor trigger zone (ctz), and metoclopramide blocks stimulation of the ctz by agents like l-dopa or apomorphine which are known to increase dopamine levels or to possess dopamine-like effects. metoclopramide also abolishes the slowing of gastric emptying caused by apomorphine. like the phenothiazines and related drugs, which are also dopamine antagonists, metoclopramide produces sedation and may produce extrapyramidal reactions, although these are comparatively rare (see warnings ). metoclopramide inhibits the central and peripheral effects of apomorphine, induces release of prolactin and causes a transient increase in circulating aldosterone levels, which may be associated with transient fluid retention. the onset of pharmacological action of metoclopramide is 1 to 3 minutes following an intravenous dose, 10 to 15 minutes following intramuscular administration, and 30 to 60 minutes following an oral dose, pharmacological effects persist for 1 to 2 hours. pharmacokinetics metoclopramide is rapidly and well absorbed. relative to an intravenous dose of 20 mg, the absolute oral bioavailability of metoclopramide is 80% ± 15.5% as demonstrated in a crossover study of 18 subjects. peak plasma concentrations occur at about 1 to 2 hours after a single oral dose. similar time to peak is observed after individual doses at steady state. in a single-use study of 12 subjects, the area under the drug concentration-time curve increases linearly with doses from 20 to 100 mg. peak concentrations increase linearly with dose; time to peak concentrations remains the same; whole body clearance is unchanged; and the elimination rate remains the same. the average elimination half-life in individuals with normal renal function is 5 to 6 hours. linear kinetic processes adequately describe the absorption and elimination of metoclopramide. approximately 85% of the radioactivity of an orally administered dose appears in the urine within 72 hours. of the 85% eliminated in the urine, about half is present as free or conjugated metoclopramide. the drug is not extensively bound to plasma proteins (about 30%). the whole body volume of distribution is high (about 3.5 l/kg) which suggests extensive distribution of drug to the tissues. renal impairment affects the clearance of metoclopramide. in a study with patients with varying degrees of renal impairment, a reduction in creatinine clearance was correlated with a reduction in plasma clearance, renal clearance, non-renal clearance, and increase in elimination half-life. the kinetics of metoclopramide in the presence of renal impairment remained linear however. the reduction in clearance as a result of renal impairment suggests that adjustment downward of maintenance dosage should be done to avoid drug accumulation. adult pharmacokinetic data parameter value vd (l/kg) ~3.5 plasma protein binding ~30% t 1/2 (hr) 5 to 6 oral bioavailability 80% ± 15.5% in pediatric patients, the pharmacodynamics of metoclopramide following oral and intravenous administration are highly variable and a concentration-effect relationship has not been established. there are insufficient reliable data to conclude whether the pharmacokinetics of metoclopramide in adults and the pediatric population are similar. although there are insufficient data to support the efficacy of metoclopramide in pediatric patients with symptomatic gastroesophageal reflux (ger) or cancer chemotherapy-related nausea and vomiting, its pharmacokinetics have been studied in these patient populations. in an open-label study, six pediatric patients (age range, 3.5 weeks to 5.4 months) with ger received metoclopramide 0.15 mg/kg oral solution every 6 hours for 10 doses. the mean peak plasma concentration of metoclopramide after the tenth dose was 2-fold (56.8 mcg/l) higher compared to that observed after the first dose (29 mcg/l) indicating drug accumulation with repeated dosing. after the tenth dose, the mean time to reach peak concentrations (2.2 hrs), half-life (4.1 hrs), clearance (0.67 l/h/kg), and volume of distribution (4.4 l/kg) of metoclopramide were similar to those observed after the first dose. in the youngest patient (age, 3.5 weeks), metoclopramide half-life after the first and the tenth dose (23.1 and 10.3 hrs, respectively) was significantly longer compared to other infants due to reduced clearance. this may be attributed to immature hepatic and renal systems at birth. single intravenous doses of metoclopramide 0.22 to 0.46 mg/kg (mean, 0.35 mg/kg) were administered over 5 minutes to nine pediatric cancer patients receiving chemotherapy (mean age, 11.7 years; range, 7 to 14 yrs) for prophylaxis of cytotoxic-induced vomiting. the metoclopramide plasma concentrations extrapolated to time zero ranged from 65 to 395 mcg/l (mean, 152 mcg/l). the mean elimination half-life, clearance, and volume of distribution of metoclopramide were 4.4 hrs (range, 1.7 to 8.3 hrs), 0.56 l/h/kg (range, 0.12 to 1.20 l/h/kg), and 3.0 l/kg (range, 1.0 to 4.8 l/kg), respectively. in another study, nine pediatric cancer patients (age range, 1 to 9 yrs) received 4 to 5 intravenous infusions (over 30 minutes) of metoclopramide at a dose of 2 mg/kg to control emesis. after the last dose, the peak serum concentrations of metoclopramide ranged from 1060 to 5680 mcg/l. the mean elimination half-life, clearance, and volume of distribution of metoclopramide were 4.5 hrs (range, 2.0 to 12.5 hrs), 0.37 l/h/kg (range, 0.10 to 1.24 l/h/kg), and 1.93 l/kg (range, 0.95 to 5.50 l/kg), respectively. pediatric pharmacokinetic studies a sem not available. 1. bateman, dn, et al. br j clin pharmac 15 : 557-559, 1983. 2. ford, c. clin pharmac ther 43:196, 1988. reference dose, route t 1/2 (hr) ci (l/hr/kg) vd (l/kg) c max (mcg/l) 1. 0.35 mg/kg iv over 5 min 4.4 ± 0.56 0.56 ± 0.10 3.0 ± 0.38 (dose/cp 0 ) 152 ± 31 2. 2 mg/kg 30 min iv infusion 4 to 5 times within 9.5 hours 4.5 a 0.37 a 1.93 a 1060 to 5680 a

minated in the urine, about half is present as free or conjugated metoclopramide. the drug is not extensively bound to plasma proteins (about 30%). the whole body volume of distribution is high (about 3.5 l/kg) which suggests extensive distribution of drug to the tissues. renal impairment affects the clearance of metoclopramide. in a study with patients with varying degrees of renal impairment, a reduction in creatinine clearance was correlated with a reduction in plasma clearance, renal clearance, non-renal clearance, and increase in elimination half-life. the kinetics of metoclopramide in the presence of renal impairment remained linear however. the reduction in clearance as a result of renal impairment suggests that adjustment downward of maintenance dosage should be done to avoid drug accumulation. adult pharmacokinetic data parameter value vd (l/kg) ~3.5 plasma protein binding ~30% t 1/2 (hr) 5 to 6 oral bioavailability 80% ± 15.5% in pediatric patients, the pharmacodynamics of metoclopramide following oral and intravenous administration are highly variable and a concentration-effect relationship has not been established. there are insufficient reliable data to conclude whether the pharmacokinetics of metoclopramide in adults and the pediatric population are similar. although there are insufficient data to support the efficacy of metoclopramide in pediatric patients with symptomatic gastroesophageal reflux (ger) or cancer chemotherapy-related nausea and vomiting, its pharmacokinetics have been studied in these patient populations. in an open-label study, six pediatric patients (age range, 3.5 weeks to 5.4 months) with ger received metoclopramide 0.15 mg/kg oral solution every 6 hours for 10 doses. the mean peak plasma concentration of metoclopramide after the tenth dose was 2-fold (56.8 mcg/l) higher compared to that observed after the first dose (29 mcg/l) indicating drug accumulation with repeated dosing. after the tenth dose, the mean time to reach peak concentrations (2.2 hrs), half-life (4.1 hrs), clearance (0.67 l/h/kg), and volume of distribution (4.4 l/kg) of metoclopramide were similar to those observed after the first dose. in the youngest patient (age, 3.5 weeks), metoclopramide half-life after the first and the tenth dose (23.1 and 10.3 hrs, respectively) was significantly longer compared to other infants due to reduced clearance. this may be attributed to immature hepatic and renal systems at birth. single intravenous doses of metoclopramide 0.22 to 0.46 mg/kg (mean, 0.35 mg/kg) were administered over 5 minutes to nine pediatric cancer patients receiving chemotherapy (mean age, 11.7 years; range, 7 to 14 yrs) for prophylaxis of cytotoxic-induced vomiting. the metoclopramide plasma concentrations extrapolated to time zero ranged from 65 to 395 mcg/l (mean, 152 mcg/l). the mean elimination half-life, clearance, and volume of distribution of metoclopramide were 4.4 hrs (range, 1.7 to 8.3 hrs), 0.56 l/h/kg (range, 0.12 to 1.20 l/h/kg), and 3.0 l/kg (range, 1.0 to 4.8 l/kg), respectively. in another study, nine pediatric cancer patients (age range, 1 to 9 yrs) received 4 to 5 intravenous infusions (over 30 minutes) of metoclopramide at a dose of 2 mg/kg to control emesis. after the last dose, the peak serum concentrations of metoclopramide ranged from 1060 to 5680 mcg/l. the mean elimination half-life, clearance, and volume of distribution of metoclopramide were 4.5 hrs (range, 2.0 to 12.5 hrs), 0.37 l/h/kg (range, 0.10 to 1.24 l/h/kg), and 1.93 l/kg (range, 0.95 to 5.50 l/kg), respectively. pediatric pharmacokinetic studies a sem not available. 1. bateman, dn, et al. br j clin pharmac 15 : 557-559, 1983. 2. ford, c. clin pharmac ther 43:196, 1988. reference dose, route t 1/2 (hr) ci (l/hr/kg) vd (l/kg) c max (mcg/l) 1. 0.35 mg/kg iv over 5 min 4.4 ± 0.56 0.56 ± 0.10 3.0 ± 0.38 (dose/cp 0 ) 152 ± 31 2. 2 mg/kg 30 min iv infusion 4 to 5 times within 9.5 hours 4.5 a 0.37 a 1.93 a 1060 to 5680 a