Metozolv

DESCRIPTION

METOZOLV ODT is an orally disintegrating tablet formulation of metoclopramide hydrochloride. The 5 mg strength is a round white tablet debossed on one side with a "5" and plain on the other side; it is comprised of 5 mg metoclopramide (as 5.91 mg of metoclopramide hydrochloride ) withgelatin, mannitol, mint flavoring, and Acesulfame K (artificial sweetener). The 10 mg strength is a round white tablet debossed on one side with a "10" and plain on the other side; it is comprised of 10 mg metoclopramide (as 11.82 mg of metoclopramide hydrochloride) with gelatin, mannitol, mint flavoring, and Acesulfame K.

The active ingredient, metoclopramide hydrochloride, is a white crystalline, odorless substance, freely soluble in water. Chemically, it is 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-methoxy benzamide monohydrochloride monohydrate. Its molecular formula is C₁₄H₂₂ClN₃O₂•HCl•H₂O. Its molecular weight is 354.3. The structural formula is shown in Figure 1.

Figure 1

METOZOLV ODT includes the following inactive ingredients: gelatin, mannitol, mint flavoring, Acesulfame potassium (artificial sweetener), and trace amounts of sodium chloride and sodium hydroxide.

我NDICATIONS

METOZOLV^®ODT is indicated in adults for the:

• Treatment for 4 to 12 weeks of symptomatic, documented gastroesophageal reflux disease (GERD) who fail to respond to conventional therapy.
• Relief of symptoms associated with acute and recurrent diabetic gastroparesis (gastric stasis).

Limitations Of Use

METOZOLV ODT is not recommended for use in pediatric patients due to the risk of developing tardive dyskinesia (TD) and other extrapyramidal symptoms and the risk of methemoglobinemia in neonates [seeUse In Specific Populations]

DOSAGE AND ADMINISTRATION

我mportant Administration Instructions

• Avoid treatment with METOZOLV ODT for longer than 12 weeks because of the increased risk of developing TD with longer-term use [seeDosage For GERD, Dosage For Acute And Recurrent Diabetic Gastroparesis (Gastric Stasis),警告ANDPRECAUTIONS].
• Take on an empty stomach at least 30 minutes before eating [seeCLINICAL PHARMACOLOGY]. Do not repeat dose if inadvertently taken with food.
• Remove each dose from the packaging just prior to taking. Handle the tablet with dry hands and place on the tongue. If the tablet should break or crumble while handling, discard and remove a new tablet.
• Place the tablet on the tongue and allow it to disintegrate (takes approximately one minute) and swallow the granules without water [seeCLINICAL PHARMACOLOGY].

Dosage For Gerd

METOZOLV ODT may be administered continuously or intermittently in patients with symptomatic GERD who fail to respond to conventional therapy:

Continuous Dosing

The recommended adult dosage of METOZOLV ODT 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.

我ntermittent Dosing

我f symptoms only occur intermittently or at specific times of the day, administer METOZOLV ODT 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 METOZOLV ODT Dosage in Patients with Gastroesophageal Reflux

	Recommended Dosage	Maximum Recommended Daily Dosage
Adult patients	10 to 15 mg four times daily (每次餐前和睡前30分钟)	60 mg
Mild hepatic impairment (Child-Pugh A)
Elderly patients1[seeUse In Specific Populations]	5 mg four times daily (每次餐前和睡前30分钟)
Moderate or severe hepatic impairment (Child-Pugh B or C) [seeUse In Specific Populations]	5 mg four times daily (每次餐前和睡前30分钟), or 10 mg taken three times daily	30 mg
CYP2D6 poor metabolizers [seeUse In Specific Populations]
同时使用强大的CYP2D6抑制剂(如。, quinidine, bupropion,fluoxetine, and paroxetine) [seeDRUG INTERACTIONS]
Moderate or severe renal impairment (creatinine clearance less than or equal to 60 mL/minute) [seeUse In Specific Populations]
Patients with End-Stage Renal Disease (ESRD) including those treated with hemodialysis and continuous ambulatory peritoneal dialysis [seeUse In Specific Populations]	5 mg four times daily (每次餐前和睡前30分钟) or 10 mg twice daily	20 mg
1Elderly patients may be more sensitive to the therapeutic or adverse effects of METOZOLV ODT; 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 (Gastric Stasis)

The recommended adult dosage for the relief of symptoms associated with diabetic gastroparesis (gastric stasis) is 10 mg four times daily for 2 to 8 eight weeks, depending on symptomatic response. Avoid METOZOLV ODT treatment for greater than 12 weeks [see警告ANDPRECAUTIONS]. Administer the dosage at least 30 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.

我f patients with diabetic gastroparesis have severe nausea or vomiting and are unable to take oral METOZOLV ODT 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 METOZOLV ODT tablets.

Table 2 Recommended METOZOLV ODT Dosage in Patients with Acute and Recurrent Diabetic Gastroparesis

	Recommended Dosage	Maximum Recommended Daily Dosage
Adult patients	10 mg four times daily (每次餐前和睡前30分钟)	40 mg
Mild hepatic impairment (Child-Pugh A)
Elderly patients [seeUse In Specific Populations]	5 mg1four times daily (每次餐前和睡前30分钟)
Moderate or severe hepatic impairment (Child-Pugh B or C) [seeUse In Specific Populations]	5 mg four times daily (每次餐前和睡前30分钟)	20 mg
CYP2D6 poor metabolizers [seeUse In Specific Populations]
同时使用强大的CYP2D6抑制剂(如。, quinidine, bupropion, fluoxetine, and paroxetine) [seeDRUG INTERACTIONS]
Moderate or severe renal impairment (creatinine clearance less than or equal to 60 mL/minute) [seeUse In Specific Populations]
Patients with End-Stage Renal Disease (ESRD) including those treated with hemodialysis and continuous ambulatory peritoneal dialysis [seeUse In Specific Populations]	5 mg twice daily	10 mg
1Elderly patients may be more sensitive to the therapeutic or adverse effects of METOZOLV ODT; 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.

HOW SUPPLIED

Dosage Forms And Strengths

Tablets

• 5 mg metoclopramide: white, round debossed with "5" on one side and plain on the other side.
• 10 mg metoclopramide: white, round debossed with "10" on one side and plain on the other side.

储存和处理

5 mg Tablets: white, round debossed with "5" on one side and plain on the other side containing 5 mg metoclopramide. Available in blister pack with 10 tablets individually sealed in a foil-backed unit-dose container; a carton contains 10 cards (NDC65649-431-02).

10 mg Tablets: white, round debossed with "10" on one side and plain on the other side containing 10 mg metoclopramide. Available in blister pack with 10 tablets individually sealed in a foil-backed unit-dose container; a carton contains 10 cards (NDC65649-432-02).

Store at controlled room temperature, between 20°C and 25°C (68°F and 77°F).

Manufactured by: Catalent UK Swindon Zydis Limited Swindon, UK. Revised: Feb 2019

SIDE EFFECTS

The following adverse reactions are described, or described in greater detail, in other sections of the labeling:

• Tardive dyskinesia [seeBOX WARNINGand警告ANDPRECAUTIONS]
• Other extrapyramidal effects [see警告ANDPRECAUTIONS]
• Neuroleptic malignant syndrome [see警告ANDPRECAUTIONS]
• Depression [see警告ANDPRECAUTIONS]
• Hypertension [see警告ANDPRECAUTIONS]
• Fluid retention [see警告ANDPRECAUTIONS]
• Hyperprolactinemia [see警告ANDPRECAUTIONS]
• Effects on the ability to drive and operate machinery [see警告ANDPRECAUTIONS]

Metoclopramide

以下不良反应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

DRUG INTERACTIONS

Effects Of Other Drugs On Metoclopramide

Table 3 displays the effects of other drugs on metoclopramide.

Table 3 Effects of Other Drugs on Metoclopramide

Antipsychotics
Clinical Impact	Potential for additive effects, including increased frequency and severity of tardive dyskinesia (TD), other extrapyramidal symptoms (EPS), and neuroleptic malignant syndrome (NMS).
干预	Avoid concomitant use [see警告ANDPRECAUTIONS].
Strong CYP2D6 Inhibitors, not Included in Antipsychotic Category Above
Clinical Impact	我ncreased plasma concentrations of metoclopramide; risk of exacerbation of extrapyramidal symptoms [seeCLINICAL PHARMACOLOGY].
干预	Reduce the METOZOLV ODT dosage [seeDOSAGE AND ADMINISTRATION].
Examples	quinidine, bupropion, fluoxetine, and paroxetine
Monoamine Oxidase Inhibitors
Clinical Impact	我ncreased risk of hypertension [see警告ANDPRECAUTIONS].
干预	Avoid concomitant use.
Central Nervous System (CNS) Depressants
Clinical Impact	我ncreased risk of CNS depression [see警告ANDPRECAUTIONS].
干预	避免METOZOLV ODT或交互联系g, depending on the importance of the drug to the patient.
Examples	alcohol, sedatives, hypnotics, opiates and anxiolytics.
Drugs that Impair Gastrointestinal Motility
Clinical Impact	Decreased systemic absorption of metoclopramide.
干预	Monitor for reduced therapeutic effect.
Examples	antiperistaltic antidiarrheal drugs, anticholinergic drugs, and opiates.
Dopaminergic Agonists and Other Drugs that Increase Dopamine Concentrations
Clinical Impact	Decreased therapeutic effect of metoclopramide, a D2antagonist, due to opposing effects on dopamine.
干预	Monitor for reduced therapeutic effect.
Examples	Apomorphine, bromocriptine, cabergoline, levodopa, pramipexole, ropinirole, and rotigotine

Effects Of Metoclopramide On Other Drugs

Table 4 displays the effects of metoclopramide on other drugs.

Table 4 Effects of Metoclopramide on Other Drugs

Dopaminergic Agonists and Other Drugs that Increase Dopamine Concentrations:
Clinical Impact	Opposing effects of metoclopramide and the interacting drug on dopamine. Potential exacerbation of symptoms (e.g., parkinsonian symptoms).
干预	Avoid concomitant use [see警告ANDPRECAUTIONS].
Examples	Apomorphine, bromocriptine, cabergoline, levodopa, pramipexole, ropinirole, rotigotine.
Succinylcholine, Mivacurium:
Clinical Impact	Metoclopramide inhibits plasma cholinesterase leading to enhanced neuromuscular blockade.
干预	Monitor for signs and symptoms of prolonged neuromuscular blockade.
Drugs with Absorption Altered due to Increased Gastrointestinal Motility:
Clinical Impact	The effect of metoclopramide on other drugs is variable. Increased gastrointestinal (GI) motility by metoclopramide may impact absorption of other drugs leading to decreased or increased drug exposure.
干预	Drugs with Decreased Absorption (e.g., digoxin, atovaquone, posaconazole oral suspension*, fosfomycin): Monitor for reduced therapeutic effect of the interacting drug. For digoxin monitor therapeutic drug concentrations and increase the digoxin dose as needed (see prescribing information for digoxin).
	Drugs with Increased Absorption (e.g., sirolimus, tacrolimus, cyclosporine):Monitor therapeutic drug concentrations and adjust the dose as needed. See prescribing information for the interacting drug.
我nsulin
Clinical Impact	我ncreased GI motility by metoclopramide may increase delivery of food to the intestines and increase blood glucose.
干预	Monitor blood glucose and adjust insulin dosage regimen as needed.
*我nteraction does not apply to posaconazole delayed-release tablets

警告

我ncluded as part of the"PRECAUTIONS"Section

PRECAUTIONS

Tardive Dyskinesia

Metoclopramide can causetardive dyskinesia(TD), a potentially irreversible and disfiguring disorder characterized byinvoluntarymovements of the face or tongue, and sometimes of the trunk and/or extremities. Movements may be choreoathetoic in appearance. The risk of developing TD and the likelihood that TD will become irreversible increases with the duration of treatment and total cumulative dosage. An analysis of utilization patterns showed that about 20% of patients who used metoclopramide took it for 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.

Additionally, the risk of developing TD is increased among the elderly, especially elderly women [seeUse In Specific Populations], and in patients withdiabetes mellitus。Due to the risk of developing TD, avoid treatment with METOZOLV ODT for longer than 12 weeks and reduce the dosage in elderly patients [seeDOSAGE AND ADMINISTRATION].

Discontinue METOZOLV ODT 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 METOZOLV ODT is withdrawn.

METOZOLV ODT 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. METOZOLV ODT is contraindicated in patients with a history of TD [seeCONTRAINDICATIONS]. Avoid METOZOLV ODT in patients receiving other drugs that can cause TD (e.g., antipsychotics).

Other Extrapyramidal Symptoms

我n 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 METOZOLV ODT.

• Extrapyramidal symptoms (EPS), such as acute dystonic reactions, occurred in patients treated with metoclopramide dosages of 30 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 (METOZOLV ODT 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,bulbartype of speech,trismus, or dystonic reactions resemblingtetanus。Rarely, dystonic reactions were present as stridor anddyspnea, possibly due to laryngospasm. Diphenhydramine hydrochloride or benztropine mesylate may be used to treat these adverse reactions. Avoid METOZOLV ODT in patients receiving other drugs that can cause EPS (e.g., antipsychotics).
• Parkinsonism症状(bradykinesia,tremor, cogwheel rigidity, mask-likefacies) 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 following discontinuation of metoclopramide. Avoid METOZOLV ODT in patients withParkinson's diseaseand other patients being treated with antiparkinsonian drugs due to potential exacerbation of symptoms. Avoid treatment with METOZOLV ODT for more than 12 weeks [seeDOSAGE AND ADMINISTRATION,Tardive Dyskinesia].
• 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 calledNeurolepticMalignantSyndrome (NMS). NMS has been reported in association with metoclopramide overdosage and concomitant treatment with another drug associated with NMS. Avoid METOZOLV ODT in patients receiving other drugs associated with NMS, including typical andatypicalantipsychotics.

Clinical manifestations of NMS includehyperthermia, muscle rigidity, altered mental status, and manifestations of autonomic instability (irregularpulseor blood pressure,tachycardia, diaphoresis and cardiac arrhythmias). Additional signs may include elevatedcreatinephosphokinase, myoglobinuria (rhabdomyolysis), andacute renal failure。Patients with such symptoms should be evaluated immediately.

我n the diagnostic evaluation, consider the presence of other serious medical illness (e.g.,pneumonia, systemic infection) and untreated or inadequately treated extrapyramidal signs and symptoms. Other important considerations in thedifferential diagnosisinclude centralanticholinergictoxicity,heat stroke,malignant hyperthermia, drug fever,serotoninsyndrome and primarycentral nervous systempathology。

Management of NMS includes:

• 我mmediate discontinuation of METOZOLV ODT and other drugs not至关重要的to concurrent therapy [seeDRUG INTERACTIONS].
• 我ntensivesymptomatic treatmentand 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 METOZOLV ODT use in patients with a history of depression.

Hypertension

Metoclopramide may elevate blood pressure. In one study inhypertensivepatients, intravenously administered metoclopramide was shown to release catecholamines; hence, avoid use in patients withhypertensionor in patients taking monoamine oxidase inhibitors [seeDRUG INTERACTIONS].

也有临床高血压cr的报告ises in some patients with undiagnosedpheochromocytoma。METOZOLV ODT is contraindicated in patients with pheochromocytoma or othercatecholamine-releasing paragangliomas [seeCONTRAINDICATIONS]. Discontinue METOZOLV ODT in any patient with a rapid rise in blood pressure.

Fluid Retention

Because metoclopramide produces a transient increase in plasmaaldosterone, patients withcirrhosisor congestive heart failure may be at risk of developing fluid retention and volume overload. Discontinue METOZOLV ODT if any of these adverse reactions occur.

Hyperprolactinemia

As with otherdopamineD₂antagonists, metoclopramide elevatesprolactinlevels.

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

Hyperprolactinemia may potentially stimulate prolactin-dependentbreast cancer。However, some clinical studies and epidemiology studies have not shown an association between administration of dopamine D₂antagonists and tumorigenesis in humans [seeNonclinical Toxicology].

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 METOZOLV ODT or the interacting drug, depending on the importance of the drug to the patient [seeDRUG INTERACTIONS].

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Adverse Reactions

我nform patients or their caregivers that METOZOLV ODT can cause serious adverse reactions. Instruct patients to discontinue METOZOLV ODT and contact a healthcare provider immediately if the following serious reactions occur:

• Tardivedyskinesiaand other extrapyramidal reactions [see警告AND PRECAUTIONS]
• Neuroleptic malignant syndrome [see警告AND PRECAUTIONS]
• Depression and/or possible suicidal ideation [see警告AND PRECAUTIONS]

我nform patients or their caregivers that concomitant treatment with numerous other medications can precipitate or worsen serious adverse reactions such as tardive dyskinesia or other extrapyramidal reactions, neuroleptic malignant syndrome, and CNS depression [seeDRUG INTERACTIONS]. Explain that the prescriber of any other medication must be made aware that the patient is taking METOZOLV ODT.

我nform patients or their caregivers that METOZOLV ODT can cause drowsiness or dizziness, or otherwise impair the mental and/or physical abilities required for the performance of hazardous tasks such as operating machinery or driving a motor vehicle [see警告AND PRECAUTIONS].

Administration

我nstruct patients to:

• Take on an empty stomach at least 30 minutes before eating. Do not repeat dose if inadvertently taken with food.
• Remove each dose from the packaging just prior to taking. Handle the tablet with dry hands and place on the tongue. If the tablet should break or crumble while handling, discard and remove a new tablet.
• Place the tablet on the tongue and allow it to disintegrate (takes approximately one minute) and swallow the granules without water [seeDOSAGE AND ADMINISTRATION].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

77周研究在大鼠口服toclopramide doses up to 40 mg/kg/day (about six times the maximum recommended human dose on body surface area basis). Metoclopramide elevated prolactin levels and the elevation persisted during chronic administration. An increase in mammary neoplasms was found in rodents after chronic administration of metoclopramide [see警告AND PRECAUTIONS]. In a rat model for assessing the tumor promotion potential, a 2-week oral treatment with metoclopramide at a dose of 260 mg/kg/day (about 35 times the maximum recommended human dose based on body surface area) enhanced the tumorigenic effect of N-nitrosodiethylamine.

Mutagenesis

Metoclopramide was positive in thein vitroChinese hamster lung cell / HGPRT forward mutation assay for mutagenic effects and thein vitrohumanlymphocytechromosome aberration assay for clastogenic effects. It was negative in thein vitroAmes mutation assay, thein vitrounscheduled DNA synthesis assay with rat and human hepatocytes and thein vivorat micronucleus assay.

我mpairment Of Fertility

Metoclopramide atintramusculardoses up to 20 mg/kg/day (about 3 times the maximum recommended human dose based on body surface area) was found to have no effect on fertility and reproductive performance of male and female rats.

Use In Specific Populations

Pregnancy

Risk Summary

Published studies, includingretrospectivecohort 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 theneonatefollowing exposure in utero to metoclopramide during delivery (seeClinical 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) (seeData).

The estimated background risk of major birth defects andmiscarriagefor 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 andmethemoglobinemiain neonates with maternal administration during delivery. Monitor neonates for extrapyramidal signs [see警告AND PRECAUTIONS,Pediatric Use].

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.

Lactation

Risk Summary

Limited published data report the presence of metoclopramide in human milk in variable amounts. Breastfed infants exposed to metoclopramide have experiencedgastrointestinaladverse reactions, including intestinal discomfort and increasedintestinal gasformation (seeData). Metoclopramide elevates prolactin levels [see警告AND PRECAUTIONS];但是,公布的数据不充分support drug effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for METOZOLV ODT and any potential adverse effects on the breastfed child from METOZOLV ODT or from the underlying maternal condition.

Clinical Considerations

Monitor breastfeeding neonates because metoclopramide may cause extrapyramidal signs (dystonias) and methemoglobinemia [see警告AND PRECAUTIONS,Pediatric Use].

Data

我n published clinical studies, the estimated amount of metoclopramide received by the breastfed infant was less than 10% of the maternal weight-adjusted dose. In one study, the estimated daily amount of metoclopramide received by infants from breast milk ranged from 6 to 24 mcg/kg/day in earlypuerperium(3 to 9 dayspostpartum) and from 1 to 13 mcg/kg/day at 8 to 12 weeks postpartum.

Pediatric Use

METOZOLV ODT 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 METOZOLV ODT in pediatric patients have not been established.

Dystonias and other extrapyramidal reactions associated with metoclopramide are more common in the pediatric patients than in adults [see警告AND PRECAUTIONS]. In addition, neonates have reduced levels ofNADH-cytochrome b₅reductase, making them more susceptible to methemoglobinemia, a possible side effect of metoclopramide use in neonates [seeNADH-Cytochrome b₅Reductase Deficiency].

Geriatric Use

Metoclopramide is known to be substantially excreted by the kidney, and the risk of adverse reactions, including tardive dyskinesia (TD), may be greater in patients with impaired renal function [seeUse In Specific Populations,CLINICAL PHARMACOLOGY]. Elderly patients are more likely to have decreased renal function and may be more sensitive to the therapeutic or adverse effects of metoclopramide; therefore, consider a reduced dosage of METOZOLOV ODT in elderly patients [seeDOSAGE AND ADMINISTRATION,警告AND PRECAUTIONS].

Renal Impairment

The clearance of metoclopramide is decreased and the systemic exposure is increased in patients with moderate to severe renal impairment compared to patients with normal renal function, which may increase the risk of adverse reactions. Reduce the METOZOLV ODT dosage in patients with moderate and severe renal impairment (creatinine clearance less than or equal to 60 mL/minute), including those receivinghemodialysisand continuous ambulatoryperitoneal dialysis[seeDOSAGE AND ADMINISTRATION,CLINICAL PHARMACOLOGY].

Hepatic Impairment

Patients with severe hepatic impairment (Child-Pugh C) have reduced systemic metoclopramide clearance (by approximately 50%) compared to patients with normal hepatic function. The resulting increase in metoclopramide blood concentrations increases the risk of adverse reactions. There are no pharmacokinetic data in patients with moderate hepatic impairment (Child-Pugh B). Reduce METOZOLV ODT dosage in patients with moderate or severe (Child-Pugh B or C) hepatic impairment [seeDOSAGE AND ADMINISTRATION]. There is no dosage adjustment required for patients with mild hepatic impairment (Child-Pugh A).

我n addition, metoclopramide, by producing a transient increase in plasma aldosterone, may increase the risk of fluid retention in patients with hepatic impairment [see警告AND PRECAUTIONS].

Monitor patients with hepatic impairment for the occurrence of fluid retention and volume overload.

NADH-Cytochrome b₅Reductase Deficiency

Metoclopramide-treated patients with NADH-cytochrome b₅reductase deficiency are at an increased risk of developing methemoglobinemia and/or sulfhemoglobinemia. For patients withglucose-6-phosphate dehydrogenase(G6PD) deficiency the metoclopramide-induced methemoglobinemia, methylene blue treatment is not recommended. Methylene blue may causehemolytic anemiain patients withG6PD deficiency, which may be fatal [seeOVERDOSE].

CYP2D6 Poor Metabolizers

Metoclopramide is a substrate of CYP2D6. The elimination of metoclopramide may be slowed in patients who are CYP2D6 poor metabolizers (compared to patients who are CYP2D6 intermediate, extensive, or ultra-rapid metabolizers); possibly increasing the risk of dystonic and other adverse reactions to METOZOLV ODT [seeCLINICAL PHARMACOLOGY]. Reduce the METOZOLV ODT dosage in patients who are poor CYP2D6 metabolizers [seeDOSAGE AND ADMINISTRATION].

OVERDOSE

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 [see警告ANDPRECAUTIONS].

There are no specific antidotes for METOZOLV ODT overdosage. If over-exposure occurs, call your Poison Control Center at 1-800-222-1222 for current information on the management ofpoisoningor overdosage.

Methemoglobinemia can be reversed by the intravenous administration of methylene blue. However, methylene blue may causehemolyticanemiain patients with G6PD deficiency, which may be fatal.

CONTRAINDICATIONS

METOZOLV ODT is contraindicated:

• 我n patients with a history of tardive dyskinesia (TD) or a dystonic reaction to metoclopramide [see警告ANDPRECAUTIONS].
• When stimulation of gastrointestinal motility might be dangerous (e.g., in the presence of gastrointestinalhemorrhage, mechanical obstruction, or perforation).
• 我n 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警告ANDPRECAUTIONS].
• 我n patients withepilepsy。灭吐可能增加联邦quency and severity of seizures [seeADVERSE REACTIONS].
• 我n patients with hypersensitivity to metoclopramide. Reactions have includedlaryngealandglossalangioedemaand bronchospasm [seeADVERSE REACTIONS].

CLINICAL PHARMACOLOGY

Mechanism Of Action

Metoclopramide stimulates motility of the uppergastrointestinal tractwithout stimulatinggastric,biliary, or pancreatic secretions. The exact mechanism of action of metoclopramide in the treatment ofgastroesophageal refluxand acute andrecurrentdiabeticgastroparesishas not been fully established. It seems to sensitize tissues to the action ofacetylcholine。The effect of metoclopramide on motility is not dependent on intact vagalinnervation, but it can be abolished by anticholinergic drugs.

Metoclopramide increases the tone and amplitude of gastric (especially antral) contractions, relaxes the pyloric sphincter and theduodenalbulb, and increasesperistalsisof theduodenumandjejunumresulting in accelerated gastric emptying and intestinal transit. It increases the resting tone of the loweresophagealsphincter. It has little, if any, effect on the motility of thecolonorgallbladder。

Pharmacodynamics

Gastroesophageal Reflux

我n patients withgastroesophagealrefluxand 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

Unless otherwise specified the PK of metoclopramide described below was obtained using other oral formulations of metoclopramide.

Absorption

Relative to an intravenous dose of 20 mg, the absolute oral bioavailability of metoclopramide was 80% ± 15.5% as demonstrated in acrossover studyof 18 subjects.

Following METOZOLV ODT tablet administration, the time reported between placing the tablet on the tongue and it completely disintegrated into fine particles was approximately one minute (with a range of 10 seconds to 14 minutes) in two clinical trials (N = 96) with a mean ± SD being 77 ± 111 seconds and a median of 54 seconds [seeDOSAGE AND ADMINISTRATION].

Peak plasma concentrations occurred at about 1 to 2 hours after a single oral dose. Similar time to peak is observed after individual doses at steady state.

我n a single dose study of 12 subjects showed that the area under the drug concentration-time curve increases linearly with doses from 20 to 100 mg of metoclopramide (5 times the maximum recommended single dose of METOZOLV ODT). Cmax increased linearly with dose; Tmax remained the same; whole body clearance was unchanged; and the elimination rate remained the same. Linearkineticprocesses adequately describe the absorption and elimination of metoclopramide.

The pharmacokinetic characteristics following single oral administration of 10 mg METOZOLV ODT under fasting conditions are shown in Table 5.

Table 5 Mean (± SD) Pharmacokinetic Parameters in Healthy Subjects Following a Single Oral Dose of 10 mg METOZOLV ODT Under Fasting Conditions

Treatment	Cmax (ng/mL)	Tmax (h)*	AUC0-inf (ng*h/mL)
Single 10 mg METOZOLV ODT (N=41)	28 ± 7.4	2.0 (0.7 to 4.0)	268 ± 72.6
*presented as median (range).

Effect of Food

When METOZOLV ODT was taken immediately after a high-fat meal (approximately 900 total calories based on the composition being 150 protein calories, 250carbohydratecalories and 500 fat calories), the Cmax was 17% lower than when taken after an overnight fast. The Tmax increased from about 1.8 hours under fasted conditions to 3 hours when taken immediately after a high-fat meal. The extent of metoclopramide absorbed (area under the curve) was comparable whether METOZOLV ODT was administered with or without food. The clinical relevance of a lower Cmax with a high-fat meal is unknown [seeDOSAGE AND ADMINISTRATION].

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

The average elimination half-life of metoclopramide in subjects with normal renal function was 5 to 6 hours.

Metabolism

Metoclopramide undergoes enzymaticmetabolismvia 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 [seeDOSAGE AND ADMINISTRATION,Use In Specific Populations].

Excretion

Approximately 85% of the radioactivity of an orally administered dose appears 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

我n a study of 24 patients with varying degrees of renal impairment (moderate, severe, andend-stage renal disease(ESRD) requiringdialysis), 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 [seeDOSAGE AND ADMINISTRATION,Use In Specific Populations].

Patients With Hepatic Impairment

我n 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 [seeDOSAGE AND ADMINISTRATION,Use In Specific Populations].

Drug Interaction Studies

Effect Of Metoclopramide On CYP2D6 Substrates

Although in vitro studiessuggest that metoclopramide can inhibit CYP2D6, metoclopramide is unlikely to interact with CYP2D6 substratesin vivoat therapeutically relevant concentrations.

Effect Of CYP2D6 Inhibitors On Metoclopramide

我n healthy subjects, 20 mg of oral 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 (seeTable 6 Metoclopramide Pharmacokinetic Parameters in Healthy Subjects with and without Fluoxetine)[seeDRUG INTERACTIONS].

Table 6 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-∞ (ng·h/mL)	313 ± 113	591 ± 140
t1/2 (h)	5.5 ± 1.1	8.5 ± 2.2

PATIENT INFORMATION

No information provided. Please refer to the警告ANDPRECAUTIONSsections.