Reglan Drug Information

• Reglan tablets are indicated for the:
• Treatment for 4 to 12 weeks of symptomatic, documented gastroesophageal reflux in adults who fail to respond to conventional therapy.
• Relief of symptoms in adults with acute and recurrent diabetic gastroparesis. Limitations of Use:
• Reglan has not been shown to be safe and effective for the treatment of symptomatic, documented gastroesophageal reflux for longer than 12 weeks.
• Reglan tablets are not recommended for use in pediatric patients due to the risk of developing tardive dyskinesia (TD) and other extrapyramidal symptoms as well as the risk of methemoglobinemia in neonates. Reglan tablets are indicated for the:

Recommended Dosage for Symptomatic, Documented Gastroesophageal Reflux in Adults Who Fail Conventional Therapy Reglan tablets may be administered continuously or intermittently in patients with symptomatic, documented gastroesophageal reflux who fail to respond to conventional therapy: Continuous Dosing • The recommended dosage of Reglan tablets is 10 to 15 mg orally four times daily. The maximum recommended daily oral dosage is 60 mg. • Administer each dose thirty minutes before a meal and at bedtime. • The recommended treatment duration is 4 to 12 weeks, as determined by endoscopic response. Use Reglan for the shortest duration of treatment and periodically reassess the need for continued treatment. • The maximum recommended duration of treatment is 12 weeks.

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 as a 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 Dosage of Reglan Tablets for Symptomatic, Documented Gastroesophageal Reflux in Adults Who Fail Conventional Therapy Moderate or severe hepatic impairment (Child-Pugh B or C) 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 Concomitant use with strong CYP2D6 inhibitors (e.g., quinidine, bupropion, fluoxetine, and paroxetine) Moderate or severe renal impairment (creatinine clearance less than or equal to 60 mL/minute) Patients with End-Stage Renal Disease (ESRD ) including those treated with hemodialysis and continuous ambulatory peritoneal dialysis 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.

Recommended Dosage for Acute and Recurrent Diabetic Gastroparesis in Adults • The recommended oral dosage of Reglan tablets for the relief of symptoms in adults with acute and recurrent diabetic gastroparesis is 10 mg four times daily. If longer-term use is unavoidable, routinely monitor for signs and symptoms of TD. 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 Adult Patients with Acute and Recurrent Diabetic Gastroparesis Moderate or severe hepatic impairment (Child-Pugh B or C) 5 mg four times daily (30 minutes before each meal and at bedtime) 20 mg CYP2D6 poor metabolizers Concomitant use with strong CYP2D6 inhibitors (e.g., quinidine).

• The following adverse reactions are described, or described in greater detail, in other sections of the labeling:
• Tardive dyskinesia
• Other extrapyramidal symptoms
• Neuroleptic malignant syndrome
• Depression
• Hypertension
• Fluid retention
• Hyperprolactinemia
• Effects on the ability to drive and operate machinery The following adverse reactions have been identified from clinical studies or postmarketing reports of metoclopramide. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The most common adverse reactions (in approximately 10% of patients receiving 10 mg of metoclopramide four times daily) were restlessness, drowsiness, fatigue, and lassitude. In general, the incidence of adverse reactions correlated with the dosage and duration of metoclopramide administration. Adverse reactions, especially those involving the nervous system, occurred after stopping metoclopramide including dizziness, nervousness, and headaches. Central Nervous System Disorders
• Tardive dyskinesia, acute dystonic reactions, drug-induced parkinsonism, akathisia, and other extrapyramidal symptoms
• Convulsive seizures
• Hallucinations
• Restlessness, drowsiness, fatigue, and lassitude occurred in approximately 10% of patients who received 10 mg four times daily. Insomnia, headache, confusion, dizziness, or depression with suicidal ideation occurred less frequently.
• Neuroleptic malignant syndrome, serotonin syndrome (in combination with serotonergic agents). Endocrine Disorders: Fluid retention secondary to transient elevation of aldosterone. Galactorrhea, amenorrhea, gynecomastia, impotence secondary to hyperprolactinemia Cardiovascular Disorders: Acute congestive heart failure, possible atrioventricular block, hypotension, hypertension, supraventricular tachycardia, bradycardia, fluid retention Gastrointestinal Disorders: Nausea, bowel disturbances (primarily diarrhea) Hepatic Disorders: Hepatotoxicity, characterized by, e.g., jaundice and altered liver function tests, when metoclopramide was administered with other drugs with known hepatotoxic potential Renal and Urinary Disorders: Urinary frequency, urinary incontinence Hematologic Disorders: Agranulocytosis, neutropenia, leukopenia, methemoglobinemia, sulfhemoglobinemia Hypersensitivity Reactions: Bronchospasm (especially in patients with a history of asthma), urticaria; rash; angioedema, including glossal or laryngeal edema Eye Disorders: Visual disturbances Metabolism Disorders: Porphyria
• Most common adverse reactions (> 10%) are restlessness, drowsiness, fatigue, and lassitude. To report SUSPECTED ADVERSE REACTIONS, contact ANI Pharmaceuticals, Inc. at 1-855-204-1431 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Effects of Other Drugs on Metoclopramide Table 3 displays the effects of other drugs on metoclopramide. Table 3. Effects of Other Drugs on Metoclopramide Increased plasma concentrations of metoclopramide; risk of exacerbation of extrapyramidal symptoms.

Table 4. Effects of Metoclopramide on Other Drugs Interaction does not apply to posaconazole delayed-release tablets

Pregnancy Risk Summary Published studies, including retrospective cohort studies, national registry studies, and meta-analyses, do not report an increased risk of adverse pregnancy-related outcomes with use of metoclopramide during pregnancy. There are potential risks to the neonate following exposure in utero to metoclopramide during delivery (see Clinical Considerations). In animal reproduction studies, no adverse developmental effects were observed with oral administration of metoclopramide to pregnant rats and rabbits at exposures about 6 and 12 times the maximum recommended human dose (MRHD) (see Data).

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in the clinically recognized pregnancies is respectively.

Clinical Considerations Fetal/Neonatal Adverse Reactions Metoclopramide crosses the placental barrier and may cause extrapyramidal signs and methemoglobinemia in neonates with maternal administration during delivery. Monitor neonates for extrapyramidal signs. Data Animal Data Reproduction studies have been performed following administration of oral metoclopramide during organogenesis in pregnant rats at about 6 times the MRHD calculated on body surface area and in pregnant rabbits at about 12 times the MRHD calculated on body surface area.

No evidence of adverse developmental effects due to metoclopramide were observed.

Pediatric Use Metoclopramide is not recommended for use in pediatric patients due to the risk of tardive dyskinesia (TD) and other extrapyramidal symptoms as well as the risk of methemoglobinemia in neonates. The safety and effectiveness of Reglan tablets in pediatric patients have not been established. Dystonias and other extrapyramidal symptoms associated with metoclopramide are more common in pediatric patients than in adults.

In addition, neonates have reduced levels of NADH-cytochrome b 5 reductase, making them more susceptible to methemoglobinemia, a possible adverse reaction of metoclopramide use in neonates.

• Reglan is contraindicated:
• In patients with a history of tardive dyskinesia (TD) or a dystonic reaction to metoclopramide.
• 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.
• In patients with epilepsy. Reglan may increase the frequency and severity of seizures.
• In patients with hypersensitivity to metoclopramide. Reactions have included laryngeal and glossal angioedema and bronchospasm.
• History of TD or dystonic reaction to metoclopramide
• When stimulation of gastrointestinal motility might be dangerous
• Pheochromocytoma, catecholamine-releasing paragangliomas
• Epilepsy
• Hypersensitivity to metoclopramide

Manifestations of metoclopramide overdosage included drowsiness, disorientation, extrapyramidal reactions, other adverse reactions associated with metoclopramide use (including, e.g., methemoglobinemia), and sometimes death. Neuroleptic malignant syndrome (NMS) has been reported in association with metoclopramide overdose and concomitant treatment with another drug associated with NMS. There are no specific antidotes for Reglan overdosage.

If over-exposure occurs, call your Poison Control Center at 1-800-222-1222 for current information on the management of poisoning or overdosage. Methemoglobinemia can be reversed by the intravenous administration of methylene blue. However, methylene blue may cause hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, which may be fatal.

Hemodialysis and continuous ambulatory peritoneal dialysis do not remove significant amounts of metoclopramide.