Methylene Blue

WARNING: SEROTONIN SYNDROME WITH CONCOMITANT USE OF SEROTONERGIC DRUGS AND OPIOIDS Methylene blue injection may cause serious or fatal serotonergic syndrome when used in combination with serotonergic drugs and opioids. Avoid concomitant use of methylene blue injection with selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs) and opioids [see Warnings and Precautions (5.1) and Drug Interactions (7.1) ] . WARNING: SEROTONIN SYNDROME WITH CONCOMITANT USE OF SEROTONERGIC DRUGS AND OPIOIDS See full prescribing information for complete boxed warning. Methylene blue injection may cause serious or fatal serotonergic syndrome when used in combination with serotonergic drugs and opioids. Avoid concomitant use of methylene blue injection with selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs) and opioids. ( 5.1 , 7.1 )

5 WARNINGS AND PRECAUTIONS Hypersensitivity: If severe or life threatening allergic reaction occurs, discontinue methylene blue injection, 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 methylene blue injection and transfuse. ( 5.4 ) Interference with In Vivo Monitoring Devices: Use methods other than pulse oximetry to assess oxygen saturation. ( 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 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 methylene blue injection with serotonergic drugs and opioids. Patients treated with methylene blue injection should be monitored for the emergence of serotonin syndrome. If symptoms of serotonin syndrome occur, discontinue use of methylene blue injection, 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 methylene blue injection [see Drug Interactions (7) , Patient Counseling Information (17) ] . 5.2 Hypersensitivity Anaphylactic reactions to methylene blue class products have been reported. Patients treated with methylene blue injection should be monitored for anaphylaxis. If anaphylaxis or other severe hypersensitivity reactions (e.g., angioedema, urticaria, bronchospasm) should occur, discontinue use of methylene blue injection and initiate supportive treatment. Methylene blue injection 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 methylene blue injection in patients with methemoglobinemia due to aryl amines such as aniline or sulfa drugs such as dapsone. Monitor response to therapy with methylene blue injection through resolution of methemoglobinemia. If methemoglobinemia does not respond to 2 doses of methylene blue injection 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 methylene blue injection to its active form in vivo . Methylene blue injection 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 methylene blue injection. 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 methylene blue injection. The anemia may require red blood cell transfusions [see Adverse Reactions (6.1) ] . Use the lowest effective number of doses of methylene blue injection to treat methemoglobinemia. Discontinue methylene blue injection and consider alternative treatments of methemoglobinemia if severe hemolysis occurs. Treatment of patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency with methylene blue injection may result in severe hemolysis and severe anemia. Methylene blue injection 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 methylene blue injection, 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 methylene blue injection 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 methylene blue injection 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 methylene blue injection have resolved. 5.7 Interference with Laboratory Tests Methylene blue injection 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 [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 Meitheal Pharmaceuticals Inc. at 1-844-824-8426 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 1 mg/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 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