Drug Safety-related Labeling Changes (SrLC)

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Drug Safety-related Labeling Changes (SrLC) Database

ANDA	Abbreviated New Drug Application
BLA	Biologics License Application
CDER	Center for Drug Evaluation and Research
MG	Medication Guide
NDA	New Drug Application
PCI	Patient Counseling Information
PI	Patient Information
PLR	Physician Labeling Rule
PLLR	Pregnancy and Lactation Labeling Rule
Italics	For the most part, italics indicate an FDA comment such as: Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section.
Underlines	Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text.

Sections

BW	Box Warning
WP	Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format)
AR	Adverse Reactions (in pre-PLR format, this may be a subheading under precautions).
DI	Drug Interactions (in pre-PLR format, this may be a subheading under precautions).
USP	Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format.
PCI/PI/MG	Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events.

Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.

Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.

METOZOLV ODT (NDA-022246)

(METOCLOPRAMIDE HYDROCHLORIDE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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02/28/2019 (SUPPL-9)

Approved Drug Label (PDF)

4 Contraindications

Additions and/or revisions underlined:

METOZOLV ODT 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.

5 Warnings and Precautions

5.1 Tardive Dyskinesia

5.2 Other Extrapyramidal Symptoms

5.3 Neuroleptic Malignant Syndrome

5.4 Depression

5.5 Hypertension

5.6 Fluid Retention

Extensive changes in the above subsections; please refer to label for complete information.

The following two subsections are newly added:

5.7 Hyperprolactinemia

As with other dopamine D2 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 antagonists and tumorigenesis in humans.

5.8 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.

6 Adverse Reactions

Addition of bulleted line listing of adverse reactions. Entire section extensively changed; please refer to label for complete information.

7 Drug Interactions

Subsections condensed down to just 2:

7.1 Effects of Other Drugs on Metoclopramide

Includes Table 3 with same title; please refer to label for complete information.

7.2 Effects of Metoclopramide on Other Drugs

Includes Table 4 with same title; please refer to label for complete information.

8 Use in Specific Populations

8.1 Pregnancy

8.2 Lactation

PLLR conversion; extensive changes. Please refer to label for complete information.

8.4 Pediatric Use

Additions and/or revisions underlined:

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.

8.5 Geriatric Use

Additions and/or revisions underlined:

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 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.

Addition of the following two subsections:

8.6 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 receiving hemodialysis and continuous ambulatory peritoneal dialysis.

8.7 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. There is no dosage adjustment required for patients with mild hepatic impairment (Child-Pugh A).

In addition, metoclopramide, by producing a transient increase in plasma aldosterone, may increase the risk of fluid retention in patients with hepatic impairment. Monitor patients with hepatic impairment for the occurrence of fluid retention and volume overload.

Additions and/or revisions underlined:

8.8 NADH-Cytochrome b5 Reductase Deficiency

Metoclopramide-treated patients with NADH-cytochrome b5 reductase deficiency are at an increased risk of developing methemoglobinemia and/or sulfhemoglobinemia. For patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency the metoclopramide-induced methemoglobinemia, methylene blue treatment is not recommended. Methylene blue may cause hemolytic anemia in patients with G6PD deficiency, which may be fatal.

Addition of the following subsection:

8.9 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. Reduce the METOZOLV ODT dosage in patients who are poor CYP2D6 metabolizers.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Extensively changed; please refer to label for complete information.