Reglan

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: • 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 gastroesophageal reflux for longer than 12 weeks ( 1 , 5.1 ). • Reglan tablets are 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 ( 1 , 8.4 )

Symptomatic, Documented Gastroesophageal Reflux in Adults Who Fail Conventional Therapy • Administer Reglan continuously or intermittently: ○ Continuous: The recommended dosage is 10 to 15 mg orally, 30 minutes before each meal and at bedtime (maximum of 60 mg per day) for 4 to 12 weeks, as determined by endoscopic response. ○ Intermittent: Single doses up to 20 mg prior to provoking situation. Acute and Recurrent Diabetic Gastroparesis in Adults • The recommended dosage is 10 mg orally, 30 minutes before each meal and at bedtime (maximum of 40 mg per day). Dosage Adjustment in Specific Populations ( 2.1 , 2.2 ) • For symptomatic, documented gastroesophageal reflux and acute and recurrent diabetic gastroparesis, see Full Prescribing Information for recommended dosage reductions for elderly patients, in patients with moderate or severe hepatic or renal impairment, and cytochrome P450 2D6 (CYP2D6) poor metabolizers.

2.1Recommended 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 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 5 mg 1 four times daily (thirty minutes before each meal and at bedtime) 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.

2.2Recommended 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. The maximum recommended daily dosage is 40 mg. • Administer each dose thirty minutes before each meal and at bedtime. • Use Reglan for the shortest duration of treatment and periodically reassess the need for continued treatment. • Avoid treatment with metoclopramide, including Reglan tablets, for longer than 12 weeks. If longer-term use is unavoidable, routinely monitor for signs and symptoms of TD . 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 . 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 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 5 mg 1 four times daily (30 minutes before each meal and at bedtime) 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).

Avoid use with bupropion, fluoxetine, and paroxetine Moderate or severe renal impairment (creatinine clearance less than 60 mL/minute) Patients with End-Stage Renal Disease (ESRD ) including those treated with hemodialysis and continuous ambulatory peritoneal dialysis 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.

5 WARNINGS AND PRECAUTIONS • Tardive Dyskinesia (TD), Other Extrapyramidal Symptoms (EPS), and Neuroleptic Malignant Syndrome (NMS) : Avoid concomitant use of other drugs known to cause TD/EPS/NMS and avoid use in patients with Parkinson’s Disease. If symptoms occur, discontinue Reglan and seek immediate medical attention ( 5.1 , 5.2 , 5.3 , 7.1 , 7.2 ) • Depression and suicidal ideation/suicide : Avoid use.

5.1Tardive Dyskinesia Metoclopramide,

including Reglan, 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. Metoclopramide, including Reglan, may also suppress, or partially suppress, the signs of TD, and may delay the diagnosis of TD because it may mask the underlying disease process. The effect of this symptomatic suppression upon the long-term course of TD is unknown.

TD may remit, partially or completely, if Reglan treatment is discontinued . In patients treated with metoclopramide, including Reglan, 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 in elderly patients, especially in elderly women , and in patients with diabetes mellitus. Prevention, Mitigation, and Monitoring for TD • Reglan is contraindicated in patients with a history of TD. • Avoid use of Reglan in patients receiving concomitant antipsychotics due to the potential additive effects of TD . • Reduce the Reglan dosage in the elderly . • Use Reglan for the shortest duration of treatment and periodically reassess the need for continued treatment. • Immediately discontinue Reglan in patients who develop signs and symptoms of TD. • In patients with symptomatic, documented gastroesophageal reflux, the maximum duration of treatment is 12 weeks . • In patients with diabetic gastroparesis, avoid a total duration of treatment with metoclopramide products, including Reglan tablets, for longer than 12 weeks.

If longer-term use is unavoidable, routinely monitor for signs and symptoms of TD. • If patients have continued TD symptoms, consider TD treatment.

5.2Other 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. If treatment is unavoidable, use Reglan for the shortest duration of treatment and periodically reassess the need for continued treatment. Routinely monitor for signs and symptoms of Parkinson’s disease . • 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.

5.3Neuroleptic 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 . • Intensive symptomatic treatment and medical monitoring. • Treatment of any concomitant serious medical problems for which specific treatments are available.

5.4Depression 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.

5.5Hypertension 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 . 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 . Discontinue Reglan in any patient with a rapid rise in blood pressure.

5.6Fluid 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.

5.7Hyperprolactinemia As with

other dopamine D 2 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 D 2 receptor antagonists and tumorigenesis in humans .

5.8Effects 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 .

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

8.1Pregnancy 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 . 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) . 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 2 to 4% and 15 to 20%, 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.

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.