FDA

Methylene Blue

Approved 5 Dec 2023IntravenousSolution

The FDA lists this product in 10 strengths and forms.

Indications

Methylene blue injection is indicated for the treatment of pediatric and adult patients with acquired methemoglobinemia. Methylene blue is an oxidation-reduction agent indicated for the treatment of pediatric and adult patients with acquired methemoglobinemia.

Contraindications

Methylene blue 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 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

Warnings and precautions

Hypersensitivity: If severe or life-threatening allergic reaction occurs, discontinue methylene blue, 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 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 )

5.1Serotonin 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).

At a glance

Brand name: Methylene Blue
Route: Intravenous
Dosage form: Solution
Applicant: Zydus Lifesciences
Status: Prescription
FDA approval: 5 Dec 2023
Application: ANDA215636-002

Contraindications

Warnings and precautions

5.1Serotonin Syndrome with Concomitant Use of Serotonergic Drugs and Opioids

Pregnancy and breastfeeding

8.1Pregnancy Risk Summary

Methylene blue 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 2-4% and 15-20%, 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 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.

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 Zydus Pharmaceuticals (USA) Inc. at 1-877-993-8779 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical 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

Methylene Blue

Indications

Contraindications

Warnings and precautions

5.1Serotonin Syndrome with Concomitant Use of Serotonergic Drugs and Opioids

At a glance

Two medicines in one question?

Methylene Blue

Indications

Contraindications

Warnings and precautions

5.1Serotonin Syndrome with Concomitant Use of Serotonergic Drugs and Opioids

At a glance

Two medicines in one question?

5.2Hypersensitivity

5.3Lack of Effectiveness

5.4Hemolytic Anemia

5.5Interference with In Vivo Monitoring Devices Inaccurate Pulse Oximeter Readings

5.6Effects on Ability to Drive and Operate Machinery Treatment

5.7Interference with Laboratory Tests

Interactions

Pregnancy and breastfeeding

8.1Pregnancy Risk Summary

Adverse reactions

6.1Clinical Trials Experience

Composition

Strengths and forms

Official product information