Mictasol Bleu

Methylene Blue:

• Warning: serotonin syndrome with concomitant use of serotonergic drugs
• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Mictasol Bleu (Methylene Blue) reviews

WARNING: SEROTONIN SYNDROME WITH CONCOMITANT USE OF SEROTONERGIC DRUGS

Mictasol Bleu (Methylene Blue) may cause serious or fatal serotonergic syndrome when used in combination with serotonergic drugs. Avoid concomitant use of Mictasol Bleu (Methylene Blue) with selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), and monoamine oxidase inhibitors ( 5.1, 7.1).

1 INDICATIONS AND USAGE

Mictasol Bleu (Methylene Blue) is indicated for the treatment of pediatric and adult patients with acquired methemoglobinemia.

This indication is approved under accelerated approval. Continued approval for this indication may be contingent upon verification of clinical benefit in subsequent trials.

Mictasol Bleu (Methylene Blue) (methylene blue) is an oxidation-reduction agent indicated for the treatment of pediatric and adult patients with acquired methemoglobinemia. This indication is approved under accelerated approval. Continued approval for this indication may be contingent upon verification of clinical benefit in subsequent trials. ( 1, 14)

2 DOSAGE AND ADMINISTRATION

• Administer 1 mg/kg intravenously over 5-30 minutes.
• If methemoglobin level remains above 30% or if clinical symptoms persist, give a repeat dose of up to 1 mg/kg one hour after the first dose. ( 2.1)

2.1 Dosage and Administration

• Ensure patent venous access prior to administration of Mictasol Bleu (Methylene Blue). Do not administer Mictasol Bleu (Methylene Blue) subcutaneously.
• Monitor vital signs, electrocardiogram and methemoglobin levels during treatment with Mictasol Bleu (Methylene Blue) and through resolution of methemoglobinemia.
• Administer Mictasol Bleu (Methylene Blue) 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 Mictasol Bleu (Methylene Blue) 1 mg/kg may be given one hour after the first dose.
• If methemoglobinemia does not resolve after 2 doses of Mictasol Bleu (Methylene Blue), consider initiating alternative interventions for treatment of methemoglobinemia.

2.2 Preparation and Storage

Each mL of Mictasol Bleu (Methylene Blue) contains 5 mg Mictasol Bleu (Methylene Blue)

Each 10 mL ampule of Mictasol Bleu (Methylene Blue) contains 50 mg Mictasol Bleu (Methylene Blue).

Mictasol Bleu (Methylene Blue) is hypotonic and may be diluted before use in a solution of 50 mL 5% Dextrose in Water (D5W) in order to avoid local pain, particularly in the pediatric population. Use the diluted solution immediately after preparation.

Do not mix with sodium chloride 9 mg/mL (0.9%) solution for injection, because it has been demonstrated that chloride reduces the solubility of Mictasol Bleu (Methylene Blue).

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

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

3 DOSAGE FORMS AND STRENGTHS

Injection: 50 mg/10 mL (5 mg/mL) clear dark blue solution in single-dose ampules

50 mg/10 mL (5 mg/mL) single-dose ampule. ( 3)

4 CONTRAINDICATIONS

Mictasol Bleu (Methylene Blue) is contraindicated in the following conditions:

• Severe hypersensitivity reactions to Mictasol Bleu (Methylene Blue) or any other thiazine dye .
• Patients with glucose-6-phosphate dehydrogenase deficiency (G6PD) due to the risk of hemolytic anemia

Mictasol Bleu (Methylene Blue) is contraindicated in the following conditions ( 4):

• Severe hypersensitivity to Mictasol Bleu (Methylene Blue)
• Patients with glucose-6-phosphate dehydrogenase deficiency (G6PD) due to the risk of hemolytic anemia

5 WARNINGS AND PRECAUTIONS

• Hypersensitivity: If severe or life threatening allergic reaction occurs, discontinue Mictasol Bleu, treat the allergic reaction, and monitor until signs and symptoms resolve ( 5.2)
• Lack of Effectiveness: Consider alternative treatments if there is no resolution of methemoglobinemia after 2 doses ( 2.1, 5.3)
• Hemolytic Anemia: Discontinue Mictasol Bleu (Methylene Blue) and transfuse ( 5.4)
• Interference with In-Vivo Monitoring Devices: Use methods other than pulse oximetry to assess oxygen satruation ( 5.5)
• Effects on Ability to Drive and Operate Machinery: Advise patients to refrain from these activities until neurologic and visual symptoms have resolved ( 5.6)

5.1 Serotonin Syndrome with Concomitant Use of Serotonergic Drugs

The development of serotonin syndrome has been reported with use of Mictasol Bleu (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). 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 Mictasol Bleu (Methylene Blue) with serotonergic drugs.

Patients treated with Mictasol Bleu (Methylene Blue) should be monitored for the emergence of serotonin syndrome. If symptoms of serotonin syndrome occur, discontinue use of Mictasol Bleu (Methylene Blue), 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 Mictasol Bleu (Methylene Blue) .

5.2 Hypersensitivity

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

5.3 Lack of Effectiveness

Methemoglobinemia may not resolve or may rebound after response to treatment with Mictasol Bleu (Methylene Blue) in patients with methemoglobinemia due to aryl amines such as aniline or sulfa drugs such as dapsone. Monitor response to therapy with Mictasol Bleu (Methylene Blue) through resolution of methemoglobinemia. If methemoglobinemia does not respond to 2 doses of Mictasol Bleu (Methylene Blue) or if methemoglobinemia rebounds after a response, consider additional treatment options .

Patients with glucose-6-phosphate dehydrogenase deficiency may not reduce Mictasol Bleu (Methylene Blue) to its active form in vivo. Mictasol Bleu (Methylene Blue) 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 Mictasol Bleu. 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 Mictasol Bleu (Methylene Blue). The anemia may require red blood cell transfusions. . Use the lowest effective number of doses of Mictasol Bleu (Methylene Blue) to treat methemoglobinemia. Discontinue Mictasol Bleu (Methylene Blue) and consider alternative treatments of methemoglobinemia if severe hemolysis occurs.

Treatment of patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency with Mictasol Bleu (Methylene Blue) may result in severe hemolysis and severe anemia. Mictasol Bleu (Methylene Blue) is contraindicated for use in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency .

5.5 Interference with In Vivo Monitoring Devices

• Inaccurate Pulse Oximeter Readings

The presence of Mictasol Bleu (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 Mictasol Bleu (Methylene Blue), 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 Mictasol Bleu (Methylene Blue) class products. If Mictasol Bleu (Methylene Blue) 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 Mictasol Bleu may cause confusion, dizziness and disturbances in vision . 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 Mictasol Bleu (Methylene Blue) have resolved.

5.7 Interference with Laboratory Tests

Mictasol Bleu (Methylene Blue) 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 ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in other sections of the labeling:

• Serotonin Syndrome with Concomitant Use of Serotonergic Drugs
• Anaphylaxis
• Lack of Effectiveness
• Hemolytic Anemia
• Interference with In-Vivo Monitoring Devices
• Effects on Ability to Drive and Operate Machinery
• Interference with Laboratory Tests

The most commonly reported adverse reactions (≥10%) are pain in extremity, chromaturia, dysgeusia, feeling hot, dizziness, hyperhidrosis, nausea, skin, discoloration and headache. ( 6.1)

To report SUSPECTED ADVERSE REACTIONS, contact American Regent at 1-800-734-9236 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 Mictasol Bleu (Methylene Blue) was determined in 82 healthy adults of median age of 36 years (range, 19-55 years); 54% were male, and 68% were white. Each individual in the safety population received a single dose of Mictasol Bleu (Methylene Blue) 2 mg/kg intravenously. There was one serious adverse reaction reported (syncope due to sinus pauses of 3-14 seconds). The most common (≥2%) moderate or severe adverse reactions were pain in the extremity (56%), headache (7%), feeling hot (6%), syncope (4%), back pain (2%), hyperhidrosis (2%) and nausea (2%). Table 1 lists the adverse reactions of any severity that occurred in at least 2% of individuals who received Mictasol Bleu (Methylene Blue).

Other adverse reactions reported to occur following administration of Mictasol Bleu (Methylene Blue) class products include the following:

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

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

7 DRUG INTERACTIONS

7.1 Serotonergic Drugs

Avoid concomitant use of Mictasol Bleu with medicinal products that enhance serotonergic transmission including SSRIs (selective serotonin reuptake inhibitors), MAO inhibitors, bupropion, buspirone, clomipramine, mirtazapine and venlafaxine; because of the potential for serious CNS reactions, including potentially fatal serotonin syndrome. Although the mechanism is not clearly, understood, literature reports suggest inhibition of MAO by Mictasol Bleu (Methylene Blue) may be involved. In addition, in vitro studies cannot rule out the potential involvement of CYP 2D6 inhibition by Mictasol Bleu (Methylene Blue). If the intravenous use of Mictasol Bleu (Methylene Blue) cannot be avoided in patients treated with serotonergic medicinal products, choose the lowest possible dose and observe closely the patient for CNS effects for up to 4 hours after administration .

7.2 Agents Metabolized by Cytochrome P450 Enzymes

Mictasol Bleu (Methylene Blue) inhibits a range of CYP isozymes in vitro, including 1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4/5. This interaction could be more pronounced with narrow therapeutic index drugs that are metabolized by one of these enzymes (e.g, digoxin, warfarin, phenytoin, alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus and tacrolimus). However, the clinical relevance of these in vitro interactions is unknown.

8 USE IN SPECIFIC POPULATIONS

• Pregnancy: Only use during pregnancy if the potential benefit justifies the potential risk to the fetus.
• Lactation: Discontinue breast-feeding for up to 8 days after treatment. ( 8.2).
• Renal Insufficiency: Monitor patients longer for toxicity and drug interactions due to delayed clearance. ( 8.6)
• Hepatic Impairment: Monitor patients longer for toxicity and drug interactions due to delayed clearance. ( 8.7)

8.1 Pregnancy

Risk Summary

Mictasol Bleu (Methylene Blue) may cause fetal harm when administered to a pregnant woman. Intra-amniotic injection of pregnant women with a Mictasol Bleu (Methylene Blue) class product during the second trimester was associated with neonatal intestinal atresia and fetal death. Mictasol Bleu (Methylene Blue) produced adverse developmental outcomes in rats and rabbits when administered orally during organogenesis at doses at least 32 and 16 times, respectively, the clinical dose of 1 mg/kg . Advise pregnant women of the potential risk to a fetus.

In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2-4% and 15-20%, respectively.

Clinical Considerations

Fetal/neonatal adverse reactions

Intra-amniotic injection of a Mictasol Bleu (Methylene Blue) class product hours to days prior to birth can result hyperbilirubinemia, hemolytic anemia, skin staining, methemoglobinemia, respiratory distress and photosensitivity in the newborn. Following administration of Mictasol Bleu (Methylene Blue) to a pregnant woman at term, observe the newborn for these adverse reactions and institute supportive care.

Data

Animal Data

Mictasol Bleu (Methylene Blue) was administered orally to pregnant rats at doses of 50 to 350 mg/kg/day, during the period of organogenesis. Maternal and embryofetal toxicities were observed at all doses of Mictasol Bleu (Methylene Blue), and were most evident at the 200 and 350 mg/kg/day doses. Maternal toxicity consisted of increased spleen weight. Embryo-fetal toxicities included reduced fetal weight, post-implantation loss, edema, and malformations including enlarged lateral ventricles. The dose of 200 mg/kg (1200 mg/m ²) in rats is approximately 32 times a clinical dose of 1 mg/kg based on body surface area.

Mictasol Bleu (Methylene Blue) was administered orally to pregnant rabbits at doses of 50, 100, or 150 mg/kg/day, during the period of organogenesis. Maternal death was observed at the Mictasol Bleu (Methylene Blue) dose of 100 mg/kg. Embryofetal toxicities included spontaneous abortion at all dose levels and a malformation (umbilical hernia) at the 100 and 150 mg/kg/day doses. The dose of 50 mg/kg (600 mg/m ²) in rabbits is approximately 16 times a clinical dose of 1 mg/kg based on body surface area.

8.2 Lactation

Risk Summary

There is no information regarding the presence of Mictasol Bleu in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions, including genotoxicity discontinue breast-feeding during and for up to 8 days after treatment with Mictasol Bleu (Methylene Blue) .

8.4 Pediatric Use

The safety and effectiveness of Mictasol Bleu (Methylene Blue) have been established in pediatric patients. Use of Mictasol Bleu (Methylene Blue) is supported by two retrospective case series that included 2 pediatric patients treated with Mictasol Bleu (Methylene Blue) and 12 treated with another Mictasol Bleu (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 .

8.5 Geriatric Use

The retrospective case series included 3 patients age 65 years and over treated with Mictasol Bleu (or a bioequivalent formulation) and 5 treated with another Mictasol Bleu (Methylene Blue) class product. The efficacy outcomes were consistent across adult and elderly patients in both case series . This drug 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 .

8.6 Renal Impairment

Approximately 40% of Mictasol Bleu (Methylene Blue) is excreted by the kidneys. Patients with any renal impairment should be monitored for toxicities and potential drug interactions for an extended period of time following treatment with Mictasol Bleu (Methylene Blue).

8.7 Hepatic Impairment

Mictasol Bleu (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 Mictasol Bleu (Methylene Blue).

10 OVERDOSAGE

Hypotension, wheezing and reduced oxygenation have been reported in patients who received Mictasol Bleu (Methylene Blue) class products in single doses of 3 mg/kg or more.

Administration of large intravenous doses (cumulative dose ≥ 7 mg/kg ) of a Mictasol Bleu (Methylene Blue) class product caused nausea, vomiting, precordial pain, dyspnea, tachypnea, chest tightness, tachycardia, apprehension, tremor, mydriasis, blue staining of the urine, the skin and mucous membranes, abdominal pain, dizziness, paresthesia, headache, confusion, mild methemoglobinemia (up to 7%) and electrocardiogram changes (T-wave flattening or inversion) These effects lasted 2-12 hours following administration.

A severe overdosage (single dose of 20 mg/kg or more) of a Mictasol Bleu (Methylene Blue) class product caused severe intravascular hemolysis, hyperbilirubinemia and death.

In case of overdose of Mictasol Bleu (Methylene Blue), maintain the patient under observation until signs and symptoms have resolved, monitor for cardiopulmonary, hematologic and neurologic toxicities, and institute supportive measures as necessary.

11 DESCRIPTION

Mictasol Bleu (Methylene Blue) is an oxidation-reduction agent. Mictasol Bleu (Methylene Blue) (methylene blue) is a sterile solution intended for intravenous administration. Each Mictasol Bleu (Methylene Blue), 10 mL ampule contains 50 mg Proveblue ^® Mictasol Bleu (Methylene Blue) and water for injection q.s. Each mL of solution contains 5 mg Mictasol Bleu (Methylene Blue) and water for injection q.s.

Mictasol Bleu (Methylene Blue) is 3,7-bis(dimethylamino)phenothiazin-5-ium, chloride. The molecular formula of Mictasol Bleu (Methylene Blue) is C ₁₆H ₁₈ClN ₃S and its molecular weight is 319.86 g/mol. Its structural formula is:

Mictasol Bleu (Methylene Blue) is a clear dark blue solution with a pH value between 3.0 and 4.5. The osmolality is between 10 and 15 mOsm/kg.

Figure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Mictasol Bleu is a water soluble thiazine dye that promotes a non-enyzmatic redox conversion of metHb to hemoglobin. In situ, Mictasol Bleu (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 Mictasol Bleu (Methylene Blue) speeds up the in vivo conversion of methemoglobin to hemoglobin. Mictasol Bleu (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 Mictasol Bleu (Methylene Blue) 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 Mictasol Bleu (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 Mictasol Bleu (Methylene Blue) was 255 L ± 58. The mean plasma protein binding of Mictasol Bleu (Methylene Blue) is approximately 94% in vitro. Mictasol Bleu (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. Mictasol Bleu (Methylene Blue) is a substrate for the P-glycoprotein (P-gp, ABCB1) transporter, but not for BCRP or OCT2 in vitro.

Elimination

Mictasol Bleu (Methylene Blue) has a half-life of approximately 24 hours.

Metabolism

Mictasol Bleu (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 Mictasol Bleu (Methylene Blue), is also formed in humans as a metabolite of Mictasol Bleu (Methylene Blue), with an overall drug/metabolite AUC ratio of greater than 6:1. Azure B has 8-fold lower potency than Mictasol Bleu (Methylene Blue).

Excretion

Approximately 40% of Mictasol Bleu (Methylene Blue) is excreted in to the urine unchanged.

Drug Interaction Studies

The clinical relevance of in vitro inhibition or induction of the metabolizing enzymes and transporter systems described below is unknown, but it cannot be excluded that the systemic exposure of medicinal products being substrates for these enzymes or transporter systems may be affected with concomitant administration with Mictasol Bleu (Methylene Blue) Injection.

Cytochrome P450

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

Glucuronosyltransferase

Mictasol Bleu (Methylene Blue) inhibits UGT1A9 and UGT1A4 in in vitro, but did not significantly inhibit UGTs 1A1, 1A3, 1A6, 2B7 or 2B15.

Transporter Interactions

Mictasol Bleu (Methylene Blue) is both a substrate for and an inhibitor of P-gp, but is not a substrate for BCRP or OCT2 in vitro. Mictasol Bleu (Methylene Blue) is not a significant inhibitor of BCRP, OAT1, OAT3, OAT1B1 or OAT1B3 in vitro. Mictasol Bleu (Methylene Blue) inhibits OCT2, MATE1 and MATE2-K in vitro. The OCT2/MATE pathway for renal transport is reported to play a significant role in the elimination of several substances, including metformin, cimetidine, acyclovir and creatinine

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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

Mictasol Bleu (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. Mictasol Bleu (Methylene Blue) was negative for micronucleus induction in bone marrow or peripheral blood collected from mice treated with Mictasol Bleu (Methylene Blue).

Fertility studies with Mictasol Bleu (Methylene Blue) have not been conducted. In vitro, Mictasol Bleu (Methylene Blue) reduced motility of human sperm in a concentration dependent manner.

14 CLINICAL STUDIES

14.1 Treatment of Acquired Methemoglobinemia

The efficacy of Mictasol Bleu (Methylene Blue) was assessed on the basis of a methemoglobin decrease of at least 50% within 1 hour after intravenous administration of 1 – 2 mg/kg Mictasol Bleu (Methylene Blue) (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 41cases of treatment of methemoglobinemia with a Mictasol Bleu (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 Mictasol Bleu (Methylene Blue) class product.

In a combined analysis of all 47 patients treated intravenously with Mictasol Bleu (Methylene Blue) (or a bioequivalent formulation) or with another Mictasol Bleu (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

Mictasol Bleu (Methylene Blue) is supplied in 10 mL single-dose ampules. Each 10 mL ampule contains 50 mg of Mictasol Bleu (Methylene Blue) as a clear dark blue solution. A box contains five ampules placed in a tray.

Box of 5 ampules: NDC 0517-0374-05

Storage:

Store at 20°C to 25°C (68°F to 77°F).

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 Mictasol Bleu (Methylene Blue) : changes in mental status, autonomic instability, or neuromuscular symptoms with or without gastrointestinal symptoms .

Pregnancy

Advise pregnant women of the potential risk to the fetus with the use of Mictasol Bleu (Methylene Blue) during pregnancy .

Breastfeeding

Advise patients to discontinue breast-feeding for up to 8 days after treatment with Mictasol Bleu (Methylene Blue) .

Driving and Using Machines

Advise patients to avoid driving and use of machines during treatment with Mictasol Bleu (Methylene Blue). Driving can be affected as a result of a confusional state, dizziness and possible eye disturbances .

Phototoxicity

Advise patients to take protective measures against exposure to light, because phototoxicity may occur after administration of Mictasol Bleu (Methylene Blue) .

Skin and Body Fluid Blue Discoloration

Advise patients that Mictasol Bleu (Methylene Blue) may cause a blue discoloration of the skin and body fluids .

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

Shirley, NY

Questions? : 1-800-734-9236

4/2016

[controlled part number code]

Principal Display Panel - 5 mg Ampule Label

NDC 0517-0374-01 28039135 Rev 4/16

Mictasol Bleu (Methylene Blue)

(methylene blue) Injection, 0.5%

50 mg/10 mL (5 mg/mL)

Intravenous use only

Single dose ampule - RX only

Discard unused portion

Manufacturer by:

CENEXI

Distributed by:

AMERICAN REGENT, INC

Shirley, NY 19967

Principal Display Panel - 5 mg Carton Label

NDC 0517-0374-05 5 ampules

Mictasol Bleu (Methylene Blue)

(methylene blue) Injection, 0.5%

50 mg/10 mL (5 mg/mL)

Intravenous use only - For slow intravenous injection.

10 mL - Single dose ampule -

Discard unused portion

Rx only

Distributed by:

AMERICAN

REGENT

Shirley, NY 11967

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