2.1 Dosage and Administration

• Ensure patent venous access prior to administration of PROVAYBLUE. Do not administer PROVAYBLUE subcutaneously.
• Administer PROVAYBLUE 1 mg/kg intravenously over 5-30 minutes.
• If the methemoglobin level remains greater than 30% or if clinical signs and symptoms persist, a repeat dose of PROVAYBLUE 1 mg/kg may be given one hour after the first dose.
• If methemoglobinemia does not resolve after 2 doses of PROVAYBLUE, consider initiating alternative interventions for treatment of methemoglobinemia.

2.2 Recommended Dosage for Renal Impairment

• The recommended dosage of PROVAYBLUE in patients with moderate or severe renal impairment (eGFR 15-59 mL/min/1.73 m2) is a single dose of 1 mg/kg.
• If the methemoglobin level remains greater than 30% or if the clinical symptoms persist 1 hour after dosing, consider initiating alternative interventions for the treatment of methemoglobinemia.

2.3 Preparation

PROVAYBLUE is hypotonic and may be diluted before use in a solution of 50 mL 5% Dextrose Injection in order to avoid local pain, particularly in the pediatric population. Use the diluted solution immediately after preparation.

Avoid diluting with sodium chloride solutions, because it has been demonstrated that chloride reduces the solubility of methylene blue.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Discard unused portion.

5.1 Serotonin Syndrome with Concomitant Use of Serotonergic Drugs and Opioids

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.

Patients treated with PROVAYBLUE should be monitored for the emergence of serotonin syndrome. If symptoms of serotonin syndrome occur, discontinue use of PROVAYBLUE, and initiate supportive treatment. Inform patients of the increased risk of serotonin syndrome and advise them to not to take serotonergic drugs within 72 hours after the last dose of PROVAYBLUE [see Drug Interactions (7), Patient Counseling Information (17)].

5.2 Hypersensitivity

Anaphylactic reactions to methylene blue class products have been reported. Patients treated with PROVAYBLUE should be monitored for anaphylaxis. If anaphylaxis or other severe hypersensitivity reactions (e.g., angioedema, urticaria, bronchospasm) should occur, discontinue use of PROVAYBLUE and initiate supportive treatment. PROVAYBLUE is contraindicated in patients who have experienced anaphylaxis or other severe hypersensitivity reactions to a methylene blue class product in the past.

5.3 Lack of Effectiveness

Methemoglobinemia may not resolve or may rebound after response to treatment with PROVAYBLUE in patients with methemoglobinemia due to aryl amines such as aniline or sulfa drugs such as dapsone. Monitor response to therapy with PROVAYBLUE through resolution of methemoglobinemia. If methemoglobinemia does not respond to 2 doses of PROVAYBLUE or if methemoglobinemia rebounds after a response, consider additional treatment options [see Dosage and Administration (2.2)].

Patients with glucose-6-phosphate dehydrogenase deficiency may not reduce PROVAYBLUE to its active form in vivo. PROVAYBLUE may not be effective in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency.

5.4 Hemolytic Anemia

Hemolysis can occur during treatment of methemoglobinemia with PROVAYBLUE. Laboratory testing may show Heinz bodies, elevated indirect bilirubin and low haptoglobin, but the Coombs test is negative. The onset of anemia may be delayed 1 or more days after treatment with PROVAYBLUE. The anemia may require red blood cell transfusions [see Adverse Reactions (6.1)]. Use the lowest effective number of doses of PROVAYBLUE to treat methemoglobinemia. Discontinue PROVAYBLUE and consider alternative treatments of methemoglobinemia if severe hemolysis occurs.

Treatment of patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency with PROVAYBLUE may result in severe hemolysis and severe anemia. PROVAYBLUE is contraindicated for use in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency [see Contraindications (4)].

5.5 Interference with In Vivo Monitoring Devices

• Inaccurate Pulse Oximeter Readings

The presence of methylene blue in the blood may result in an underestimation of the oxygen saturation reading by pulse oximetry. If a measure of oxygen saturation is required during or shortly after infusion of PROVAYBLUE, it is advisable to obtain an arterial blood sample for testing by an alternative method.

• Bispectral index monitor

A fall in the Bispectral Index (BIS) has been reported following administration of methylene blue class products. If PROVAYBLUE is administered during surgery, alternative methods for assessing the depth of anesthesia should be employed.

5.6 Effects on Ability to Drive and Operate Machinery

Treatment with PROVAYBLUE may cause confusion, dizziness and disturbances in vision [see Adverse Reactions (6)]. Advise patients to refrain from driving or engaging in hazardous occupations or activities such as operating heavy or potentially dangerous machinery until such adverse reactions to PROVAYBLUE have resolved.

5.7 Interference with Laboratory Tests

PROVAYBLUE is a blue dye which passes freely into the urine and may interfere with the interpretation of any urine test which relies on a blue indicator, such as the dipstick test for leucocyte esterase.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

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 (≥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.

Other adverse reactions reported to occur following the administration of methylene blue class products include the following:

Blood and lymphatic system disorders: hemolytic anemia, hemolysis, hyperbilirubinemia

Cardiac disorders: palpitations, tachycardia

Eye disorders: eye pruritus, ocular hyperemia, vision blurred

Gastrointestinal disorders: abdominal pain lower, dry mouth, flatulence, glossodynia, tongue eruption

General disorders and administration site conditions: death, infusion site extravasation, infusion site induration, infusion site pruritus, infusion site swelling, infusion site urticaria, peripheral swelling, thirst

Investigations: elevated liver enzymes

Musculoskeletal and connective tissue disorders: myalgia

Renal and urinary disorders: dysuria

Respiratory, thoracic and mediastinal disorders: nasal congestion, oropharyngeal pain, rhinorrhea, sneezing

Skin and subcutaneous tissue disorders: necrotic ulcer, papule, phototoxicity

Vascular disorders: hypertension

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)].

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

The safety and effectiveness of PROVAYBLUE for the treatment of acquired methemoglobinemia have been established in pediatric patients. Use of PROVAYBLUE is supported by two retrospective case series that included 2 pediatric patients treated with PROVAYBLUE and 12 treated with another methylene blue class product. The case series included pediatric patients in the following age groups: 3 neonates (less than 1 month), 4 infants (1 month up to less than 2 years), 4 children (2 years up to less than 12 years), and 3 adolescents (12 years to less than 17 years). The efficacy outcomes were consistent across pediatric and adult patients in both case series [see Clinical Studies (14)].

8.5 Geriatric Use

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. Because elderly patients are more likely to have decreased renal function, treatment of methemoglobinemia in these patients should use the lowest number of doses needed to achieve a response [see Dosage and Administration (2)].

8.6 Renal Impairment

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).

8.7 Hepatic Impairment

Methylene blue is extensively metabolized in the liver. Monitor patients with any hepatic impairment for toxicities and potential drug interactions for an extended period of time following treatment with PROVAYBLUE.

12.1 Mechanism of Action

Methylene blue is a water soluble thiazine dye that promotes a non-enyzmatic redox conversion of metHb to hemoglobin. In situ, methylene blue is first converted to leucomethylene blue (LMB) via NADPH reductase. It is the LMB molecule which then reduces the ferric iron of metHb to the ferrous state of normal hemoglobin.

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.

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.

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.

14.1 Treatment of Acquired Methemoglobinemia

The efficacy of PROVAYBLUE  in the treatment of patients with methemoglobinemia was evaluated in 31 adult patients with acquired methemoglobinemia across two studies: NCT03395223, a prospective, interventional, open-label, single-arm study, and NCT03542760, a prospective, multicenter, observational registry. Of the 31 subjects enrolled 90% were white, 10% were black, 58% were female, and 42% were male. Hispanic or Latino was 9.7%; non-Hispanic or Latino was 67.7%, and ethnicity data were missing for 22.6%. The mean age was 45.6 years, and the ages ranged from 19 to 72 years.  Each individual received at least 1 intravenous dose of PROVAYBLUE; two received 2 doses and one received 3 doses. Most doses administered were 1 mg/kg (82.9%), but doses from 0.78 mg/kg to 2 mg/kg were administered. The recommended PROVAYBLUE dose is 1 mg/kg; lower or greater doses are not recommended. The maximum recommended number of doses is two , a prospective, interventional, open-label, single-arm study, and NCT03542760, a prospective, multicenter, observational registry. Of the 31 subjects enrolled 90% were white, 10% were black, 58% were female, and 42% were male. Hispanic or Latino was 9.7%; non-Hispanic or Latino was 67.7%, and ethnicity data were missing for 22.6%. The mean age was 45.6 years, and the ages ranged from 19 to 72 years.  Each individual received at least 1 intravenous dose of PROVAYBLUE; two received 2 doses and one received 3 doses. Most doses administered were 1 mg/kg (82.9%), but doses from 0.78 mg/kg to 2 mg/kg were administered. The recommended PROVAYBLUE dose is 1 mg/kg; lower or greater doses are not recommended. The maximum recommended number of doses is two [see Dosage and Administration (2.1)].

In total, 29 of the 31 (93.5%) subjects had post treatment methemoglobin (metHb) assessment; 28 of the 29 subjects had baseline metHb with a mean concentration of 18.4% and a range of 4.1% to 74.4%. Twenty-six of the 28 (92.9%) subjects who had baseline metHb had at least a 50% reduction in metHB from baseline in their first assessment post baseline. This first post dosing assessment occurred from 0.2 to 27.3 hours from the end of first PROVAYBLUE infusion with a median time of 2.7 hours. There were 12 subjects that had baseline metHb and had metHb assessed within 2 hours of the end of the first PROVAYBLUE treatment; 9 of the 12 (75%; 95% CI (42.8%,93.3%)) had at least a 50% reduction in metHb at 1 hour postdosing.

Available vital sign data including blood pressure, heart rate and respiratory rate were reviewed at baseline and compared to data collected within 2 hours post PROVAYBLUE infusion.  Prior to treatment with PROVAYBLUE, 16 of the 23 (70%) of patients had a respiratory rate exceeding the upper limit of normal (≥ 20 bpm). Of these, 10 of the 16 (63%) experienced a normalization of respiratory rate within 2 hours post ProvayBlue infusion.  There was minimal impact on other vital signs.

At baseline, the most common prespecified signs and symptoms of methemoglobinemia (reported by ≥2 subjects [6.5%] overall) were cyanosis (32.3%), dyspnea (25.8%), fatigue (25.8%), depressed CNS (9.7%), headache (6.5%), weakness (6.5%), and dizziness (6.5%). Following treatment with PROVAYBLUE, signs and symptoms of methemoglobinemia improved. 

The efficacy of PROVAYBLUE in the treatment of methemoglobinemia in pediatric patients was assessed in 14 patients in two retrospective case series (2 patients received PROVAYBLUE and 12 who received another methylene blue product). The ages ranged from 6 days to 16 years. The efficacy outcomes were consistent across the pediatric and adult populations.

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)].

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

Ampules manufactured by:

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

Vials manufactured by: CENEXI HSC
2 rue Louis Pasteur
14200 Hérouville-Saint-Clair, France

Distributed by:

American Regent, Inc.
Shirley, NY 11967

Questions? : 1-800-734-9236