Methylene Blue

Boxed Warning 11/2023 Indications and Usage ( 1 ) 01/2024 Warnings and Precautions ( 5 ) 11/2023

1 INDICATIONS AND USAGE Methylene blue injection is indicated for the treatment of pediatric and adult patients with acquired methemoglobinemia. Methylene blue injection (methylene blue) is an oxidation-reduction agent indicated for the treatment of pediatric and adult patients with acquired methemoglobinemia.

2 DOSAGE AND ADMINISTRATION Administer 1 mg/kg intravenously over 5-30 minutes. ( 2.1 ) 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 ) Administer a single dose of 1 mg/kg in patients with moderate or severe renal impairment. ( 2.2 ) 2.1 Dosage and Administration Ensure patent venous access prior to administration of methylene blue injection. Do not administer methylene blue injection subcutaneously. Administer methylene blue injection 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 methylene blue injection 1 mg/kg may be given one hour after the first dose. If methemoglobinemia does not resolve after 2 doses of methylene blue injection, consider initiating alternative interventions for treatment of methemoglobinemia. 2.2 Recommended Dosage for Renal Impairment The recommended dosage of methylene blue injection in patients with moderate or severe renal impairment (eGFR 15-59 mL/min/1.73 m 2 ) 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 Methylene blue injection 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. 2.4 Instructions for Use of prefilled syringe Remove the Pre-filled Syringe from the carton Inspect visually for particulate matter and discoloration prior to administration. Do not use the solution if it contains particulate matter. Figure 1 3. Hold the syringe upright on the Luer Lock part/luer cover of the syringe barrel. With the other hand, take hold of the cap/closure and gently turn anti-clockwise as shown in the figure 2. Figure 2 4.Do not touch the syringe tip or the working surface to keep it sterile. 5. Connect the syringe to an appropriate injection connection depending on the route of administration. 6. Expel air bubble(s). Adjust the dose (if applicable). 7. Administer the dose ensuring that pressure is maintained on the plunger rod during the entire administration. 8. Discard unused portion. image description image description

3 DOSAGE FORMS AND STRENGTHS Methylene blue injection, USP: 50 mg/10 mL (5 mg/mL) (0.5%) clear dark blue solution in single-dose ampules or single-dose prefilled syringes. 50 mg/10 mL (5 mg/mL) (0.5%) single-dose ampule. ( 3 ) 50 mg/10 mL (5 mg/mL) (0.5%) single-dose prefilled syringe. ( 3 )

4 CONTRAINDICATIONS Methylene blue injection is contraindicated in the following conditions: Severe hypersensitivity reactions to methylene blue or any other thiazine dye [see Warnings and Precautions ( 5.2 )] . Patients with glucose-6-phosphate dehydrogenase deficiency (G6PD) due to the risk of hemolytic anemia [see Warnings and Precautions ( 5.3 , 5.4 )] . Methylene blue injection is contraindicated in the following conditions ( 4 ): Severe hypersensitivity to methylene blue Patients with glucose-6-phosphate dehydrogenase deficiency (G6PD) due to the risk of hemolytic anemia

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 [see Warnings and Precautions ( 5.1 )] Anaphylaxis [see Warnings and Precautions ( 5.2 )] Lack of Effectiveness [see Warnings and Precautions ( 5.3 ) ] Hemolytic Anemia [see Warnings and Precautions ( 5.4 )] Interference with In-Vivo Monitoring Devices [see Warnings and Precautions ( 5.5 )] Effects on Ability to Drive and Operate Machinery [see Warnings and Precautions ( 5.6 )] Interference with Laboratory Tests [see Warnings and Precautions ( 5.7 )] The most commonly reported adverse reactions (≥2%) included headache, hypokalemia, diarrhea, hypomagnesemia, myoclonus, nausea, and seizure-like phenomena (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Steriscience at 1-888-278-1784 or www.steriscience.com 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 methylene blue injection in adults with acquired methemoglobinemia was assessed in 24 patients who received at least 1 dose of methylene blue injection [see Clinical Studies (14)] . Most doses administered were 1mg/kg (88.5%), but doses from 1 mg/kg to 2 mg/kg were administered. All patients received at least one dose of methylene blue injection; two received two doses. Serious adverse reactions occurred in 4.2% of patients who received methylene blue injection. 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 methylene blue injection in pediatric patients with acquired methemoglobinemia was assessed in two retrospective case series that included two pediatric patients treated with methylene blue injection 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 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

7 DRUG INTERACTIONS Clinically significant drug interactions with methylene blue injection are described below: The concomitant use of methylene blue injection with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Although the mechanism is not clearly understood, literature reports suggest methylene blue injection is a potent reversible inhibitor of monoamine oxidase. Avoid concomitant use of methylene blue injection 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 methylene blue injection 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 [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ] .

8 USE IN SPECIFIC POPULATIONS Pregnancy: Only use during pregnancy if the potential benefit justifies the potential risk to the fetus. ( 8.1 ) Lactation: Discontinue breast-feeding for up to 8 days after treatment. ( 8.2 ). Hepatic Impairment: Monitor patients longer for toxicity and drug interactions due to delayed clearance. ( 8.7 ) See 17 for PATIENT COUNSELING INFORMATION. 8.1 Pregnancy Risk Summary Methylene blue injection may cause fetal harm when administered to a pregnant woman. Intra-amniotic injection of pregnant women with a methylene blue class product during the second trimester was associated with neonatal intestinal atresia and fetal death. 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 (see Data) . 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 to 4% and 15 to 20%, respectively. Clinical Considerations Fetal/neonatal adverse reactions Intra-amniotic injection of a 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 Methylene blue injection to a pregnant woman at term, observe the newborn for these adverse reactions and institute supportive care. Data Animal Data 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 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. 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 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 methylene blue 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 Methylene blue injection [see Clinical Pharmacology (12.3)] . 8.4 Pediatric Use The safety and effectiveness of methylene blue for the treatment of acquired methemoglobinemia have been established in pediatric patients. Use of methylene blue is supported by two retrospective case series that included 2 pediatric patients treated with methylene blue 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 Methylene blue injection did not include suffcient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not ide …

12.1 Mechanism of Action Methylene blue is a water-soluble thiazine dye that promotes a non-enzymatic 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.

11 DESCRIPTION Methylene Blue Injection, USP is an oxidation-reduction agent. Its chemical name is 3,7-bis(dimethylamino)phenothiazin-5-ium, chloride hydrate. The molecular formula of methylene blue is C 16 H 18 CIN 3 SxH 2 O and its molecular weight of 319.86 g/mol for the anhydrous form. The structural formula of methylene blue, USP is: Methylene Blue Injection, USP is a sterile solution intended for intravenous administration. Each mL of solution contains 5 mg methylene blue and water for injection. Methylene Blue Injection, USP 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. Methylene Blue Injection, USP strength is expressed in terms of trihydrate. Structural Formula

10 OVERDOSAGE Hypotension, wheezing and reduced oxygenation have been reported in patients who received 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 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 to 12 hours following administration. A severe overdosage (single dose of 20 mg/kg or more) of a methylene blue class product caused severe intravascular hemolysis, hyperbilirubinemia and death. In case of overdose of methylene blue injection, maintain the patient under observation until signs and symptoms have resolved, monitor for cardiopulmonary, hematologic and neurologic toxicities, and institute supportive measures as necessary.

16 HOW SUPPLIED/STORAGE AND HANDLING Methylene blue injection, USP is supplied in 10 mL single-dose ampules or single-dose pre-filled syringes. Each 10 mL ampule or pre-filled syringes contains 50 mg of methylene blue as a clear dark blue solution. A box contains five ampules or pre-filled syringes. Box of 5 ampules of 50 mg/10 mL (0.5%): NDC 82449-002-06 Box of 5 prefilled syringe of 50 mg/10 mL (0.5%): NDC 82449-003-06 Storage: Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°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 or pre-filled syringe in the original package to protect from light.