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.

METAXALONE (NDA-022503)

(METAXALONE)

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

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01/10/2024 (SUPPL-3)

Approved Drug Label (PDF)

4 Contraindications

Additions and/or revisions underlined:
The use of Metaxalone Tablets, 640 mg is contraindicated in patients with:

Known hypersensitivity to any components of this product.
Known tendency for drug-induced, hemolytic, or other anemias.
Severe renal or hepatic impairment.

5 Warnings and Precautions

5.1 Serotonin Syndrome

Additions and/or revisions underlined:

Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of metaxalone (within the recommended dosage range) and other serotonergic drugs [see Drug Interactions (7)] and with the use of metaxalone as the only serotonergic drug taken at a dosage higher than the recommended dosage [see Overdosage (10)].

…

The onset of symptoms generally occurs within several hours to a few days after initiation of a serotonergic drug but may occur later than that.

If concomitant use of Metaxalone Tablets, 640 mg and another serotonergic drug is warranted, reassess the patient, particularly during treatment initiation and dosage modification. Discontinue Metaxalone Tablets, 640 mg if serotonin syndrome is suspected or occurs.

5.2 Central Nervous System Depression

Additions and/or revisions underlined:

Because of central nervous system (CNS) depressant effects , metaxalone may impair mental and/or physical abilities required for performance of hazardous tasks, such as operating machinery or driving a motor vehicle, especially when used with other CNS depressants including alcohol. Geriatric patients may be especially susceptible to CNS depression associated with metaxalone use. When used concomitantly, the sedative effects of metaxalone and other CNS depressants (e.g., alcohol, benzodiazepines, opioids, tricyclic antidepressants) may be additive [see Drug Interactions (7)].

Follow patients treated with Metaxalone Tablets, 640 mg closely for signs and symptoms of respiratory depression and sedation. If concomitant use of metaxalone and another CNS depressant is warranted, closely monitor for signs of respiratory depression and sedation, particularly during treatment initiation and dosage increases.

5.3 Risk with Inappropriate Switching to Metaxalone Tablets, 640 mg

Newly added subsection:

Inappropriate switching on a mg-to-mg basis from SKELAXIN (metaxalone) tablets, 800 mg to Metaxalone Tablets, 640 mg to achieve the same total daily metaxalone dosage may result in a clinically significant increase in metaxalone exposure which may increase the risk of metaxalone-associated adverse reactions including CNS depression. For example, it is inappropriate to switch from four SKELAXIN 800 mg tablets (3,200 mg) per day to five tablets of Metaxalone Tablets, 640 mg (3,200 mg) per day [1.25 times the maximum recommended daily dosage of 2,560 mg] [see Dosage and Administration (2)]. Metaxalone Tablets 640 mg and SKELAXIN (metaxalone) tablets, 800 mg are not mutually substitutable on a mg-to-mg basis [see Clinical Pharmacology (12.3)].

It is generally inappropriate to switch between Metaxalone Tablets, 640 mg and SKELAXIN 800 mg to mediate metaxalone-associated adverse reactions.

For recommendations on how to switch from SKELAXIN (metaxalone) tablets, 800 mg, to Metaxalone Tablets, 640 mg, see Dosage and Administration (2).

6 Adverse Reactions

Additions and/or revisions underlined:

The following adverse reactions associated with the use of metaxalone were identified in clinical studies or postmarketing reports. Because some of these reactions were 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 frequent reactions to metaxalone were:

…

Other adverse reactions were:

…

Allergic: anaphylaxis have been reported with metaxalone.
CNS: cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of metaxalone (within the recommended dosage range) and other serotonergic drugs and with the use of metaxalone as the only serotonergic drug taken at a dosage higher than the recommended dosage [see Warnings and Precautions (5.1), Drug Interactions (7.2), and Overdosage (10)].

7 Drug Interactions

7.1 Serotonergic Drugs

Additions and/or revisions underlined:

If concomitant use of Metaxalone Tablets, 640 mg and another serotonergic drug is warranted, carefully observe the patient, particularly during treatment initiation and dosage modification. Discontinue Metaxalone Tablets, 640 mg if serotonin syndrome is suspected or if it occurs.

Serotonin syndrome has resulted from concomitant use of metaxalone (within the recommended dosage range) and other serotonergic drugs [see Warnings and Precautions (5.1)].

7.2 CNS Depressants

Additions and/or revisions underlined:

If concomitant use of Metaxalone Tablets, 640 mg and another CNS depressant is warranted, closely monitor for signs of respiratory depression and sedation, particularly during treatment initiation and dosage modification.

Due to the additive pharmacologic effect, concomitant use of Metaxalone Tablets, 640 mg with other CNS depressants may increase the risk of sedation and respiratory depression [see Warnings and Precautions (5.2)].

7.3 Interaction of Metaxalone with Benedict’s Tests

Newly added subsection:

False-positive Benedict's tests, due to an unknown reducing substance, have been noted in metaxalone-treated patients. A glucose-specific test will differentiate findings.

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

…

In the U.S. general population, the estimated risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

8.4 Pediatric Use

Additions and/or revisions underlined:
Metaxalone Tablets, 640 mg are indicated as an adjunct to rest, physical therapy, and other measures for the relief of discomforts associated with acute, painful musculoskeletal conditions in pediatric patients 13 years of age and older.

The safety and effectiveness of Metaxalone Tablets, 640 mg in pediatric patients less than 13 years of age have not been established.

8.5 Geriatric Use

Additions and/or revisions underlined:

Clinical studies of Metaxalone Tablets, 640 mg did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients. The effects of age on the pharmacokinetics of Metaxalone Tablets, 640 mg have not been evaluated. Geriatric patients may be especially susceptible to CNS depression associated with metaxalone use [see Warnings and Precautions (5.2)].

8.6 Hepatic Impairment

Additions and/or revisions underlined:

Metaxalone Tablets. 640 mg are contraindicated in patients with severe hepatic impairment. Metaxalone Tablets, 640 mg should be used with caution and additional monitoring should be considered in patients with mild to moderate hepatic impairment. The effect of hepatic impairment on metaxalone pharmacokinetics is unknown; however, metaxalone undergoes extensive hepatic metabolism [see Clinical Pharmacology (12.3)].

8.7 Renal Impairment

Additions and/or revisions underlined:

Metaxalone Tablets, 640 mg are contraindicated in patients with severe renal impairment. Metaxalone Tablets, 640 mg should be used with caution and additional monitoring should be considered in patients with mild to moderate renal impairment. The effect of renal impairment on metaxalone pharmacokinetics is unknown; however, metaxalone undergoes renal excretion as unidentified metabolites [see Clinical Pharmacology (12.3)].

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Serotonin Syndrome

Inform patients that Metaxalone Tablets, 640 mg could cause a rare but potentially life-threatening condition called serotonin syndrome. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their healthcare providers if they are taking, or plan to take, serotonergic drugs [see Warnings and Precautions (5.1) and Drug Interactions (7.1)].

Central Nervous System Depression

Advise patients that Metaxalone Tablets, 640 mg may impair mental and/or physical abilities required for performance of hazardous tasks, such as operating machinery or driving a motor vehicle, especially when used with alcohol and other CNS depressants [see Drug Interactions (7.2)].

02/25/2022 (SUPPL-1)

Approved Drug Label (PDF)

4 Contraindications

Addition of the following to the bulleted line listing:

Known hypersensitivity to any components of this product.

5 Warnings and Precautions

5.1 Serotonin Syndrome

New subsection added

Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of serotonergic drugs with metaxalone used within the recommended dosage range [See Drug Interactions (7)] and with metaxalone as a single agent taken at doses higher than the recommended dose [See Overdosage (10)]. Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, opioids (particularly fentanyl, meperidine, and methadone), drugs that affect the serotonergic neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), and drugs that impair metabolism of serotonin (including monoamine oxidase (MAO) inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue) [See Drug Interactions (7)].

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms generally occurs within several hours to a few days, but may occur later than that.

Discontinue Metaxalone Tablets if serotonin syndrome is suspected.

6 Adverse Reactions

Additions underlined

…

CNS: cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of serotonergic drugs with metaxalone used within the recommended dosage range and with metaxalone as a single agent taken at doses higher than the recommended dose [See Warnings and Precautions (5.1), Drug Interactions (7), and Overdosage (10)].

…

7 Drug Interactions

Additions underlined

…

Serotonergic Drugs

Serotonin syndrome has resulted from concomitant use of serotonergic drugs with metaxalone used within the recommended dosage range [See Warnings and Precautions (5.3)]. If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue Metaxalone Tablets if serotonin syndrome is suspected.

Examples of serotonergic drugs include: selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, opioids (particularly fentanyl, meperidine, and methadone), drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

8 Use in Specific Populations

8.1 Pregnancy

PLLR conversion

Risk Summary

There are no available data on metaxalone use in pregnant women to evaluate for a drug- associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes despite decades of metaxalone use. Reproduction studies in rats have not revealed evidence of impaired fertility or harm to fetus due to metaxalone.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

8.2 Lactation

PLLR conversion

Risk Summary

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

PATIENT COUNSELING INFORMATION

Additions underlined

…

Serotonin Syndrome

Inform patients that Metaxalone Tablets could cause a rare but potentially life-threatening condition resulting from administration of doses higher than the recommended dose or from concomitant administration of serotonergic drugs with Metaxalone Tablets used within the recommended dosage range. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their healthcare providers if they are taking, or plan to take, serotonergic medications.