Reglan Tablets

Important Administration Instructions

Avoid treatment with Reglan for longer than 12 weeks because of the increased risk of developing TD with longer-term use [see Dosage and Administration (2.2, 2.3), Warnings and Precautions (5.1)].

Dosage for Gastroesophageal Reflux

Reglan Tablets may be administered continuously or intermittently in patients with symptomatic gastroesophageal reflux who fail to respond to conventional therapy:

Continuous Dosing

The recommended adult dosage of Reglan is 10 to 15 mg four times daily for 4 to 12 weeks. The treatment duration is determined by endoscopic response. Administer the dosage thirty minutes before each meal and at bedtime. The maximum recommended daily dosage is 60 mg.

Table 1 displays the recommended daily dosage and maximum daily dosage for adults and dosage adjustments for patients with moderate or severe hepatic impairment (Child-Pugh B or C), in patients with creatinine clearance less than 60 mL/minute, in cytochrome P450 2D6 (CYP2D6) poor metabolizers, and with concomitant use with strong CYP2D6 inhibitors.

Intermittent Dosing

If symptoms only occur intermittently or at specific times of the day, administer Reglan in single dose up to 20 mg prior to the provoking situation. Consider dosage reductions for the populations and situations in Table 1.

  Table 1. Recommended Reglan Tablet Dosage in Patients with Gastroesophageal Reflux

	Recommended Dosage	Maximum Recommended Daily Dosage
Adult patients	10 to 15 mg four times daily (thirty minutes before each meal and at bedtime)	60 mg
Mild hepatic impairment (Child-Pugh A)
Elderly patients [see Use in Specific Populations (8.5)]	5 mg1 four times daily (thirty minutes before each meal and at bedtime)
Moderate or severe hepatic impairment (Child-Pugh B or C) [see Use in Specific Populations (8.7)]	5 mg four times daily (thirty minutes before each meal and at bedtime), or 10 mg taken three times daily	30 mg
CYP2D6 poor metabolizers [see Use in Specific Populations (8.9)]
Concomitant use with strong CYP2D6 inhibitors (e.g., quinidine, bupropion, fluoxetine, and paroxetine) [see Drug Interactions (7.1)]
Moderate or severe renal impairment (creatinine clearance less than or equal to 60 mL/minute) [see Use in Specific Populations (8.6)]
Patients with End-Stage Renal Disease (ESRD) including those treated with hemodialysis and continuous ambulatory peritoneal dialysis [see Use in Specific Populations (8.6)]	5 mg four times daily (thirty minutes before each meal and at bedtime) or 10 mg twice daily	20 mg

1 Elderly patients may be more sensitive to the therapeutic or adverse effects of Reglan; therefore, consider a lower starting dosage of 5 mg four times daily with titration to the recommended adult dosage of 10 to 15 mg four times daily based upon response and tolerability.

Dosage for Acute and Recurrent Diabetic Gastroparesis

The recommended adult dosage for the treatment of acute and recurrent diabetic gastroparesis is 10 mg four times daily for 2 to 8 weeks, depending on symptomatic response. Avoid Reglan treatment for greater than 12 weeks [see Warnings and Precautions (5.1)]. Administer the dosage thirty minutes before each meal and at bedtime. The maximum recommended daily dosage is 40 mg.

Table 2 displays the recommended daily dosage and maximum daily dosage for adults and dosage adjustments for patients with moderate or severe hepatic impairment (Child-Pugh B or C), in patients with creatinine clearance less than 60 mL/minute, in cytochrome P450 2D6 (CYP2D6) poor metabolizers, and with concomitant use with strong CYP2D6 inhibitors.

If patients with diabetic gastroparesis have severe nausea or vomiting and are unable to take oral Reglan Tablets, consider starting therapy with metoclopramide injection given intramuscularly or intravenously for up to 10 days (see the prescribing information for metoclopramide injection). After patients are able to take oral therapy, switch to Reglan Tablets.

  Table 2. Recommended Reglan Tablet Dosage in Patients with Acute and Recurrent Diabetic Gastroparesis

	Recommended Dosage	Maximum Recommended Daily Dosage
Adult Patients	10 mg four times daily (30 minutes before each meal and at bedtime)	40 mg
Mild hepatic impairment (Child-Pugh A)
Elderly patients [see Use in Specific Populations (8.5)]	5 mg1 four times daily (30 minutes before each meal and at bedtime)
Moderate or severe hepatic impairment (Child-Pugh B or C) [see Use in Specific Populations (8.7)]	5 mg four times daily (30 minutes before each meal and at bedtime)	20 mg
CYP2D6 poor metabolizers [see Use in Specific Populations (8.9)]
Concomitant use with strong CYP2D6 inhibitors (e.g., quinidine). Avoid use with bupropion, fluoxetine, and paroxetine [see Drug Interactions (7.1)]
Moderate or severe renal impairment (creatinine clearance less than 60 mL/minute) [see Use in Specific Populations (8.6)]
Patients with End-Stage Renal Disease (ESRD) including those treated with hemodialysis and continuous ambulatory peritoneal dialysis [see Use in Specific Populations (8.6)]	5 mg twice daily	10 mg

  1 Elderly patients may be more sensitive to the therapeutic or adverse effects of Reglan; therefore, consider a lower dosage of 5 mg four times daily with titration to the recommended adult dosage of 10 mg four times daily based upon response and tolerability.

Reglan is contraindicated:

• In patients with a history of tardive dyskinesia (TD) or a dystonic reaction to metoclopramide [see Warnings and Precautions (5.1, 5.2)]. • When stimulation of gastrointestinal motility might be dangerous (e.g., in the presence of gastrointestinal hemorrhage, mechanical obstruction, or perforation). • In patients with pheochromocytoma or other catecholamine-releasing paragangliomas. Reglan may cause a hypertensive/pheochromocytoma crisis, probably due to release of catecholamines from the tumor [see Warnings and Precautions (5.5)]. • In patients with epilepsy. Reglan may increase the frequency and severity of seizures [see Adverse Reactions (6)]. • In patients with hypersensitivity to metoclopramide. Reactions have included laryngeal and glossal angioedema and bronchospasm [see Adverse Reactions (6)].

Tardive Dyskinesia

Metoclopramide can cause tardive dyskinesia (TD), a syndrome of potentially irreversible and disfiguring involuntary movements of the face or tongue, and sometimes of the trunk and/or extremities. Movements may be choreoathetotic in appearance. The risk of developing TD and the likelihood that TD will become irreversible increases with duration of treatment and total cumulative dosage. Additionally, the risk of developing TD is increased among the elderly, especially elderly women [see Use in Specific Populations (8.5)], and in patients with diabetes mellitus. Due to the risk of developing TD, avoid treatment with Reglan for longer than 12 weeks and reduce the dosage in elderly patients [see Dosage and Administration (2.2, 2.3)].

Discontinue Reglan immediately in patients who develop signs and 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 Reglan is withdrawn.

Reglan 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. Reglan is contraindicated in patients with a history of TD [see Contraindications (4)]. Avoid Reglan in patients receiving other drugs that are likely to cause TD (e.g., antipsychotics).

Other Extrapyramidal Symptoms

In addition to TD, metoclopramide may cause other extrapyramidal symptoms (EPS), parkinsonian symptoms, and motor restlessness. Advise patients to seek immediate medical attention if such symptoms occur and to discontinue Reglan.

• Extrapyramidal symptoms (EPS), such as acute dystonic reactions, occurred in patients treated with metoclopramide dosages of 30 mg to 40 mg daily. Such reactions occurred more frequently in adults less than 30 years of age and at higher than recommended dosages. EPS occurred more frequently in pediatric patients compared to adults (Reglan is not approved for use in pediatric patients). Symptoms can occur in the first 24 to 48 hours after starting metoclopramide. Symptoms included 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 were present as stridor and dyspnea, possibly due to laryngospasm. Diphenhydramine hydrochloride or benztropine mesylate may be used to treat these adverse reactions. Avoid Reglan in patients receiving other drugs that can cause EPS (e.g., antipsychotics). • Parkinsonian symptoms (bradykinesia, tremor, cogwheel rigidity, mask-like facies) have occurred after starting metoclopramide, more commonly within the first 6 months, but also after longer periods. Symptoms generally have subsided within 2 to 3 months after discontinuation of Reglan. Avoid Reglan in patients with Parkinson’s disease and other patients being treated with antiparkinsonian drugs due to potential exacerbation of symptoms. Avoid treatment with Reglan for more than 12 weeks [see Dosage and Administration (2.2, 2.3), Warnings and Precautions (5.1)]. • Motor restlessness (akathisia) has developed and consisted of feelings of anxiety, agitation, jitteriness, and insomnia, as well as inability to sit still, pacing, and foot tapping. If symptoms resolve, consider restarting at a lower dosage.

Neuroleptic Malignant Syndrome

Metoclopramide may cause a potentially fatal symptom complex called neuroleptic malignant syndrome (NMS). NMS has been reported in association with metoclopramide overdosage and concomitant treatment with another drug associated with NMS. Avoid Reglan in patients receiving other drugs associated with NMS, including typical and atypical antipsychotics.

Clinical manifestations of NMS include hyperpyrexia, muscle rigidity, altered mental status, and manifestations of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac arrhythmias). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. Patients with such symptoms should be evaluated immediately.

In the diagnostic evaluation, consider the presence of other serious medical conditions (e.g., pneumonia, systemic infection) and untreated or inadequately treated extrapyramidal signs and symptoms. Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, malignant hyperthermia, drug fever, serotonin syndrome, and primary central nervous system pathology.

Management of NMS includes:

• Immediate discontinuation of Reglan and other drugs not essential to concurrent therapy [see Drug Interactions (7.1)]. • Intensive symptomatic treatment and medical monitoring. • Treatment of any concomitant serious medical problems for which specific treatments are available.

Depression

Depression has occurred in metoclopramide-treated patients with and without a history of depression. Symptoms have included suicidal ideation and suicide. Avoid Reglan use in patients with a history of depression.

Hypertension

Metoclopramide may elevate blood pressure. In one study in hypertensive patients, intravenously administered metoclopramide was shown to release catecholamines; hence, avoid use in patients with hypertension or in patients taking monoamine oxidase inhibitors [see Drug Interactions (7.1)].

There are also clinical reports of hypertensive crises in patients with undiagnosed pheochromocytoma. Reglan is contraindicated in patients with pheochromocytoma or other catecholamine-releasing paragangliomas [see Contraindications (4)]. Discontinue Reglan in any patient with a rapid rise in blood pressure.

Fluid Retention

Because Reglan produces a transient increase in plasma aldosterone, patients with cirrhosis or congestive heart failure may be at risk of developing fluid retention and volume overload. Discontinue Reglan if any of these adverse reactions occur.

Hyperprolactinemia

As with other dopamine D2 receptor antagonists, metoclopramide elevates prolactin levels.

Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported with prolactin-elevating drugs, including metoclopramide.

Hyperprolactinemia may potentially stimulate prolactin-dependent breast cancer. However, some clinical studies and epidemiology studies have not shown an association between administration of dopamine D2 receptor antagonists and tumorigenesis in humans [see Nonclinical Toxicology (13.1)].

Effects on the Ability to Drive and Operate Machinery

Metoclopramide may impair the mental and/or physical abilities required for the performance of hazardous tasks such as operating machinery or driving a motor vehicle. Concomitant use of central nervous system (CNS) depressants or drugs associated with EPS may increase this effect (e.g., alcohol, sedatives, hypnotics, opiates, and anxiolytics). Avoid Reglan or the interacting drug, depending on the importance of the drug to the patient [see Drug Interactions (7.1)].

Mechanism of Action

Metoclopramide stimulates motility of the upper gastrointestinal tract without stimulating gastric, biliary, or pancreatic secretions. The exact mechanism of action of metoclopramide in the treatment of gastroesophageal reflux and acute and recurrent diabetic gastroparesis has not been fully established. It seems to sensitize tissues to the action of acetylcholine. The effect of metoclopramide on motility is not dependent on intact vagal innervation, but it can be abolished by anticholinergic drugs.

Metoclopramide increases the tone and amplitude of gastric (especially antral) contractions, relaxes the pyloric sphincter and the duodenal bulb, and increases peristalsis of the duodenum and jejunum resulting in accelerated gastric emptying and intestinal transit. It increases the resting tone of the lower esophageal sphincter. It has little, if any, effect on the motility of the colon or gallbladder.

Pharmacodynamics

Gastroesophageal Reflux

In patients with gastroesophageal reflux and low lower esophageal sphincter pressure (LESP), single oral doses of Reglan produced dose-related increases in LESP. Effects began at about 5 mg and increased through 20 mg. The increase in LESP from a 5 mg dose lasted about 45 minutes and that of 20 mg lasted between 2 and 3 hours. Increased rate of stomach emptying was observed with single oral doses of 10 mg.

Pharmacokinetics

Absorption

Relative to an intravenous dose of 20 mg, the absolute bioavailability of oral metoclopramide is 80% ± 15.5% as demonstrated in a crossover study of 18 subjects. Peak plasma concentrations occurred at about 1 to 2 hours after a single oral dose. Similar time to peak was observed after individual doses at steady state.

In a single dose study of 12 subjects, the area under the drug concentration-time curve increased linearly with doses from 20 to 100 mg (5 times the maximum recommended single dose). Peak concentrations increased linearly with dose; time to peak concentrations remained the same; whole body clearance was unchanged; and the elimination rate remained the same. The mean elimination half-life in subjects with normal renal function was 5 to 6 hours. Linear kinetic processes adequately describe the absorption and elimination of metoclopramide.

Distribution

Metoclopramide 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.

Elimination

  Metabolism: Metoclopramide undergoes enzymatic metabolism via oxidation as well as glucuronide and sulfate conjugation reactions in the liver. Monodeethylmetoclopramide, a major oxidative metabolite, is formed primarily by CYP2D6, an enzyme subject to genetic variability [see Dosage and Administration (2.2, 2.3), Use in Specific Populations (8.9)].   Excretion: Approximately 85% of the radioactivity of an orally administered dose appeared in the urine within 72 hours. After oral administration of 10 or 20 mg, a mean of 18% and 22% of the dose, respectively, was recovered as free metoclopramide in urine within 36 hours.

Specific Populations

  Patients with Renal Impairment: In a study of 24 patients with varying degrees of renal impairment (moderate, severe, and end-stage renal disease (ESRD) requiring dialysis), the systemic exposure (AUC) of metoclopramide in patients with moderate to severe renal impairment was about 2-fold the AUC in subjects with normal renal function. The AUC of metoclopramide in patients with ESRD on dialysis was about 3.5-fold the AUC in subjects with normal renal function [see Dosage and Administration (2.2, 2.3) and Use in Specific Populations (8.6)].   Patients with Hepatic Impairment: In a group of 8 patients with severe hepatic impairment (Child-Pugh C), the average metoclopramide clearance was reduced by approximately 50% compared to patients with normal hepatic function [see Dosage and Administration (2.2, 2.3) and Use in Specific Populations (8.7)].

Drug Interaction Studies

  Effect of Metoclopramide on CYP2D6 Substrates   Although in vitro studies suggest that metoclopramide can inhibit CYP2D6, metoclopramide is unlikely to interact with CYP2D6 substrates in vivo at therapeutically relevant concentrations.   Effect of CYP2D6 Inhibitors on Metoclopramide   In healthy subjects, 20 mg of metoclopramide and 60 mg of fluoxetine (a strong CYP2D6 inhibitor) were administered, following prior exposure to 60 mg fluoxetine orally for 8 days. The patients who received concomitant metoclopramide and fluoxetine had a 40% and 90% increase in metoclopramide Cmax and AUC0-∞, respectively, compared to patients who received metoclopramide alone (see Table 5) [see Drug Interactions (7.1)].

Table 5. Metoclopramide Pharmacokinetic Parameters in Healthy Subjects with and without Fluoxetine

Parameter	Metoclopramide alone (mean ± SD)	Metoclopramide with fluoxetine (mean ± SD)
Cmax (ng/mL)	44 ±15	62.7 ± 9.2
AUC0-∞ (ngˑh/mL)	313 ± 113	591 ± 140
t1/2 (h)	5.5 ± 1.1	8.5 ± 2.2