Methylene Blue

Methylene blue is approved across multiple intravenous products for the treatment of acquired methemoglobinemia. Here is the full picture of supported uses:

• Methylene Blue injection (intravenous) is indicated to treat acquired methemoglobinemia in pediatric and adult patients
• Methylene Blue INJ (intravenous) is indicated to treat acquired methemoglobinemia in pediatric and adult patients
• Provayblue (intravenous) is indicated to treat acquired methemoglobinemia in pediatric and adult patients
• Arthcal 1% Methylene Blue (extracorporeal solution) is used according to established research protocols via the extracorporeal route
• Ozipco 1% Methylene Blue (extracorporeal solution) is used according to established research protocols via the extracorporeal route

Methylene blue is a water-soluble dye that acts as an oxidation-reduction (redox) agent. In acquired methemoglobinemia, the iron inside hemoglobin has been oxidized to a form (ferric iron) that can no longer bind or carry oxygen. Methylene blue is converted inside the body — using an enzyme called NADPH reductase — into leucomethylene blue, which then chemically reduces that abnormal ferric iron back to normal ferrous iron, restoring the hemoglobin's ability to carry oxygen.

Methylene blue is also a potent inhibitor of monoamine oxidase (MAO), which is the basis for its dangerous interaction with serotonergic drugs. This enzyme-blocking effect can allow serotonin to build up to toxic levels in the brain when certain antidepressants or opioids are on board at the same time.

Methylene blue injection is given intravenously (into a vein) by a healthcare professional — never injected under the skin or into the spinal canal. It is infused slowly over several minutes. If symptoms do not fully resolve, a second dose may be given about one hour after the first; if two doses don't work, alternative treatments are considered.

• Patients with moderate or severe kidney disease receive only a single dose
• Provayblue may be diluted in 5% Dextrose before infusion to reduce local discomfort, especially in children — sodium chloride solutions must not be used for dilution
• Dose and number of doses are determined by your care team based on your response and kidney function — always follow their guidance

The most commonly reported side effects with methylene blue injection include:

• Headache
• Nausea
• Diarrhea
• Low potassium (hypokalemia)
• Low magnesium (hypomagnesemia)
• Myoclonus (sudden, brief muscle jerks)
• Seizure-like episodes
• Blue discoloration of urine (expected — methylene blue is a dye)

Seek immediate medical attention for signs of serotonin syndrome (agitation, rapid heartbeat, high fever, muscle rigidity), severe allergic reaction (swelling, hives, trouble breathing), or hemolytic anemia (fatigue, yellowing of the skin or eyes, dark urine) — these are serious and require prompt care.

• Serotonin syndrome: The biggest risk. Methylene blue injection is a potent MAO inhibitor. Combining it with SSRIs, SNRIs, MAOIs, opioids, bupropion, buspirone, clomipramine, mirtazapine, linezolid, or dextromethorphan can trigger a potentially fatal buildup of serotonin. Symptoms include agitation, hallucinations, fever, rapid heart rate, sweating, muscle twitching, and seizures. Some reported cases were fatal.
• Hemolytic anemia: Methylene blue injection can destroy red blood cells (hemolysis), sometimes starting a day or more after treatment. Patients with G6PD deficiency are at especially high risk of severe hemolysis.
• Hypersensitivity: Serious allergic reactions including anaphylaxis have been reported. The drug must be stopped immediately if this occurs.
• Interference with monitoring devices: Methylene blue can make pulse oximeters (oxygen finger sensors) give falsely low readings. It can also affect BIS monitors used to gauge anesthesia depth during surgery. Alternative monitoring methods should be used.
• Pregnancy: Methylene blue is contraindicated in pregnancy — it has been associated with serious fetal harm including intestinal defects and fetal death.
• Driving and machinery: Do not drive or operate dangerous machinery until dizziness, confusion, or visual problems have fully resolved.

Methylene blue injection has several serious drug interactions that your care team needs to know about before you receive it:

• SSRIs (e.g., fluoxetine, sertraline) — high risk of fatal serotonin syndrome; avoid together
• SNRIs (e.g., venlafaxine, duloxetine) — same serotonin syndrome risk; avoid together
• MAOIs (e.g., phenelzine, selegiline) — dangerous combination; avoid together
• Opioid pain medications — increase serotonin syndrome risk when combined with methylene blue injection
• Dextromethorphan (common in cough syrups) — raises serotonin syndrome risk
• Bupropion, buspirone, clomipramine, mirtazapine, linezolid — all increase CNS serotonin-related risks with methylene blue injection
• Avoid all serotonergic medications for at least 72 hours after your last dose of methylene blue injection
• Methylene blue inhibits several liver enzymes (CYP450 enzymes) in lab studies, though clinical studies with some common drugs did not show significant interactions — your prescriber should review all your medications

This is not a complete list of interactions. Always talk with your doctor or pharmacist before starting, stopping, or changing any medication.

• Tell your doctor about every medication you take, especially antidepressants, opioids, and cough medicines containing dextromethorphan — these can cause a dangerous reaction with methylene blue injection
• Tell your doctor if you have G6PD deficiency — methylene blue injection may not work for you and could cause severe hemolytic anemia
• Tell your doctor if you have kidney disease — the drug clears more slowly, and dosing must be adjusted for moderate or severe impairment
• Tell your doctor if you have liver disease — metabolism may be slower, and you may need extended monitoring for side effects and interactions
• Pregnancy: Methylene blue injection is contraindicated in pregnancy. It has been associated with serious fetal harm, including intestinal defects and fetal death
• Breastfeeding: Stop breastfeeding during treatment and for up to 8 days afterward due to potential serious harm to the infant
• Older adults: More likely to have reduced kidney function; should receive the lowest number of doses needed
• Methylene blue must never be injected subcutaneously (under the skin) or intrathecally (into the spinal canal) — these routes are contraindicated

Receiving too large a dose of methylene blue injection can cause nausea, vomiting, chest pain, rapid breathing, rapid heart rate, tremor, dizziness, headache, confusion, blue staining of skin and urine, and abnormal heart rhythm changes. Very high doses have caused severe destruction of red blood cells and death. If overdose is suspected, the patient should be kept under close observation with monitoring of heart, blood, and neurological function, and supportive care should be provided until symptoms resolve.

At low concentrations, methylene blue speeds up the conversion of methemoglobin back to normal hemoglobin in the body, restoring the blood's ability to carry oxygen. It has also been observed to stain tissues selectively. Studies show that at the recommended intravenous dose, methylene blue does not affect the heart's electrical activity (it had no effect on QT, PR, or QRS intervals in a dedicated cardiac study).

After intravenous infusion, methylene blue distributes widely throughout the body and is about 94% bound to plasma proteins. It has a half-life of approximately 24 hours, meaning it takes roughly a day for the body to clear half of the drug. Methylene blue is broken down mainly in the liver and about 40% is excreted unchanged in the urine. In people with kidney disease, the drug accumulates significantly — levels can be nearly three times higher in severe kidney impairment compared to normal kidney function — which is why dosing is adjusted in those patients.

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F). Do not refrigerate or freeze. protect from light.