Methylene Blue Prescribing Information
The development of serotonin syndrome has been reported with 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
7.1)
The development of serotonin syndrome has been reported with 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
7.1)]
Methylene blue injection, USP is indicated for the treatment of pediatric and adult patients with acquired methemoglobinemia.
Methylebe blue Injection, USP: 50 mg/10 mL (5 mg/mL) (0.5%) clear dark blue solution in single-dose ampules.
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 HypersensitivityAnaphylactic reactions to methylene blue injection 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 injection class product in the past.
- Patients with glucose-6-phosphate dehydrogenase deficiency (G6PD) due to the risk of hemolytic anemia[see Warnings and Precautions (,
5.3 Lack of EffectivenessMethemoglobinemia 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 AnemiaHemolysis 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 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)].
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 Serotonin Syndrome with Concomitant Use of Serotonergic Drugs and OpiodsThe development of serotonin syndrome has been reported with 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)]. - Anaphylaxis[see Warnings and Precautions ()]
5.2 HypersensitivityAnaphylactic reactions to methylene blue injection 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 injection class product in the past.
- Lack of Effectiveness[see Warnings and Precautions ()
5.3 Lack of EffectivenessMethemoglobinemia 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.] - Hemolytic Anemia[see Warnings and Precautions ()]
5.4 Hemolytic AnemiaHemolysis 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 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)]. - Interference with In-Vivo Monitoring Devices[see Warnings and Precautions ()]
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.
- Effects on Ability to Drive and Operate Machinery[see Warnings and Precautions ()]
5.6 Effects on Ability to Drive and Operate MachineryTreatment 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. - Interference with Laboratory Tests[see Warnings and Precautions ()]
5.7 Interference with Laboratory TestsMethylene 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.
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 [