Prescription Drug Information: PROVAYBLUE (Page 3 of 3)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In a two-year carcinogenicity study, rats were administered oral doses of methylene blue at 5, 25, or 50 mg/kg. Methylene blue caused pancreatic islet adenomas or carcinomas (combined) in male rats. In a two-year carcinogenicity study, mice were administered oral doses of methylene blue at 2.5, 12.5, or 25 mg/kg. There were no drug-related neoplastic findings in mice.

Methylene blue was genotoxic in gene mutation assays in bacteria (Ames test), and in an in vitro sister chromatid exchange test and an in vitro chromosomal aberration test in Chinese hamster ovary (CHO) cells. Methylene blue was negative for micronucleus induction in bone marrow or peripheral blood collected from mice treated with methylene blue.

Fertility studies with methylene blue have not been conducted. In vitro, methylene blue reduced motility of human sperm in a concentration dependent manner.

14 CLINICAL STUDIES

14.1 Treatment of Acquired Methemoglobinemia

The efficacy of PROVAYBLUE ® was assessed on the basis of a methemoglobin decrease of at least 50% within 1 hour after intravenous administration of 1 – 2 mg/kg PROVAYBLUE ® (or a bioequivalent formulation) in 6 patients identified by retrospective chart review or literature search. The 6 patients included 3 males and 3 females of median age 54 years (range, 6 days to 69 years). The median methemoglobin level at baseline was 37% (range, 11% to 47%). All 6 (100%) patients had a decrease in methemoglobin by at least 50% within 1 hour after treatment.

An additional 41 cases of treatment of methemoglobinemia with a methylene blue class product were identified in the published literature. These cases included 24 males and 17 females of median age 33 years (range, 9 days to 80 years). The median methemoglobin level at baseline was 40% (range, 10% to 98%). Of these 41 patients, 37 (90%) had a methemoglobin decrease of at least 50% within 1 hour after intravenous administration of the methylene blue class product.

In a combined analysis of all 47 patients treated intravenously with PROVAYBLUE ® (or a bioequivalent formulation) or with another methylene blue class product, there was no difference in response rate by dose. The methemoglobin decreased by at least 50% within 1 hour of infusion for 15/17 (88%) of patients treated with 1 mg/kg, 12/13 (92%) treated with 2 mg/kg and 16/17 (94%) treated with a different dose or for those whose dose was not reported.

16 HOW SUPPLIED/STORAGE AND HANDLING

PROVAYBLUE ® is supplied in 10 mL and 2 mL single-dose ampules. Each 10 mL ampule contains 50 mg of methylene blue as a clear dark blue solution. Each 2 mL ampule contains 10 mg of methylene blue as a clear dark blue solution. A box contains five ampules placed in a tray.

Box of 5 ampules of 50 mg/10 mL: NDC 0517-0374-05
Box of 5 ampules of 10 mg/2 mL: NDC 0517-0125-05

Storage:


Store at 20°C to 25°C (68°F to 77°F). [See USP Controlled Room Temperature]


Any unused product or waste material should be disposed of in accordance with local practice.


Do not refrigerate or freeze.


Keep the ampule in the original package to protect from light.

17 PATIENT COUNSELING INFORMATION

Serotonin Syndrome

Advise patients of the possibility of serotonin syndrome, especially with concomitant use of serotonergic agents such as medications to treat depression and migraines. Advise patients to seek immediate medical attention if the following symptoms occur after treatment with PROVAYBLUE ®: changes in mental status, autonomic instability, or neuromuscular symptoms with or without gastrointestinal symptoms [see Warnings and Precautions ( 5.1)].

Pregnancy

Advise pregnant women of the potential risk to the fetus with the use of PROVAYBLUE ® during pregnancy [see Use in Specific populations ( 8.1)].

Breastfeeding

Advise patients to discontinue breast-feeding for up to 8 days after treatment with PROVAYBLUE ® [see Use in Specific populations ( 8.2)] .

Driving and Using Machines

Advise patients to avoid driving and use of machines during treatment with PROVAYBLUE ®. Driving can be affected as a result of a confusional state, dizziness and possible eye disturbances [see Warnings and Precautions ( 5.6)] .

Phototoxicity

Advise patients to take protective measures against exposure to light, because phototoxicity may occur after administration of methylene blue [see Adverse Reactions ( 6.1)] .

Skin and Body Fluid Blue Discoloration

Advise patients that PROVAYBLUE ® may cause a blue discoloration of the skin and body fluids [see Adverse Reactions ( 6.1)].

Manufactured for:
PROVEPHARM SAS
22 rue Marc Donadille
13013 Marseille, France

Manufactured by:

CENEXI
52 rue Marcel et Jacques Gaucher
94120 Fontenay sous Bois, FRANCE

Distributed by:
American Regent, Inc.
Shirley, NY 11967
Questions? : 1-800-734-9236

04/2021

Principal Display Panel — 50 mg/10 mL (5 mg/mL) Ampule Label

NDC 0517-0374-01

ProvayBlue ® (methylene blue) Injection USP

50 mg/10 mL (5 mg/mL)

Intravenous use only

Use 5% Dextrose in Water When Diluting

Single dose ampule — RX only

Discard unused portion

Manufactured by CENEXI for:

PROVEPHARM SAS

Distributed by:

AMERICAN REGENT, INC

Shirley, NY 11967

Ampule Label 10 mL
(click image for full-size original)

Principal Display Panel — 50 mg/10 mL (5 mg/mL) Carton Label

NDC 0517-0374-05 5 ampules

ProvayBlue®

(methylene blue) Injection USP, 0.5%

50 mg/10 mL (5 mg/mL)

Intravenous use only

For slow intravenous injection.

Use 5% Dextrose in Water When Diluting

10 mL — Single dose ampule
Discard unused portion

Rx only

Patented : US 8,765,942; US 9,227,945

Distributed by:

AMERICAN REGENT

10 mL Carton
(click image for full-size original)

Principal Display Panel — 10 mg/2 mL (5 mg/mL) Carton Label

NDC 0517-0125-05 5 ampules

ProvayBlue ®

(methylene blue) Injection USP 10 mg/2 mL (5 mg/mL)

Intravenous use only
For slow intravenous injection.
Use 5% Dextrose
in Water When Diluting

2 mL — Single dose ampule
Discard unused portion

Rx only

Patented: US 8,765,942; US 9,227,945

Distributed by:
AMERICAN
REGENT Shirley, NY 11967

2 mL Carton
(click image for full-size original)

Principal Display Panel — 10 mg/2 mL (5 mg/mL) Ampule Label

NDC 0517-0125-01

ProvayBlue®
(methylene blue) Injection USP
10 mg/2 mL (5 mg/mL)

Intravenous use only

Use 5% Dextrose in Water When
Diluting

Single dose ampule — RX only
Discard unused portion

Manufactured by CENEXI for:
PROVEPHARM SAS

Distributed by: AMERICAN REGENT, INC.

Shirley, NY 11967

2 mL Ampule Label
(click image for full-size original)
PROVAYBLUE methylene blue injection
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0517-0374
Route of Administration INTRAVENOUS DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
METHYLENE BLUE (METHYLENE BLUE CATION) METHYLENE BLUE 5 mg in 1 mL
Inactive Ingredients
Ingredient Name Strength
WATER
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:0517-0374-05 5 AMPULE in 1 CARTON contains a AMPULE (0517-0374-01)
1 NDC:0517-0374-01 10 mL in 1 AMPULE This package is contained within the CARTON (0517-0374-05)
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA204630 04/08/2016
PROVAYBLUE methylene blue injection
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0517-0125
Route of Administration INTRAVENOUS DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
METHYLENE BLUE (METHYLENE BLUE CATION) METHYLENE BLUE 5 mg in 1 mL
Inactive Ingredients
Ingredient Name Strength
WATER
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:0517-0125-05 5 AMPULE in 1 CARTON contains a AMPULE (0517-0125-01)
1 NDC:0517-0125-01 2 mL in 1 AMPULE This package is contained within the CARTON (0517-0125-05)
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA204630 04/08/2020
Labeler — American Regent, Inc. (002033710)
Registrant — Provepharm SAS (296789410)
Establishment
Name Address ID/FEI Operations
Cenexi 573309239 manufacture (0517-0374), manufacture (0517-0125)

Revised: 06/2021 American Regent, Inc.

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