Methylene Blue Prescribing Information
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
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 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 the patient closely for CNS effects for up to 4 hours after administration
- Administer 1 mg/kg intravenously over 5-30 minutes. ()
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.
- 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 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.
- Administer a single dose of 1 mg/kg in patients with moderate or severe renal impairment. ()
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 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.
Methylene Blue Injection, USP: 50 mg per 10 mL (5 mg per mL) (0.5%) clear dark blue solution in single-dose vials.
- Pregnancy: Only use during pregnancy if the potential benefit justifies the potential risk to the fetus. ()
8.1 PregnancyRisk SummaryMethylene 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
. 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 ConsiderationsFetal/neonatal adverse reactionsIntra-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.
DataAnimal DataMethylene 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 (1,200 mg/m2) 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/m2) in rabbits is approximately 16 times a clinical dose of 1 mg/kg based on body surface area.
- Lactation: Discontinue breast-feeding for up to 8 days after treatment. ()
8.2 LactationRisk SummaryThere 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)]. - Hepatic Impairment: Monitor patients longer for toxicity and drug interactions due to delayed clearance. ()
8.7 Hepatic ImpairmentMethylene 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 methylene blue injection.
Methylene blue injection is contraindicated in the following conditions:
- Severe hypersensitivity reactions to methylene blue or any other thiazine dye [see.]
5.2 HypersensitivityAnaphylactic 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.
- Patients with glucose-6-phosphate dehydrogenase deficiency (G6PD) due to the risk of hemolytic anemia [see.,
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 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)].