Bedside Snapshot

Use It For: Symptomatic acquired methemoglobinemia (labeled); refractory vasoplegic shock after bypass or in septic shock (off-label, ICU)
Adult Dose: MetHb: 1 mg/kg IV over 5–30 min; repeat up to 1 mg/kg at 1 hr if MetHb >30% or symptoms persist (max 2)
Vasoplegia (off-label, ICU): 2 mg/kg IV over 15 min, then protocol infusion
Pediatric Dose: 1 mg/kg IV over 5–30 min (same as adult; no separate cap in label); repeat up to 1 mg/kg once after 1 hr if MetHb stays above 30% or symptoms persist. Vasoplegia: not established in children; specialist use only
Onset / Duration: IV: 9 of 12 patients (75%) with baseline MetHb assessed within 2 hr of the infusion had a fall of at least 50% at 1 hr (label series; small n); terminal half-life about 24 hr
Do Not Give / Hold If: G6PD deficiency (contraindicated); severe hypersensitivity to methylene blue or thiazine dyes; serotonergic drugs or opioids (avoid); more than 2 doses; hemolysis
Watch For: Serotonin syndrome (agitation, clonus, hyperthermia); hemolysis, often 1 or more days later; SpO₂ falsely low; hypotension and wheeze after doses of 3 mg/kg or more
Reversal / Rescue: No specific reversal. Not responding after 2 doses: alternatives and poison center (1-800-222-1222). Serotonin toxicity: stop methylene blue and serotonergic drugs; supportive care
Must Remember: Check the serotonergic list before the first dose. G6PD deficiency is contraindicated; if status is unknown and MetHb is life-threatening, involve poison center or toxicology. SpO₂ reads low: use an arterial sample.

Indications

Emergency & Prehospital

Symptomatic acquired methemoglobinemia (the labeled indication). Cyanosis, dyspnea or altered mental status, with SpO₂ that won't rise on oxygen. Treat symptomatic patients per protocol
Oxidant exposures: think aniline-type chemicals, dapsone (both named in the label) and other oxidant drugs. Check MetHb by co-oximetry

ED / ICU / Transport

Refractory vasoplegic shock: after cardiopulmonary bypass or in septic shock, when norepinephrine and vasopressin are not enough. It is off-label, and the evidence is small trials and case series.
Serotonin-syndrome caution: methylene blue treats MetHb, and it is still a serotonergic hazard in its own right. See Contraindications

Other Uses

Ifosfamide-induced neurotoxicity (off-label, oncology): pediatric and adult critical-care literature reviews it. It is not an ED or prehospital indication

Recognizing Methemoglobinemia

Clue: SpO₂ sits near 85% and will not climb on oxygen. The blood looks chocolate-brown while the PaO₂ is normal. Pulse oximetry cannot measure MetHb.
Confirm: co-oximetry on an arterial or venous blood gas.

Dosing & Administration

Doses vary by protocol; follow local protocols and medical direction.

Available Forms

ProvayBlue (US): 5 mg/mL (0.5%) clear dark blue solution: 50 mg/10 mL and 10 mg/2 mL single-dose ampules or vials; boxes of five.
Strength check: other methylene blue injections on DailyMed carry different labels. Read the strength on the vial before you draw up. Dose in mg, then convert to mL.

Adult Dosing

Indication	Dose & Route	Repeat / Max	Notes
Symptomatic acquired methemoglobinemia	1 mg/kg IV over 5–30 min (0.2 mL/kg of 5 mg/mL)	If MetHb stays above 30% or symptoms persist, repeat up to 1 mg/kg one hour after the first dose; max 2 doses	Dosing weight: the label gives mg/kg and does not define the weight; follow local protocol or pharmacy guidance. Do not give subcutaneously.
Moderate or severe renal impairment (eGFR 15–59 mL/min/1.73 m²)	1 mg/kg IV over 5–30 min	Single dose only; reassess MetHb at 1 hour and consider alternatives if still above 30%	Label adjustment. Metabolite and drug levels rise with reduced eGFR.
Refractory vasoplegic shock (off-label)	2 mg/kg IV over about 15 min, then infusion (protocol-dependent). Sustained trial rates were 0.25–0.5 mg/kg/hr; 2 mg/kg/hr was a brief top step in one escalation protocol (Kirov)	Infusion durations in trials were 12–72 hr; no validated maximum. Label: cumulative dose of 7 mg/kg or more caused adverse effects. Arithmetic: a 2 mg/kg bolus plus 0.5 mg/kg/hr for 12 hr is 8 mg/kg cumulative; a 2 mg/kg bolus plus 2 mg/kg/hr passes 7 mg/kg in about 2.5 hr	ICU or cardiac surgery decision only; not an EMS or prehospital dose. Dosing is protocol-driven and not standardized; the evidence is small trials and case series. The 2025 review reports dose-dependent arrhythmia, coronary vasoconstriction and reduced mesenteric and renal blood flow above 2 mg/kg, and mesenteric vasoconstriction and paradoxical methemoglobinemia at 4 mg/kg.

Pediatric Dosing

Indication	Dose (per kg) & Route	Max Single / Max Total	Notes
Symptomatic acquired methemoglobinemia	1 mg/kg IV over 5–30 min	No separate cap in the label; repeat up to 1 mg/kg one hour after the first dose if needed; max 2 doses	Labeled as established in children, based on two retrospective case series (2 patients treated with ProvayBlue, 12 with another methylene blue product, including 3 neonates). Same dose as adults.
Refractory vasoplegic shock	Not established in children	—	Specialist use only, with critical-care and toxicology input.

The per-kg method is laid out on the weight-based dosing page.

Preparation & Administration

Dilution: it may be diluted in 50 mL of 5% dextrose (D5W) to reduce local pain, especially in children. Use the diluted solution right away. Don't dilute it with sodium chloride. Chloride reduces solubility.
Push rate: over 5–30 minutes. The label's QT study ran 2 mg/kg over 5 minutes.
Line: IV only. Make sure venous access is patent first. Infusion-site pain, swelling and extravasation are reported.
Inspection: check for particles and discoloration before use. Discard any unused portion.
Pump: the label does not require one. Use a controlled-rate method so a 5–30 minute run stays on time.

Dosing Notes:

Volume check: 70 kg = 70 mg = 14 mL of 5 mg/mL; 20 kg = 20 mg = 4 mL; 10 kg = 10 mg = 2 mL.
Recheck: about one hour after the first dose, check MetHb by co-oximetry and look at the symptoms. That is when the label decides on a repeat dose. Methylene blue can throw off co-oximeter readings. Read them alongside the clinical picture and the lab's guidance.
Poison center: 1-800-222-1222.
Renal and hepatic: the details sit under Special Populations.

Contraindications & Precautions

Contraindications

Glucose-6-phosphate dehydrogenase (G6PD) deficiency: the hemolytic anemia risk is why the label contraindicates use
Severe hypersensitivity to methylene blue or any thiazine dye. That includes anaphylaxis to a methylene blue product in the past

Precautions

Serotonergic drugs and opioids: avoid SSRIs, SNRIs, MAOIs, bupropion, buspirone, clomipramine, mirtazapine, linezolid, opioids and dextromethorphan. If IV methylene blue can't be avoided, use the lowest dose and watch for CNS effects for up to 4 hours. Keep serotonergic drugs off for 72 hours after the last dose.
Aniline and dapsone methemoglobinemia: MetHb may not resolve, or it may rebound. Recheck MetHb after the response. After two doses, consider other options.
Hemolysis: look for Heinz bodies, rising indirect bilirubin and low haptoglobin with a negative Coombs test. Anemia can appear one or more days after treatment.
Pregnancy: it may cause fetal harm, so use it only when the benefit justifies the risk. Intra-amniotic exposure to a methylene blue class product was linked to intestinal atresia and fetal death. Watch the newborn after maternal dosing near term.
Lactation: stop breastfeeding during treatment and for up to 8 days after the last dose.
Pulse oximetry: methylene blue pulls pulse-oximeter readings down. During or shortly after the infusion, use an arterial sample.
Driving and machinery: confusion, dizziness and visual change can happen. Avoid driving and machinery until they resolve.

Hold / Reassess If

MetHb does not fall after 2 doses, or it rebounds after a response. Consider alternative treatment, and call a poison center or toxicology.
Falling hemoglobin, rising indirect bilirubin or dark urine: stop methylene blue. Treat hemolysis and transfuse as needed.
Signs of serotonin toxicity (agitation, clonus, hyperreflexia, hyperthermia, tachycardia): stop methylene blue and all serotonergic drugs. Start supportive care.
Anaphylaxis or angioedema: stop the infusion and treat per protocol.

FDA Boxed Warning: Serotonin syndrome may be serious or fatal. The danger is pairing methylene blue with serotonergic drugs or opioids, so steer clear of SSRIs, SNRIs, MAOIs and opioids with it. No way around the IV route? Take the lowest dose and monitor for serotonin toxicity for up to 4 hours.

Adverse Effects & Toxicity

Common

Headache, nausea and diarrhea (2% or more in the label trial of 31 adults)
Hypokalemia and hypomagnesemia (2% or more)
Myoclonus and seizure-like phenomena (2% or more; serious in one patient in the label trial)
Blue discoloration of skin, urine and body fluids. It is expected. The urine can also interfere with dipstick leukocyte esterase tests
Infusion-site reactions: pain, swelling, urticaria

Serious / Life-Threatening

Effect	Recognition	Management
Serotonin syndrome	Mental status change, autonomic instability (tachycardia, labile BP, hyperthermia, diaphoresis), tremor, rigidity, myoclonus, hyperreflexia, seizure, nausea or diarrhea	Stop methylene blue and serotonergic drugs; supportive care; monitor for hours
Hemolytic anemia	Heinz bodies, rising indirect bilirubin, low haptoglobin, negative Coombs; anemia may appear 1 or more days later	Stop; alternative treatment; transfuse as needed. Worse in G6PD deficiency
Anaphylaxis	Angioedema, urticaria, bronchospasm	Stop; treat per protocol; monitor until resolved
Lack of effect or rebound	MetHb not falling after 2 doses, or rebounding (aniline, dapsone)	Recheck MetHb; alternative treatment; poison center

Overdose & Toxicity Management

Single dose 3 mg/kg or more: hypotension, wheezing and lower oxygenation have been reported.
Cumulative 7 mg/kg or more: nausea, vomiting, precordial pain, dyspnea, tachycardia, tremor, mydriasis, mild MetHb (up to 7%), and T-wave flattening or inversion. They lasted 2–12 hours.
Single dose 20 mg/kg or more: severe intravascular hemolysis, hyperbilirubinemia and death.
Management: observe until the signs resolve. Monitor cardiopulmonary, hematologic and neurologic status, and give supportive care. There is no specific reversal for methylene blue. Poison center 1-800-222-1222.

Monitoring

Parameter	When / How Often	Target / Act If
Clinical	Before the first dose and about 1 hour after	Cyanosis, dyspnea, mental status and RR: repeat up to 1 mg/kg once if symptoms persist or MetHb stays above 30%
Laboratory	MetHb by co-oximetry before the dose and about 1 hour after (see SaO₂)	Above 30% or symptomatic: repeat once (max 2 doses). Not falling after 2 doses: alternative treatment
Laboratory	Creatinine and eGFR before dosing (ABG panel for context)	eGFR 15–59: single dose only
Laboratory	Hemoglobin, bilirubin and haptoglobin daily for several days after treatment (a suggested schedule, not a label figure), and sooner if dark urine or pallor appears; the label says anemia may be delayed 1 or more days after treatment (see hemoglobin)	Falling Hb or rising bilirubin: stop methylene blue; transfuse per protocol
Infusion Safety	Each dose and infusion site	Pain, swelling or extravasation: stop and resite the line
Serotonin Safety	Throughout and up to 4 hours after an unavoidable serotonergic co-exposure	Clonus, agitation, hyperthermia: stop methylene blue and serotonergic drugs

Don't trust SpO₂ during or shortly after the infusion. Make oxygenation decisions off an arterial sample. If smoke or CO exposure is possible, compare with carbon monoxide co-oximetry.

Interactions & Compatibility

Clinically Significant Interactions

Drug / Class	Effect	What To Do
SSRIs, SNRIs, bupropion, buspirone, clomipramine, mirtazapine	Serotonin syndrome (boxed warning)	Avoid. If unavoidable, lowest dose and observe up to 4 hours; no serotonergic drugs for 72 hours after the last dose
MAOIs and linezolid	Serotonin syndrome; methylene blue acts as a reversible MAO inhibitor	Avoid; discuss antidote choice with a poison center
Opioids	Serotonin syndrome (boxed warning); also additive CNS and respiratory effects	Avoid where possible; if not, lowest dose and close CNS monitoring
Dextromethorphan	Serotonin syndrome	Avoid during and for 72 hours after methylene blue
Hydroxocobalamin (Cyanokit)	Red chromophore interferes with photometric and co-oximetry lab assays; a rise in MetHb after hydroxocobalamin has been reported (case report)	If possible, draw co-oximetry or other key samples before the antidote or tell the lab; do not delay the antidote
Midazolam, warfarin, caffeine	In vitro CYP inhibition; no change in exposure in the label cocktail study at 2 mg/kg	No routine adjustment; watch for interactions if hepatic impairment

IV Compatibility

Diluent: 5% dextrose (50 mL) per the label; avoid sodium chloride, which reduces solubility.
Line: use a patent venous line; do not give subcutaneously. Verify with an institutional compatibility resource.

Special Populations

Pediatrics: methemoglobinemia use is established on two retrospective case series. They treated 2 patients with ProvayBlue and 12 with another methylene blue product. The doses are in the Pediatric Dosing table.
Neonates: 3 neonates were in the case series, and their outcomes were consistent. Newborns exposed to methylene blue near term, through maternal dosing, can develop hyperbilirubinemia, hemolysis, skin staining and methemoglobinemia.
Pregnancy: may cause fetal harm, so use it only if the benefit justifies the risk. Intra-amniotic exposure is linked to fetal death and intestinal atresia. Animal developmental effects appeared at about 16–32 times the clinical dose.
Lactation: stop breastfeeding during treatment and for up to 8 days after the last dose.
Older Adults: trials enrolled too few patients aged 65 and over to judge response. Kidney elimination falls with age, so use the fewest doses that work.
Renal Impairment: at eGFR 15–59, give a single 1 mg/kg dose. At eGFR 60–89, no adjustment. After 1 mg/kg, AUC rose 116% in moderate and 192% in severe impairment (label).
Hepatic Impairment: it is extensively metabolized in the liver, so monitor longer for toxicity and drug interactions.
Obesity / Dosing Weight: the label is written per kg but does not define the weight. Follow local protocol or pharmacy guidance. This page does not assume actual body weight.
Congenital NADH-cytochrome b5 reductase deficiency: methylene blue can reduce the cyanosis. It does not change the neurologic outcome. Ascorbic acid or riboflavin are the alternatives. Involve hematology and toxicology.
G6PD Deficiency: contraindicated. Methylene blue may not be converted to its active form, and the hemolysis can be severe. Talk through alternatives with toxicology or a poison center.

Field & Transport Considerations

Scope: it varies by state and agency protocol. Confirm whether your system stocks it or may give it.
Storage & Stability: 20–25 °C (68–77 °F), excursions 15–30 °C. Do not refrigerate or freeze. Keep in the original package to protect from light.
Carried Concentration: 5 mg/mL. Other methylene blue strengths exist, so read the mg/mL on the label at every draw-up.
Infusions in Transport: plan for a 5–30 minute run. Use a controlled-rate method and a dedicated IV line, and verify the dose by weight at handoff.
Handoff Essentials: give the time and mg/kg, the weight used, MetHb before and after, any serotonergic drugs given within 72 hours, the G6PD status, and whether SpO₂ readings were affected.

Clinical Pearls

Oxygen trap: SpO₂ near 85% that won't rise with oxygen points to MetHb. The methylene blue itself pulls pulse-oximeter readings down. Confirm with co-oximetry or an arterial sample.

Discriminator (CCRN, CFRN): a SpO₂ stuck near 85% that won't rise on oxygen suggests MetHb. CO poisoning looks different. The SpO₂ reads normal while COHb runs high. Methylene blue is not its treatment.

Not every blue-brown blood is MetHb: sulfhemoglobinemia does not reverse with methylene blue. Routine co-oximetry may miss it. Think about it when the PaO₂ is normal and the patient looks less sick than the cyanosis suggests.

Serotonin check first: before the first dose, run through SSRIs, SNRIs, MAOIs, linezolid, opioids and dextromethorphan. Serotonin syndrome is the boxed warning.

Two doses, then rethink: the label caps treatment at two doses. If MetHb is still above 30%, look hard for aniline or dapsone exposure or another cause, and call a poison center.

Methemoglobinemia vs carbon monoxide:

MetHb: SpO₂ near 85%, chocolate-brown blood, treat with methylene blue
CO: SpO₂ can read normal, COHb high, treat with 100% oxygen
Cyanide: lactate runs high. Treat per the cyanide antidote pages. Nitrite-based regimens raise MetHb on purpose, and hydroxocobalamin has been reported to raise it too (case report). Discuss methylene blue with toxicology

Pharmacology

Mechanism of Action

Target: an NADPH-dependent reductase turns methylene blue into leucomethylene blue (LMB).
Physiologic effect: LMB turns the ferric iron in MetHb back into the ferrous state that normal hemoglobin carries.
Clinical consequence: oxygen-carrying capacity recovers and the cyanosis clears. The response depends on NADPH, so G6PD deficiency may block activation.
Serotonin effect: the label describes methylene blue as a potent reversible MAO inhibitor. That is the basis for the serotonin syndrome warning.

Pharmacokinetics

Route	Onset	Peak	Duration
IV (5-min infusion)	9 of 12 patients (75%) with baseline MetHb assessed within 2 hr of the infusion had a fall of at least 50% at 1 hr (label series; 95% CI 43–93%)	End of infusion (Cmax 2,917 ng/mL after 2 mg/kg)	Terminal half-life about 24 hours

MetHb response overall: 26 of 28 patients with baseline MetHb (93%) had at least a 50% fall at their first post-dose check. That check ran 0.2–27.3 hr after infusion (median 2.7 hr). These are single-arm, observational label data. Small and uncontrolled.
Half-life: about 24 hours terminal in humans. Mild to moderate renal impairment does not change it.
Metabolism: CYP1A2, 2C19 and 2D6 in vitro, but UGT conjugation is the main route (UGT1A4, UGT1A9). Azure B is a metabolite (AUC ratio over 6:1, about 8-fold less potent).
Elimination: about 40% excreted unchanged in urine.
Protein binding / Vd: about 94% bound in vitro; Vd about 255 L at steady state after 2 mg/kg.
Cardiac effects: in a thorough QT study, 2 mg/kg over 5 minutes had no effect on QT, PR or QRS.

Names & Classification

Generic Name: Methylene blue (chloride hydrate)
Brand Names: ProvayBlue (US, approved 2016; American Regent distributes). No other US brand reviewed.
Pharmacologic Class: Thiazine dye; oxidation-reduction agent
Therapeutic Class: Antidote (methemoglobin reducer)
Controlled Substance: Not controlled
ISMP High-Alert: No (not named on the ISMP acute-care list as reviewed; owner to confirm)
Look-Alike / Sound-Alike: None commonly reported
Error-Prone Abbreviations: None commonly reported

References

American Regent, Inc. ProvayBlue (methylene blue) injection, USP: prescribing information. DailyMed; revised 2025 (SPL version 28, published June 12, 2025). https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4f6848e5-35ed-4046-b13c-3032b5ba3232
Elmati PR, Nagaradona T, Raghove V, Jagirdhar GSK, Surani S. Methylene blue in the critical care setting. World J Crit Care Med. 2025;14(3):105350. https://doi.org/10.5492/wjccm.v14.i3.105350
Pushparajah Mak RS, Liebelt EL. Methylene blue: an antidote for methemoglobinemia and beyond. Pediatr Emerg Care. 2021:474–477. https://doi.org/10.1097/PEC.0000000000002526
Gourlain H, Buneaux F, Borron SW, Gouget B, Levillain P. Interference of methylene blue with CO-oximetry of hemoglobin derivatives. Clin Chem. 1997;43(6 Pt 1):1078–1080. https://pubmed.ncbi.nlm.nih.gov/9191565/
Carlsson CJ, Hansen HE, Hilsted L, Malm J, Ødum L, Szecsi PB. An evaluation of the interference of hydroxycobalamin with chemistry and co-oximetry tests on nine commonly used instruments. Scand J Clin Lab Invest. 2011;71(5):378–386. https://doi.org/10.3109/00365513.2011.573573
Morales A, Walsh R, Brown W, Checinski P, Williams SR. Case report: phenazopyridine-induced sulfhemoglobinemia in an 83-year-old presenting with dyspnea. J Emerg Med. 2021;61(2):147–150. https://doi.org/10.1016/j.jemermed.2021.03.002
Kiernan E, Carpenter JE, Dunkley CA, Koch D, Morgan BW, Steck AR, Murray BP. Elevated methemoglobin levels in a patient treated with hydroxocobalamin after suspected cyanide exposure. J Emerg Med. 2020;59(5):e157–e162. https://doi.org/10.1016/j.jemermed.2020.07.008
Neven J, Beyltjens T, Meuwissen M, De Bisschop B, Bouziotis J, van den Akker M. Recessive congenital methemoglobinemia: a systematic review of reported cases. Orphanet J Rare Dis. 2026;21(1):89. https://doi.org/10.1186/s13023-026-04215-7

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