PROVAYBLUE (Page 4 of 5)

12.2 Pharmacodynamics

Low concentrations of methylene blue speeds up the in vivo conversion of methemoglobin to hemoglobin. Methylene blue has been observed to stain tissues selectively. The exposure-response or –safety relationship for methylene is unknown.

Cardiac Electrophysiology

The results of a thorough QT study demonstrated PROVAYBLUE ® at an intravenous dose of 2 mg/kg as a 5-minute intravenous infusion had no effect on the QT, PR or QRS intervals.

12.3 Pharmacokinetics

The mean (CV%) Cmax and AUC of methylene blue 2,917 ng/mL (39%) and 13977 ng.hr/mL (21%) following a 2 mg/kg dose administered as a 5-minute intravenous infusion.

Distribution

The mean± standard deviation steady state volume of distribution of a 2 mg/kg dose of PROVAYBLUE ® was 255 L ± 58. The mean plasma protein binding of methylene blue is approximately 94% in vitro. Methylene blue exhibits concentration-dependent partitioning into blood cells in vitro. The blood-to-plasma ratio was 5.1±2.8 at 5 minutes from the start of a 2 mg/kg dose administered as a 5-minute intravenous infusion and reached a plateau of 0.6 at 4 hours in a clinical study. Methylene Blue is a substrate for the P-glycoprotein (P-gp, ABCB1) transporter, but not for BCRP or OCT2 in vitro.

Elimination

Methylene blue has a half-life of approximately 24 hours in humans.

Metabolism

Methylene blue is metabolized by CYPs 1A2, 2C19 and 2D6 in vitro; however, the predominant in vitro pathway appears to be UGT-mediated conjugation by multiple UGT enzymes, including UGT1A4 and UGT1A9.

Azure B, which is a minor impurity in methylene blue, is also formed in humans as a metabolite of methylene blue, with an overall drug/metabolite AUC ratio of greater than 6:1. Azure B has 8-fold lower potency than methylene blue.

Excretion

Approximately 40% of methylene blue is excreted in to the urine unchanged.

Specific Populations

Renal Impairment


After a single 1 mg/kg dose of PROVAYBLUE, AUC0-96h increased by 52%, 116%, and 192% in subjects with mild (estimated glomerular filtration rate (eGFR) 60 – 89 mL/min/1.73 m2), moderate (eGFR 30-59 mL/min/1.73m2), and severe (eGFR 15-29 mL/min/1.732m2) renal impairment, respectively. Cmax increased by 42%, 34%, and 15% in subjects with mild, moderate, and severe renal impairment respectively [see Dosage and Administration ( 2.2) and Use in Specific Populations ( 8.6)]. The half-life was unchanged in patients with mild to moderate renal impairment.


The AUC0-96h of Azure B after a single 1 mg/kg dose increased by 29%, 94%, and 339% in subjects with mild (estimated glomerular filtration rate (eGFR) 60 – 89 mL/min/1.73 m2), moderate (eGFR 30-59 mL/min/1.73m2), and severe (eGFR 15-29 mL/min/1.732m2) renal impairment, respectively. Cmax increased by 23%, 13%, and 65% in subjects with mild, moderate, and severe renal impairment respectively [see Dosage and Administration ( 2.2) and Use in Specific Populations ( 8.6)]

Drug Interactions Studies

Clinical Studies:


The coadministration of 2 mg/kg dose of PROVAYBLUE® with midazolam (a CYP3A4 substrate), caffeine (a CYP1A2 substrate), warfarin (a CYP2C9 substrate), and dextromethorphan (a CYP2D6 substrate) in a cocktail study did not affect the exposure of these substrates compared to their exposure without PROVAYBLUE® administration.

In Vitro Studies:


Cytochrome P450 (CYP450) Enzymes:


Methylene blue inhibits CYP isozymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4/5. Possible time-dependent inhibition of CYP2C9, CYP2D6 and CYP3A4/5 (testosterone as substrate) was also observed. Methylene blue induces CYP1A2 but does not induce CYP2B6 or CYP3A4.


UDP-Glucuronosyltransferase (UGT):


Methylene blue inhibits UGT1A9 and UGT1A4, but did not significantly inhibit UGTs 1A1, 1A3, 1A6, 2B7 or 2B15.

Transporter:

Methylene blue is both a substrate for and an inhibitor of P-gp but is not a substrate for BCRP or OCT2 in vitro. Methylene blue is not a significant inhibitor of BCRP, OAT1, OAT3, OAT1B1 or OAT1B3. Methylene blue inhibits OCT2, MATE1 and MATE2-K.

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

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