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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.

PROVAYBLUE (NDA-204630)

(METHYLENE BLUE)

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

01/08/2024 (SUPPL-21)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

…

The safety of PROVAYBLUE in adults with acquired methemoglobinemia was assessed in 31 patients who received at least 1 dose of PROVAYBLUE [see Clinical Studies (14)]. Most doses administered were 1 mg/kg (82.9%), but doses from 0.78 mg/kg to 2 mg/kg were administered. All patients received at least one dose of PROVAYBLUE; two received two doses, and one received three doses. Serious adverse reactions occurred in 3.2% of patients who received PROVAYBLUE. A serious adverse reaction of seizure-like phenomenon was reported in one patient. Adverse reactions (greater than or equal to 2%) included headache, hypokalemia, diarrhea, hypomagnesemia, myoclonus, nausea, and seizure-like phenomena.

The safety of PROVAYBLUE in pediatric patients with acquired methemoglobinemia was assessed in two retrospective case series that included two pediatric patients treated with PROVAYBLUE and 12 treated with another methylene blue product. The case series included patients in the following age groups: 3 neonates (<1 month), 4 infants (1 month to <2 years), 4 children (2 years to <12 years), and 3 adolescents (12 years to <17 years). The safety profile in pediatric patients was similar to that in adult patients.

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

The safety and effectiveness of PROVAYBLUE for the treatment of acquired methemoglobinemia have been established in pediatric patients.

…

8.5 Geriatric Use

Additions and/or revisions underlined:

Clinical studies of PROVAYBLUE did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. PROVAYBLUE is known to be substantially excreted by the kidney, so the risk of adverse reactions to this drug may be greater in patients with impaired renal function.

11/02/2023 (SUPPL-22)

Approved Drug Label (PDF)

Boxed Warning

Additions and/or revisions underlined:

WARNING: SEROTONIN SYNDROME WITH CONCOMITANT USE OF SEROTONERGIC DRUGS AND OPIOIDS

PROVAYBLUE® may cause serious or fatal serotonergic syndrome when used in combination with serotonergic drugs and opioids. Avoid concomitant use of PROVAYBLUE® with selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs) and opioids. [see Warnings and Precautions (5.1) and Drug Interactions (7.1)]

5 Warnings and Precautions

5.1 Serotonin Syndrome with Concomitant Use of Serotonergic Drugs and Opioids

Additions and/or revisions underlined:

The development of serotonin syndrome has been reported with the use of methylene blue class products. Most reports have been associated with concomitant use of serotonergic drugs (e.g., selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs). Opioids and dextromethorphan may increase the risk of developing serotonin syndrome Some of the reported cases were fatal. Symptoms associated with serotonin syndrome may include the following combination of signs and symptoms: mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, and hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, and incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Avoid concomitant use of PROVAYBLUE® with serotonergic drugs and opioids.

…

7 Drug Interactions

Additions and/or revisions underlined:

Clinically significant drug interactions with PROVAYBLUE® are described below:

The concomitant use of PROVAYBLUE® with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Although the mechanism is not clearly understood, literature reports suggest PROVAYBLUE® is a potent reversible inhibitor of monoamine oxidase. Avoid concomitant use of PROVAYBLUE® with medicinal products that enhance serotonergic transmission including antidepressants like SSRIs (selective serotonin reuptake inhibitors), SNRIs (serotonin and norepinephrine reuptake inhibitors), MAOIs (monoamine oxidase inhibitors), bupropion, buspirone, clomipramine, mirtazapine, linezolid, opioids, and dextromethorphan because of the potential for serious CNS reactions, including potentially fatal serotonin syndrome. If the intravenous use of PROVAYBLUE® cannot be avoided in patients treated with serotonergic medicinal products, choose the lowest possible dose and observe the patient closely for CNS effects for up to 4 hours after administration [see Warning and Precautions (5.1) and Clinical Pharmacology (12.3)].

05/26/2021 (SUPPL-11)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.6 Renal Impairment

(Additions and/or revisions underlined)

Methylene blue concentrations increased in subjects with renal impairment (eGFR 15 to 89 mL/min/1.73m2) significantly [see Clinical Pharmacology (12.3)]. Adjust PROVAYBLUE® dosage in patients with moderate or severe renal impairment (eGFR 15 to 59 mL/min/1.73 m2) [see Dosage and Administration (2.2)]. No dose adjustment is recommended in patients with mild renal impairment (eGFR 60 – 89 mL/min/1.73 m2).