methylene blue (Rx)

>10%

Pain in extremity (84%)

Chromaturia (74%)

Dysgeusia (20%)

Feeling hot (17%)

Dizziness (16%)

Hyperhidrosis (13%)

Nausea (13%)

Skin discoloration (13%)

1-10%

Headache (10%)

Musculoskeletal pain (9%)

Paresthesia oral (9%)

Paresthesia (9%)

Infusion site pain (6%)

Feeling cold (6%)

Pallor (5%)

Contact dermatitis (5%)

Syncope (4%)

Pruritus (4%)

Anxiety (4%)

Decreased appetite (4%)

Chest discomfort (4%)

Back pain (2%)

Cold sweat (2%)

Dizziness postural (2%)

Muscle spasms (2%)

Presyncope (2%)

Arthralgia (2%)

Chills (2%)

Diarrhea (2%)

Discomfort (2%)

Dyspnea (2%)

Erythema (2%)

Hypoesthesia oral (2%)

Infusion site discomfort (2%)

Limb discomfort (2%)

Oral discomfort (2%)

Catheter site pain (2%)

Ecchymosis (2%)

Contraindications

Severe hypersensitivity reactions to methylene blue or any other thiazine dye

Patients with glucose-6-phosphate dehydrogenase deficiency (G6PD) due to the risk of hemolytic anemia

Cautions

Hypersensitivity reactions (eg, anaphylaxis, angioedema, urticaria, bronchospasm) reported; monitor vital signs and ECG during treatment; if severe hypersensitivity occurs, discontinue drug and initiate supportive treatment (see Administration and Contraindications)

Methemoglobinemia may not resolve or may rebound after response to treatment due to aryl amines (eg, aniline, sulfa drugs [dapsone]); monitor response to therapy with through resolution of methemoglobinemia

Patients with G6PD deficiency may not reduce methylene blue to its active form in vivo and thereby be ineffective (see Contraindications)

Hemolysis can occur during treatment of methemoglobinemia with methylene blue and anemia may occur; hemolytic anemia may not be apparent until ≥1 day after

The presence of methylene blue in the blood may result in an underestimation of the oxygen saturation reading by pulse oximetry

A fall in the Bispectral Index (BIS) has been reported following administration of methylene blue class products; if methylene blue is administered during surgery, alternative methods for assessing the depth of anesthesia should be employed

May cause confusion, dizziness and disturbances in vision; patients should refrain from driving or engaging in hazardous occupations or activities

Methylene blue 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 (eg, dipstick test for leucocyte esterase)

Methylene 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

Approximately 40% of methylene blue is excreted by the kidneys; patients with any renal impairment should be monitored for toxicities and potential drug interactions for an extended period of time following treatment

Serotonin syndrome

• Avoid coadministration with serotonergic psychiatric drugs (eg, SSRIs, SNRIs, TCAs, MAOIs) due to increased risk of serotonin syndrome, unless indicated for life-threatening conditions or when urgent treatment is required such as emergency treatment of methemoglobinemia, ifosfamide-induced encephalopathy, or cyanide poisoning; methylene blue may increase serotonin CNS levels by MAO-A inhibition
• If methylene blue must be administered to a patient currently taking a serotonergic drug, stop serotonergic drug immediately and monitor for CNS toxicity; serotonergic therapy may be resumed 24 hours after the last dose of methylene blue, or after 2 weeks of monitoring (5 weeks if fluoxetine was taken), whichever comes first
• If possible, discontinue serotonergic psychiatric medication at least 2 weeks in advance of methylene blue treatment; fluoxetine, should be stopped at least 5 weeks in advance due to longer half-life
• Also see Black Box Warnings

Pregnancy

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

Lactation

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 breastfeeding during and for up to 8 days after treatment

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Methylene blue is a water soluble thiazine dye that promotes a nonenyzmatic 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

It also combines with cyanide to form cyanmethemoglobin, which prevents the interference of cyanide with the cytochrome system

Absorption

Peak plasma concentration: 2,917 ng/mL

AUC: 13,977 ng·hr/mL

Distribution

Protein bound: 94%

Vd: 255 L

Metabolism

Metabolized by CYPs 1A2, 2C19 and 2D6 in vitro; however, the predominant in vitro pathway appears to be UGT-mediated conjugation by multiple UGT enzymes, including UGT1A4 and UGT1A9

Elimination

Half-life: 24 hr

Excretion: 40% unchanged in urine

IV Incompatibilities

0.9% NaCl (reduces methylene blue solubility)

Incompatible with caustic alkalis, iodides, dichromates, and oxidizing or reducing substances

IV Preparation

Solution is hypotonic and may be diluted before use in a solution of 50 mL D5W to avoid local pain, particularly in the pediatric population

Use the diluted solution immediately after preparation

Do not mix with 0.9% NaCl, 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

IV Administration

Ensure patent venous access prior to administration

For IV use only, do not administer SC or IM

Administer IV slowly over 5-30 minutes

If the methemoglobin level remains >30% or if clinical signs and symptoms persist, a repeat dose of 1 mg/kg may be given 1 hr after the first dose

If methemoglobinemia does not resolve after 2 doses, consider initiating alternative interventions for treatment of methemoglobinemia

Monitor vital signs, ECG, and methemoglobin levels during treatment and through resolution of methemoglobinemia

Storage

Store at 20-25°C (68-77°F)

Do not refrigerate or freeze

Keep ampule in original container to protect from light