PROVAYBLUE

Antidotes, Systemic
Other Urinary Antiseptics

Injectable Administration

Do not administer intrathecally, intraspinally, or subcutaneously.
Visually inspect parenteral product for particulate matter and discoloration prior to administration whenever solution and container permit. Methylene blue is a clear dark blue solution.
Monitor vital signs, electrocardiogram, and methemoglobin concentrations during treatment and through resolution of methemoglobinemia.

Intravenous Administration

Dilution
Methylene blue is hypotonic. To avoid local pain, dilute with 50 mL of 5% Dextrose Injection. Use the diluted solution immediately after preparation.
Avoid diluting with sodium chloride solutions; chloride reduces the solubility of methylene blue.
 
Intravenous Infusion
Ensure patent venous access prior to administration.
Administer over 5 to 30 minutes.

Severe

hot flashes / Early / 6.0-6.0
methemoglobinemia / Early / Incidence not known
anaphylactoid reactions / Rapid / Incidence not known
serotonin syndrome / Delayed / Incidence not known

Moderate

headache / Early / 7.0-7.0
dizziness / Early / 4.0-4.0
chest pain (unspecified) / Early / 4.0-4.0
nausea / Early / 2.0-2.0
back pain / Delayed / 2.0-2.0
erythema / Early / 2.0-2.0
hyperhidrosis / Delayed / 2.0-2.0
dyspnea / Early / 2.0-2.0
vomiting / Early / 1.0-1.0
dysgeusia / Early / 1.0-1.0
arthralgia / Delayed / 1.0-1.0
muscle cramps / Delayed / 1.0-1.0
pruritus / Rapid / 1.0-1.0
influenza / Delayed / 1.0-1.0
anemia / Delayed / Incidence not known
hemolysis / Early / Incidence not known
hyperbilirubinemia / Delayed / Incidence not known
sinus tachycardia / Rapid / Incidence not known
hypertension / Early / Incidence not known
palpitations / Early / Incidence not known
edema / Delayed / Incidence not known
infusion-related reactions / Rapid / Incidence not known
peripheral edema / Delayed / Incidence not known
blurred vision / Early / Incidence not known
contact dermatitis / Delayed / Incidence not known
elevated hepatic enzymes / Delayed / Incidence not known
dysuria / Early / Incidence not known

Mild

urine discoloration / Early / 74.0-74.0
skin discoloration / Delayed / 13.0-13.0
paresthesias / Delayed / 9.0-9.0
musculoskeletal pain / Early / 9.0-9.0
pallor / Early / 5.0-5.0
anorexia / Delayed / 4.0-4.0
anxiety / Delayed / 4.0-4.0
syncope / Early / 4.0-4.0
diarrhea / Early / 2.0-2.0
chills / Rapid / 2.0-2.0
ecchymosis / Delayed / 2.0-2.0
flatulence / Early / Incidence not known
abdominal pain / Early / Incidence not known
xerostomia / Early / Incidence not known
myalgia / Early / Incidence not known
urticaria / Rapid / Incidence not known
rhinorrhea / Early / Incidence not known
hypoesthesia / Delayed / Incidence not known
nasal congestion / Early / Incidence not known
sneezing / Early / Incidence not known
photosensitivity / Delayed / Incidence not known

MAOI therapy

Avoid the concomitant use of methylene blue with selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), and monoamine oxidase inhibitors (MAOI therapy). Serotonergic drugs should not be used within 72 hours after the last dose of methylene blue. Cases of serotonin syndrome, some fatal, have been reported with the use of methylene blue. Most reports were associated with the concomitant use of serotonergic drugs. Serotonin syndrome may include the following combination of signs and symptoms: autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, and hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, and incoordination), mental status changes (e.g., agitation, hallucinations, delirium, and coma), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, and diarrhea). Monitor all drug recipients for symptoms of serotonin syndrome. If symptoms occur, discontinue methylene blue and begin supportive treatment.

PROVAYBLUE

Rx

Water-soluble thiazine dye
For acquired methemoglobinemia
Black box warning for serotonin syndrome with concomitant use of serotonergic drugs

For use as a diagnostic aid to determine the presence of a gastrointestinal fistula (e.g., gastrointestinal fistula diagnosis). Oral dosage Adults

In patients with a suspected gastrointestinal fistula, a small quantity (e.g., 5—10 ml) of methylene blue can be administered either orally or via a nasogastric tube. The appearance of a blue discoloration of ascitic or peritoneal fluid suggests a communicating fistula with the gastrointestinal tract.

For the treatment of acquired methemoglobinemia. Intravenous dosage Adults

1 mg/kg via IV infusion over 5 to 30 minutes. If the methemoglobin concentration remains more than 30% or if clinical signs and symptoms persist, a repeat dose of 1 mg/kg IV may be given 1 hour after the first dose. If methemoglobinemia does not resolve after 2 doses, consider initiating alternative interventions. Monitor vital signs, electrocardiogram (ECG), and methemoglobin concentrations during treatment and through the resolution of methemoglobinemia.

Infants, Children, and Adolescents

1 mg/kg via IV infusion over 5 to 30 minutes. If the methemoglobin concentration remains more than 30% or if clinical signs and symptoms persist, a repeat dose of 1 mg/kg IV may be given 1 hour after the first dose. If methemoglobinemia does not resolve after 2 doses, consider initiating alternative interventions. Monitor vital signs, electrocardiogram (ECG), and methemoglobin concentrations during treatment and through the resolution of methemoglobinemia.

Neonates

1 mg/kg via IV infusion over 5 to 30 minutes. If the methemoglobin concentration remains more than 30% or if clinical signs and symptoms persist, a repeat dose of 1 mg/kg IV may be given 1 hour after the first dose. If methemoglobinemia does not resolve after 2 doses, consider initiating alternative interventions. Monitor vital signs, electrocardiogram (ECG), and methemoglobin concentrations during treatment and through the resolution of methemoglobinemia.

For ifosfamide-induced neurotoxicity prophylaxis† and for the management of ifosfamide-induced neurotoxicity†. Intravenous dosage Adults

A single dose of methylene blue 1 mg/kg IV in 250 ml of 5% dextrose over 30 minutes has been used successfully in one patient. Other reports indicate multiple doses may be needed to resolve symptoms. In a report of 12 cases, 50 mg IV up to six times daily was effective. The time to resolution of symptoms varied, with reports describing benefit within minutes to several days. For prophylaxis of neurotoxicity in subsequent chemotherapy cycles, 50 mg IV administered 3—4 times daily has been used successfully. The optimal duration of treatment for ifosfamide-induced neurotoxicity is not known; treatment for 24 hours after the resolution of symptoms has been described.

Oral dosage Adults

Methylene blue 50 mg PO x 1 dose the day before initiation chemotherapy, and then methylene blue 50 mg PO three times daily throughout the duration of ifosfamide may effectively reduce the risk of ifosfamide-induced encephalopathy to almost 0%. Reports suggest successful secondary prophylaxis of ifosfamide-induced neurotoxicity with methylene blue 50 mg PO 3—4 times daily.

For use as an adjunct to lymphography† for direct visualization of the lymphatic system draining the region of injection. For evaluation of lymph node involvement of primary or secondary neoplasm (i.e., sentinel lymph node mapping†).
NOTE: For sentinel lymph node mapping, methylene blue can be used alone or in combination with radiocolloid technetium 99m sulfur colloid. When used in combination, up to 2 doses of radiocolloid is typically injected 0—1 days prior to surgery. In the majority of cancers, it appears that combination therapy increases the identification rate of sentinel lymph node mapping.
NOTE: The recommended volume in each of the indications is based on reports in the literature; other volumes may also be used in practice. Intradermal, Peritumoral, or Subdermal dosage Adults with breast cancer

3—5 ml injected via intradermal, peritumoral, or subdermal injection, approximately 3—5 minutes prior to making the surgical incision. When injecting peritumorally, injecting into each of the 4 quadrants surrounding the tumor has been recommended. Some authors recommend massaging the breast for up to 5 minutes after the dye is injected. After incision, the exposed surgical site can be visualized for blue-stained lymph nodes. Intradermal injections have been associated with skin lesions at the injection site.

Intracervical dosage Adult females with cervical cancer

A volume of 4 ml injected directly into the cervix in the 4 quadrants surrounding the tumor (12, 3, 6, and 9 o'clock position) has been suggested. Alternatively, the dye can be divided into 2 injections at the 3 and 9 o'clock positions, which may minimize staining of the bladder flap. If no blue nodes are noted, a second 2 ml dose can be injected into the cervix.

Peritumoral dosage Adults with colon cancer

After mobilization of the tumor in the bowel, 2—5 ml is injected peritumorally; injections should be circumferential (injected into each of the 4 quadrants around the tumor) and into the subserosal space, which optimizes sentinel lymph node identification. The colon should be inspected visually for blue-stained nodes, usually occurring within 5—10 minutes after injection. Unlike identification of other sentinel lymph nodes, some authors do not immediately excise blue-stained nodes, but rather mark them with sutures; the tumor and supporting mesentery are then resected after lymph node identification and marking. Sentinel lymph node mapping can also be accomplished after the colon is resected (i.e., ex vivo) or during laparoscopic colectomy.

Adults with lung cancer

Intraoperatively, a volume of 4 ml has been injected peritumorally in four quadrants of the peritumor tissue. After injection, the visceral pleura should be closely observed to identify blue-stained lymphatic channels leading to a sentinel node.

Adults with papillary thyroid carcinoma

0.2 ml of 2% methylene blue has been injected into the parenchyma surrounding the primary tumor. Lymphatic channels should stain within a few minutes of injection.

Intradermal dosage Adults with melanoma

A volume of 1—5 ml of methylene blue injected intradermally around the primary melanoma site has been suggested; usually 1.5—2 ml of methylene blue is adequate. On average, the blue dye will stain the sentinel lymph node within 5—15 minutes after injection.

Intramuscular or Intracervical dosage Adult females with uterine cancer

A volume of 4 ml injected via deep injection directly into the cervix in 4 quadrants (12, 3, 6, and 9 o'clock positions) has been suggested. Alternatively, a volume of 2 ml injected intramuscularly into the uterine fundus after opening the abdomen, or into the subserosal myometrium has been used.

For parathyroid gland localization†. Intravenous dosage Adults

Doses of 5 to 10 mg/kg administered as an IV infusion over 15 to 30 minutes have been studied and results in localization of parathyroid glands; in one study of 35 patients, a dose of 7.5 mg/kg IV over 15 to 30 minutes resulted in identification of abnormal tissue in 34 (97%) of patients. Very few adverse reactions have been reported; post-operative neurological complications including tonic-clonic seizures and prolonged disorientation have been rarely reported.

For hypotension† associated with vasoplegic syndrome in cardiac surgery patients. For the treatment of catecholamine-resistant hypotension† associated with vasoplegic syndrome after cardiopulmonary bypass. Intravenous dosage Adults

2 mg/kg IV over 20 minutes or 1.5 mg/kg IV over 1 hour. Catecholamine-resistance has been defined as simply requiring vasopressor therapy or specifically as requiring at least 0.5 mcg/kg/minute of norepinephrine or more than 0.2 mcg/kg/minute of norepinephrine plus more than 2 units/hour of vasopressin.

For the prevention of hypotension† associated with vasoplegic syndrome in high-risk patients undergoing cardiopulmonary bypass. Intravenous dosage Adults

2 mg/kg IV over at least 20 to 30 minutes and beginning 1 hour prior to cardiopulmonary bypass. Alternately, 3 mg/kg IV after cardiopulmonary bypass start, initial cardioplegia dose, and 5 minutes of hemodynamic stabilization. Methylene blue administration to patients receiving medications known to increase the risk of vasoplegic syndrome has been shown to improve hemodynamics and decrease lengths of ICU and hospital stay.

For the treatment of septic shock†. Intravenous dosage Adults

Various doses used. 1 or 3 mg/kg IV over 20 minutes or 2 mg/kg IV over 15 minutes followed 2 hours later by 0.25, 0.5, 1, and 2 mg/kg/hour continuous IV infusion for 1 hour each or 0.5 mg/kg/hour continuous IV infusion for 6 hours.

†Indicates off-label use

Hepatic Impairment

Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Renal Impairment

eGFR 15 to 59 mL/minute/1.73 m2: Single dose of 1 mg/kg IV; if the methemoglobin concentration remains greater than 30% or if the clinical symptoms persist 1 hour after dosing, consider initiating alternative interventions for the treatment of methemoglobinemia.

Acetaminophen; Caffeine; Dihydrocodeine: (Contraindicated) Dihydrocodeine use in patients taking methylene blue or within 14 days of stopping such treatment is contraindicated due to the risk of serotonin syndrome or opioid toxicity. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses of another opioid to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.
Acetaminophen; Chlorpheniramine; Dextromethorphan: (Major) Because of the potential risk and severity of serotonin syndrome, coadministration of dextromethorphan and IV methylene blue should be avoided if possible. Methylene blue has been demonstrated to be a potent monoamine oxidase inhibitor (MAOI) and may cause potentially fatal serotonin toxicity (serotonin syndrome) when combined with serotonin reuptake inhibitors (SRIs). Dextromethorphan increases central serotonin effects. If methylene blue is judged to be indicated, all SRIs, including dextromethorphan, must be ceased prior to treatment/procedure/surgery. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Major) Because of the potential risk and severity of serotonin syndrome, coadministration of dextromethorphan and IV methylene blue should be avoided if possible. Methylene blue has been demonstrated to be a potent monoamine oxidase inhibitor (MAOI) and may cause potentially fatal serotonin toxicity (serotonin syndrome) when combined with serotonin reuptake inhibitors (SRIs). Dextromethorphan increases central serotonin effects. If methylene blue is judged to be indicated, all SRIs, including dextromethorphan, must be ceased prior to treatment/procedure/surgery. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Major) Because of the potential risk and severity of serotonin syndrome, coadministration of dextromethorphan and IV methylene blue should be avoided if possible. Methylene blue has been demonstrated to be a potent monoamine oxidase inhibitor (MAOI) and may cause potentially fatal serotonin toxicity (serotonin syndrome) when combined with serotonin reuptake inhibitors (SRIs). Dextromethorphan increases central serotonin effects. If methylene blue is judged to be indicated, all SRIs, including dextromethorphan, must be ceased prior to treatment/procedure/surgery. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Acetaminophen; Codeine: (Contraindicated) Codeine use in patients taking methylene blue or within 14 days of stopping such treatment is contraindicated due to the risk of serotonin syndrome or opioid toxicity. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses of another opioid to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.
Acetaminophen; Dextromethorphan: (Major) Because of the potential risk and severity of serotonin syndrome, coadministration of dextromethorphan and IV methylene blue should be avoided if possible. Methylene blue has been demonstrated to be a potent monoamine oxidase inhibitor (MAOI) and may cause potentially fatal serotonin toxicity (serotonin syndrome) when combined with serotonin reuptake inhibitors (SRIs). Dextromethorphan increases central serotonin effects. If methylene blue is judged to be indicated, all SRIs, including dextromethorphan, must be ceased prior to treatment/procedure/surgery. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Acetaminophen; Dextromethorphan; Doxylamine: (Major) Because of the potential risk and severity of serotonin syndrome, coadministration of dextromethorphan and IV methylene blue should be avoided if possible. Methylene blue has been demonstrated to be a potent monoamine oxidase inhibitor (MAOI) and may cause potentially fatal serotonin toxicity (serotonin syndrome) when combined with serotonin reuptake inhibitors (SRIs). Dextromethorphan increases central serotonin effects. If methylene blue is judged to be indicated, all SRIs, including dextromethorphan, must be ceased prior to treatment/procedure/surgery. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Major) Because of the potential risk and severity of serotonin syndrome, coadministration of dextromethorphan and IV methylene blue should be avoided if possible. Methylene blue has been demonstrated to be a potent monoamine oxidase inhibitor (MAOI) and may cause potentially fatal serotonin toxicity (serotonin syndrome) when combined with serotonin reuptake inhibitors (SRIs). Dextromethorphan increases central serotonin effects. If methylene blue is judged to be indicated, all SRIs, including dextromethorphan, must be ceased prior to treatment/procedure/surgery. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Acetaminophen; Dextromethorphan; Guaifenesin; Pseudoephedrine: (Major) Because of the potential risk and severity of serotonin syndrome, coadministration of dextromethorphan and IV methylene blue should be avoided if possible. Methylene blue has been demonstrated to be a potent monoamine oxidase inhibitor (MAOI) and may cause potentially fatal serotonin toxicity (serotonin syndrome) when combined with serotonin reuptake inhibitors (SRIs). Dextromethorphan increases central serotonin effects. If methylene blue is judged to be indicated, all SRIs, including dextromethorphan, must be ceased prior to treatment/procedure/surgery. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Acetaminophen; Dextromethorphan; Phenylephrine: (Major) Because of the potential risk and severity of serotonin syndrome, coadministration of dextromethorphan and IV methylene blue should be avoided if possible. Methylene blue has been demonstrated to be a potent monoamine oxidase inhibitor (MAOI) and may cause potentially fatal serotonin toxicity (serotonin syndrome) when combined with serotonin reuptake inhibitors (SRIs). Dextromethorphan increases central serotonin effects. If methylene blue is judged to be indicated, all SRIs, including dextromethorphan, must be ceased prior to treatment/procedure/surgery. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Acetaminophen; Dextromethorphan; Pseudoephedrine: (Major) Because of the potential risk and severity of serotonin syndrome, coadministration of dextromethorphan and IV methylene blue should be avoided if possible. Methylene blue has been demonstrated to be a potent monoamine oxidase inhibitor (MAOI) and may cause potentially fatal serotonin toxicity (serotonin syndrome) when combined with serotonin reuptake inhibitors (SRIs). Dextromethorphan increases central serotonin effects. If methylene blue is judged to be indicated, all SRIs, including dextromethorphan, must be ceased prior to treatment/procedure/surgery. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Acetaminophen; Hydrocodone: (Major) Avoid concomitant use of hydrocodone in patients receiving methylene blue or within 14 days of stopping treatment with methylene blue due to the risk of serotonin syndrome or opioid toxicity, including respiratory depression. If cannot avoid use, choose the lowest possible methylene blue dose and observe the patient closely for up to 4 hours after administration.
Acetaminophen; Oxycodone: (Major) Avoid concomitant use of oxycodone in patients receiving methylene blue or within 14 days of stopping treatment with methylene blue due to the risk of serotonin syndrome or opioid toxicity, including respiratory depression. If cannot avoid use, choose the lowest possible methylene blue dose and observe the patient closely for up to 4 hours after administration.
Alfentanil: (Major) Avoid concomitant use of methylene blue with alfentanil due to risk of serotonin syndrome or opioid toxicity. If cannot avoid use, choose the lowest possible methylene blue dose and observe the patient closely for up to 4 hours after administration. Monitor patients for hypertension and serotonin syndrome and ensure ready availability of vasodilators and beta-blockers for the treatment of hypertension, as needed, if alfentanil is administered to patients who have received methylene blue within 14 days. Do not administer alfentanil within 72 hours of the last dose of methylene blue. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Amitriptyline: (Contraindicated) Per the manufacturer, treatment initiation with amitriptyline is contraindicated in patients currently receiving intravenous (IV) methylene blue due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than amitriptyline (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving amitriptyline and requiring urgent treatment with IV methylene blue, amitriptyline should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits outweigh the risks. The patient should be monitored for serotonin syndrome for 2 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Amitriptyline may be re-initiated 24 hours after the last dose of methylene blue. Results from an in vitro study indicate that methylene blue is a potent, reversible inhibitor of the monoamine oxidase type A enzyme (MAO-A). MAO-A is responsible for the metabolism of serotonin. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent, in patients receiving serotonergic agents. It is not known if patients receiving other serotonergic psychiatric agents with IV methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between IV methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Signs and symptoms of serotonin syndrome include fever, diaphoresis, shivering, myoclonus, tremor, tachycardia, diarrhea, nausea, headache, incoordination, mental status changes (e.g., agitation, confusion), hyperreflexia, seizures, and coma.
Amoxapine: (Moderate) Amoxapine should be used cautiously with intravenous methylene blue. Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin and norepinephrine in the brain (MAO-A). Amoxapine primarily increases the activity of norepinephrine, with in vitro data suggesting an insignificant binding affinity for serotonin. Therefore, the potential for serotonin syndrome during coadministration of amoxapine and methylene blue is unclear. Monitoring for potential increases in blood pressure is advised due to the potential for additive noradrenergic activity.
Amphetamine: (Contraindicated) Amphetamines should not be administered during or within 14 days after the use of methylene blue. Methylene blue is a potent, reversible monoamine oxidase inhibitor (MAOI) which can prolong and intensify the cardiac stimulation and vasopressor effects of amphetamines, potentially resulting in hypertensive crisis. Methylene blue also has the potential to interact with serotonergic agents, such as amphetamines, which may increase the risk for serotonin syndrome. Serotonin syndrome is characterized by mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea), and in rare instances, death. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents, such as amphetamines, with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma.
Amphetamine; Dextroamphetamine: (Contraindicated) Amphetamines should not be administered during or within 14 days after the use of methylene blue. Methylene blue is a potent, reversible monoamine oxidase inhibitor (MAOI) which can prolong and intensify the cardiac stimulation and vasopressor effects of amphetamines, potentially resulting in hypertensive crisis. Methylene blue also has the potential to interact with serotonergic agents, such as amphetamines, which may increase the risk for serotonin syndrome. Serotonin syndrome is characterized by mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea), and in rare instances, death. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents, such as amphetamines, with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma.
Amphetamines: (Contraindicated) Amphetamines should not be administered during or within 14 days after the use of methylene blue. Methylene blue is a potent, reversible monoamine oxidase inhibitor (MAOI) which can prolong and intensify the cardiac stimulation and vasopressor effects of amphetamines, potentially resulting in hypertensive crisis. Methylene blue also has the potential to interact with serotonergic agents, such as amphetamines, which may increase the risk for serotonin syndrome. Serotonin syndrome is characterized by mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea), and in rare instances, death. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents, such as amphetamines, with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma.
Aspirin, ASA; Carisoprodol; Codeine: (Contraindicated) Codeine use in patients taking methylene blue or within 14 days of stopping such treatment is contraindicated due to the risk of serotonin syndrome or opioid toxicity. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses of another opioid to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.
Aspirin, ASA; Oxycodone: (Major) Avoid concomitant use of oxycodone in patients receiving methylene blue or within 14 days of stopping treatment with methylene blue due to the risk of serotonin syndrome or opioid toxicity, including respiratory depression. If cannot avoid use, choose the lowest possible methylene blue dose and observe the patient closely for up to 4 hours after administration.
Benzhydrocodone; Acetaminophen: (Major) The use of benzhydrocodone is not recommended in patients who have received a monoamine oxidase inhibitor (MAOI) within 14 days. Methylene blue is a reversible inhibitor of MAO. Concomitant use of benzhydrocodone with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as benzhydrocodone.
Benzphetamine: (Contraindicated) Amphetamines should not be administered during or within 14 days after the use of methylene blue. Methylene blue is a potent, reversible monoamine oxidase inhibitor (MAOI) which can prolong and intensify the cardiac stimulation and vasopressor effects of amphetamines, potentially resulting in hypertensive crisis. Methylene blue also has the potential to interact with serotonergic agents, such as amphetamines, which may increase the risk for serotonin syndrome. Serotonin syndrome is characterized by mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea), and in rare instances, death. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents, such as amphetamines, with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma.
Bromocriptine: (Moderate) Theoretically, concurrent use of methylene blue and ergot alkaloid derivatives such as bromocriptine may increase the risk of serotonin syndrome. Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A) and ergot alkaloids increase central serotonin effects. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Serotonin syndrome is characterized by rapid development of various symptoms such as hyperthermia, hypertension, myoclonus, rigidity, hyperhidrosis, incoordination, diarrhea, mental status changes (e.g., confusion, delirium, or coma), and in rare cases, death.
Brompheniramine; Dextromethorphan; Phenylephrine: (Major) Because of the potential risk and severity of serotonin syndrome, coadministration of dextromethorphan and IV methylene blue should be avoided if possible. Methylene blue has been demonstrated to be a potent monoamine oxidase inhibitor (MAOI) and may cause potentially fatal serotonin toxicity (serotonin syndrome) when combined with serotonin reuptake inhibitors (SRIs). Dextromethorphan increases central serotonin effects. If methylene blue is judged to be indicated, all SRIs, including dextromethorphan, must be ceased prior to treatment/procedure/surgery. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Brompheniramine; Pseudoephedrine; Dextromethorphan: (Major) Because of the potential risk and severity of serotonin syndrome, coadministration of dextromethorphan and IV methylene blue should be avoided if possible. Methylene blue has been demonstrated to be a potent monoamine oxidase inhibitor (MAOI) and may cause potentially fatal serotonin toxicity (serotonin syndrome) when combined with serotonin reuptake inhibitors (SRIs). Dextromethorphan increases central serotonin effects. If methylene blue is judged to be indicated, all SRIs, including dextromethorphan, must be ceased prior to treatment/procedure/surgery. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Buprenorphine: (Major) Avoid concomitant use of buprenorphine in patients receiving methylene blue or within 14 days of stopping treatment with methylene blue due to the risk of serotonin syndrome or opioid toxicity, including respiratory depression. If cannot avoid use, choose the lowest possible methylene blue dose and observe the patient closely for up to 4 hours after administration.
Buprenorphine; Naloxone: (Major) Avoid concomitant use of buprenorphine in patients receiving methylene blue or within 14 days of stopping treatment with methylene blue due to the risk of serotonin syndrome or opioid toxicity, including respiratory depression. If cannot avoid use, choose the lowest possible methylene blue dose and observe the patient closely for up to 4 hours after administration.
Bupropion: (Contraindicated) Due to an increased risk of hypertensive reactions, treatment initiation with bupropion is contraindicated in patients currently receiving intravenous methylene blue. If urgent psychiatric treatment is required, interventions other than bupropion (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving bupropion and requiring urgent treatment with intravenous methylene blue, bupropion should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits of methylene blue outweigh the risks. The patient should be monitored for hypertensive reactions for two weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Bupropion may be re-initiated 24 hours after the last dose of methylene blue. It is not known if administration of methylene blue by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome.
Bupropion; Naltrexone: (Contraindicated) Due to an increased risk of hypertensive reactions, treatment initiation with bupropion is contraindicated in patients currently receiving intravenous methylene blue. If urgent psychiatric treatment is required, interventions other than bupropion (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving bupropion and requiring urgent treatment with intravenous methylene blue, bupropion should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits of methylene blue outweigh the risks. The patient should be monitored for hypertensive reactions for two weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Bupropion may be re-initiated 24 hours after the last dose of methylene blue. It is not known if administration of methylene blue by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome.
Buspirone: (Moderate) Theoretically, concurrent use of methylene blue and buspirone may increase the risk of serotonin syndrome. Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A) and buspirone increases central serotonin effects. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Serotonin syndrome is characterized by rapid development of various symptoms such as hyperthermia, hypertension, myoclonus, rigidity, hyperhidrosis, incoordination, diarrhea, mental status changes (e.g., confusion, delirium, or coma), and in rare cases, death.
Butalbital; Acetaminophen; Caffeine; Codeine: (Contraindicated) Codeine use in patients taking methylene blue or within 14 days of stopping such treatment is contraindicated due to the risk of serotonin syndrome or opioid toxicity. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses of another opioid to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.
Butalbital; Aspirin; Caffeine; Codeine: (Contraindicated) Codeine use in patients taking methylene blue or within 14 days of stopping such treatment is contraindicated due to the risk of serotonin syndrome or opioid toxicity. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses of another opioid to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.
Capsaicin; Metaxalone: (Moderate) Concomitant use of IV methylene blue and metaxalone may increase the risk for serotonin syndrome. Consult the IV methylene blue product label for management. Monitor patients for serotonin syndrome if concomitant use is necessary.
Celecoxib; Tramadol: (Contraindicated) Tramadol use is contraindicated in patients who are receiving or who have received monoamine oxidase inhibitors (MAOIs) within the previous 14 days. Methylene blue is a reversible inhibitor of MAO. Concomitant use of tramadol with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome or seizures. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as tramadol.
Chlordiazepoxide; Amitriptyline: (Contraindicated) Per the manufacturer, treatment initiation with amitriptyline is contraindicated in patients currently receiving intravenous (IV) methylene blue due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than amitriptyline (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving amitriptyline and requiring urgent treatment with IV methylene blue, amitriptyline should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits outweigh the risks. The patient should be monitored for serotonin syndrome for 2 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Amitriptyline may be re-initiated 24 hours after the last dose of methylene blue. Results from an in vitro study indicate that methylene blue is a potent, reversible inhibitor of the monoamine oxidase type A enzyme (MAO-A). MAO-A is responsible for the metabolism of serotonin. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent, in patients receiving serotonergic agents. It is not known if patients receiving other serotonergic psychiatric agents with IV methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between IV methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Signs and symptoms of serotonin syndrome include fever, diaphoresis, shivering, myoclonus, tremor, tachycardia, diarrhea, nausea, headache, incoordination, mental status changes (e.g., agitation, confusion), hyperreflexia, seizures, and coma.
Chlorpheniramine; Codeine: (Contraindicated) Codeine use in patients taking methylene blue or within 14 days of stopping such treatment is contraindicated due to the risk of serotonin syndrome or opioid toxicity. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses of another opioid to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.
Chlorpheniramine; Dextromethorphan: (Major) Because of the potential risk and severity of serotonin syndrome, coadministration of dextromethorphan and IV methylene blue should be avoided if possible. Methylene blue has been demonstrated to be a potent monoamine oxidase inhibitor (MAOI) and may cause potentially fatal serotonin toxicity (serotonin syndrome) when combined with serotonin reuptake inhibitors (SRIs). Dextromethorphan increases central serotonin effects. If methylene blue is judged to be indicated, all SRIs, including dextromethorphan, must be ceased prior to treatment/procedure/surgery. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Chlorpheniramine; Dextromethorphan; Phenylephrine: (Major) Because of the potential risk and severity of serotonin syndrome, coadministration of dextromethorphan and IV methylene blue should be avoided if possible. Methylene blue has been demonstrated to be a potent monoamine oxidase inhibitor (MAOI) and may cause potentially fatal serotonin toxicity (serotonin syndrome) when combined with serotonin reuptake inhibitors (SRIs). Dextromethorphan increases central serotonin effects. If methylene blue is judged to be indicated, all SRIs, including dextromethorphan, must be ceased prior to treatment/procedure/surgery. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Major) Because of the potential risk and severity of serotonin syndrome, coadministration of dextromethorphan and IV methylene blue should be avoided if possible. Methylene blue has been demonstrated to be a potent monoamine oxidase inhibitor (MAOI) and may cause potentially fatal serotonin toxicity (serotonin syndrome) when combined with serotonin reuptake inhibitors (SRIs). Dextromethorphan increases central serotonin effects. If methylene blue is judged to be indicated, all SRIs, including dextromethorphan, must be ceased prior to treatment/procedure/surgery. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Contraindicated) Dihydrocodeine use in patients taking methylene blue or within 14 days of stopping such treatment is contraindicated due to the risk of serotonin syndrome or opioid toxicity. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses of another opioid to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.
Chlorpheniramine; Hydrocodone: (Major) Avoid concomitant use of hydrocodone in patients receiving methylene blue or within 14 days of stopping treatment with methylene blue due to the risk of serotonin syndrome or opioid toxicity, including respiratory depression. If cannot avoid use, choose the lowest possible methylene blue dose and observe the patient closely for up to 4 hours after administration.
Citalopram: (Contraindicated) According to the manufacturer of citalopram, treatment initiation with citalopram is contraindicated in patients currently receiving intravenous (IV) methylene blue due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than citalopram (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving citalopram and requiring urgent treatment with IV methylene blue, citalopram should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits outweigh the risks. The patient should be monitored for serotonin syndrome for 2 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Citalopram may be re-initiated 24 hours after the last dose of methylene blue. Results from an in vitro study indicate that methylene blue is a potent, reversible inhibitor of the monoamine oxidase type A enzyme (MAO-A). MAO-A is responsible for the metabolism of serotonin; therefore, concurrent use of an MAO-A inhibitor with a serotonergic agent may result in a clinically significant interaction. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent, in patients receiving SSRIs, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with IV methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. One case describes a patient receiving citalopram who experienced agitation, restlessness, pupil dilation with sluggish response to light, myoclonic movements of the lower limbs, and brisk reflexes following an infusion of methylene blue, while another patient receiving paroxetine developed tachycardia, agitation, dystonia and abnormal eye movements. During a retrospective study of 193 surgical patients who had received a methylene blue injection, it was found that all 12 of the patients who experienced postoperative neurological sequelae had been taking a serotonin reuptake inhibitor preoperatively. One of the 12 patients experienced cardiopulmonary arrest and died. Of the remaining 181 patients who did not experience neurological sequelae, 8.8% were taking a serotonin reuptake inhibitor. Published interaction reports between IV methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and coma. Signs and symptoms of serotonin syndrome include fever, diaphoresis, shivering, myoclonus, tremor, tachycardia, diarrhea, nausea, headache, incoordination, mental status changes (e.g., agitation, confusion), hyperreflexia, seizures, and coma.
Clomipramine: (Contraindicated) According to the manufacturer of clomipramine, treatment initiation with clomipramine is contraindicated in patients currently receiving intravenous methylene blue due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than clomipramine (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving clomipramine and requiring urgent treatment with intravenous methylene blue, clomipramine should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits of methylene blue outweigh the risks. The patient should be monitored for serotonin syndrome for two weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Clomipramine may be re-initiated 24 hours after the last dose of methylene blue. Results from an in vitro study indicate that methylene blue is a potent, reversible inhibitor of the monoamine oxidase type A enzyme (MAO-A). MAO-A is responsible for the metabolism of serotonin; therefore, concurrent use of an MAO-A inhibitor with a serotonergic agent may result in a clinically significant interaction. Clomipramine, a tricyclic antidepressant, is the most selective and potent inhibitor of serotonin within its class. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. One case report describes a patient receiving clomipramine who experienced jerky movements in all four limbs, as well as confusion and agitation after intravenous administration of methylene blue, with a return to her pre-operative state by day 4. Although the authors attribute this reaction to methylene blue toxicity, they did not exclude the possibility of a drug interaction based upon previous reports of an interaction between injectable methylene blue and selective serotonin reuptake inhibitors (SSRIs). Published interaction reports between intravenousely administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Signs and symptoms of serotonin syndrome include fever, diaphoresis, shivering, myoclonus, tremor, tachycardia, diarrhea, nausea, headache, incoordination, mental status changes (e.g., agitation, confusion), hyperreflexia, seizures, and coma.
Cocaine: (Moderate) Theoretically, concurrent use of methylene blue and cocaine may increase the risk of serotonin syndrome. Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A) and cocaine increases central serotonin effects. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic agents, like cocaine, with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Serotonin syndrome is characterized by rapid development of various symptoms such as hyperthermia, hypertension, myoclonus, rigidity, hyperhidrosis, incoordination, diarrhea, mental status changes (e.g., confusion, delirium, or coma), and in rare cases, death.
Codeine: (Contraindicated) Codeine use in patients taking methylene blue or within 14 days of stopping such treatment is contraindicated due to the risk of serotonin syndrome or opioid toxicity. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses of another opioid to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.
Codeine; Guaifenesin: (Contraindicated) Codeine use in patients taking methylene blue or within 14 days of stopping such treatment is contraindicated due to the risk of serotonin syndrome or opioid toxicity. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses of another opioid to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.
Codeine; Guaifenesin; Pseudoephedrine: (Contraindicated) Codeine use in patients taking methylene blue or within 14 days of stopping such treatment is contraindicated due to the risk of serotonin syndrome or opioid toxicity. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses of another opioid to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.
Codeine; Phenylephrine; Promethazine: (Contraindicated) Codeine use in patients taking methylene blue or within 14 days of stopping such treatment is contraindicated due to the risk of serotonin syndrome or opioid toxicity. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses of another opioid to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.
Codeine; Promethazine: (Contraindicated) Codeine use in patients taking methylene blue or within 14 days of stopping such treatment is contraindicated due to the risk of serotonin syndrome or opioid toxicity. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses of another opioid to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.
Desipramine: (Contraindicated) According to the manufacturer, treatment initiation with desipramine is contraindicated in patients currently receiving intravenous (IV) methylene blue due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than desipramine (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving desipramine and requiring urgent treatment with IV methylene blue, desipramine should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits outweigh the risks. The patient should be monitored for serotonin syndrome for 2 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Desipramine may be re-initiated 24 hours after the last dose of methylene blue. Results from an in vitro study indicate that methylene blue is a potent, reversible inhibitor of the monoamine oxidase type A enzyme (MAO-A). MAO-A is responsible for the metabolism of serotonin. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent, in patients receiving serotonergic agents. It is not known if patients receiving other serotonergic psychiatric agents with IV methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between IV methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Signs and symptoms of serotonin syndrome include fever, diaphoresis, shivering, myoclonus, tremor, tachycardia, diarrhea, nausea, headache, incoordination, mental status changes (e.g., agitation, confusion), hyperreflexia, seizures, and coma.
Desvenlafaxine: (Contraindicated) Concurrent use of methylene blue and serotonin norepinephrine reuptake inhibitors (SNRIs) (e.g., venlafaxine, duloxetine, desvenlafaxine, milnacipran) should generally be avoided due to the potential for serotonin syndrome. Results from an in vitro study indicate that methylene blue is a potent, reversible inhibitor of the monoamine oxidase type A enzyme (MAO-A). MAO-A is responsible for the metabolism of serotonin; therefore, concurrent use of an MAO-A inhibitor with serotonergic agents such as SNRIs may result in a clinically significant interaction. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, SNRIs, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. One case report suggests that serotonin toxicity may have occurred post-operatively following administration of standard infusions of methylene blue in a patient receiving duloxetine. The patient experienced disorientation, a mildly elevated temperature, tachycardia, elevated blood pressure, mild agitation, and nystagmus. In a separate case, a patient who had been receiving venlafaxine developed expressive aphasia, confusion, and disinhibition following a methylene blue infusion. The authors concluded that methylene blue toxicity had occurred; however, they did not exclude the possibility of a drug interaction based upon previous reports of an interaction between injectable methylene blue and selective serotonin reuptake inhibitors (SSRIs). Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Signs and symptoms of serotonin syndrome include fever, diaphoresis, shivering, myoclonus, tremor, tachycardia, diarrhea, nausea, headache, incoordination, mental status changes (e.g., agitation, confusion), hyperreflexia, seizures, and coma. If emergent treatment with methylene blue is required in a patient receiving an SNRI, the SNRI must be stopped immediately and the patient should be monitored for symptoms of CNS toxicity for two weeks or until 24 hours after the last dose of methylene blue, whichever comes first. During non-emergent use of methylene blue, the SNRI should be stopped at least 2 weeks prior to methylene blue treatment, but also taking into consideration the half-life of the SNRI being discontinued.
Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Major) Because of the potential risk and severity of serotonin syndrome, coadministration of dextromethorphan and IV methylene blue should be avoided if possible. Methylene blue has been demonstrated to be a potent monoamine oxidase inhibitor (MAOI) and may cause potentially fatal serotonin toxicity (serotonin syndrome) when combined with serotonin reuptake inhibitors (SRIs). Dextromethorphan increases central serotonin effects. If methylene blue is judged to be indicated, all SRIs, including dextromethorphan, must be ceased prior to treatment/procedure/surgery. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Dextroamphetamine: (Contraindicated) Amphetamines should not be administered during or within 14 days after the use of methylene blue. Methylene blue is a potent, reversible monoamine oxidase inhibitor (MAOI) which can prolong and intensify the cardiac stimulation and vasopressor effects of amphetamines, potentially resulting in hypertensive crisis. Methylene blue also has the potential to interact with serotonergic agents, such as amphetamines, which may increase the risk for serotonin syndrome. Serotonin syndrome is characterized by mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea), and in rare instances, death. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents, such as amphetamines, with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma.
Dextromethorphan: (Major) Because of the potential risk and severity of serotonin syndrome, coadministration of dextromethorphan and IV methylene blue should be avoided if possible. Methylene blue has been demonstrated to be a potent monoamine oxidase inhibitor (MAOI) and may cause potentially fatal serotonin toxicity (serotonin syndrome) when combined with serotonin reuptake inhibitors (SRIs). Dextromethorphan increases central serotonin effects. If methylene blue is judged to be indicated, all SRIs, including dextromethorphan, must be ceased prior to treatment/procedure/surgery. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Dextromethorphan; Bupropion: (Contraindicated) Due to an increased risk of hypertensive reactions, treatment initiation with bupropion is contraindicated in patients currently receiving intravenous methylene blue. If urgent psychiatric treatment is required, interventions other than bupropion (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving bupropion and requiring urgent treatment with intravenous methylene blue, bupropion should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits of methylene blue outweigh the risks. The patient should be monitored for hypertensive reactions for two weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Bupropion may be re-initiated 24 hours after the last dose of methylene blue. It is not known if administration of methylene blue by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. (Major) Because of the potential risk and severity of serotonin syndrome, coadministration of dextromethorphan and IV methylene blue should be avoided if possible. Methylene blue has been demonstrated to be a potent monoamine oxidase inhibitor (MAOI) and may cause potentially fatal serotonin toxicity (serotonin syndrome) when combined with serotonin reuptake inhibitors (SRIs). Dextromethorphan increases central serotonin effects. If methylene blue is judged to be indicated, all SRIs, including dextromethorphan, must be ceased prior to treatment/procedure/surgery. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Dextromethorphan; Diphenhydramine; Phenylephrine: (Major) Because of the potential risk and severity of serotonin syndrome, coadministration of dextromethorphan and IV methylene blue should be avoided if possible. Methylene blue has been demonstrated to be a potent monoamine oxidase inhibitor (MAOI) and may cause potentially fatal serotonin toxicity (serotonin syndrome) when combined with serotonin reuptake inhibitors (SRIs). Dextromethorphan increases central serotonin effects. If methylene blue is judged to be indicated, all SRIs, including dextromethorphan, must be ceased prior to treatment/procedure/surgery. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Dextromethorphan; Guaifenesin: (Major) Because of the potential risk and severity of serotonin syndrome, coadministration of dextromethorphan and IV methylene blue should be avoided if possible. Methylene blue has been demonstrated to be a potent monoamine oxidase inhibitor (MAOI) and may cause potentially fatal serotonin toxicity (serotonin syndrome) when combined with serotonin reuptake inhibitors (SRIs). Dextromethorphan increases central serotonin effects. If methylene blue is judged to be indicated, all SRIs, including dextromethorphan, must be ceased prior to treatment/procedure/surgery. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Dextromethorphan; Guaifenesin; Phenylephrine: (Major) Because of the potential risk and severity of serotonin syndrome, coadministration of dextromethorphan and IV methylene blue should be avoided if possible. Methylene blue has been demonstrated to be a potent monoamine oxidase inhibitor (MAOI) and may cause potentially fatal serotonin toxicity (serotonin syndrome) when combined with serotonin reuptake inhibitors (SRIs). Dextromethorphan increases central serotonin effects. If methylene blue is judged to be indicated, all SRIs, including dextromethorphan, must be ceased prior to treatment/procedure/surgery. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Dextromethorphan; Guaifenesin; Potassium Guaiacolsulfonate: (Major) Because of the potential risk and severity of serotonin syndrome, coadministration of dextromethorphan and IV methylene blue should be avoided if possible. Methylene blue has been demonstrated to be a potent monoamine oxidase inhibitor (MAOI) and may cause potentially fatal serotonin toxicity (serotonin syndrome) when combined with serotonin reuptake inhibitors (SRIs). Dextromethorphan increases central serotonin effects. If methylene blue is judged to be indicated, all SRIs, including dextromethorphan, must be ceased prior to treatment/procedure/surgery. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Dextromethorphan; Guaifenesin; Pseudoephedrine: (Major) Because of the potential risk and severity of serotonin syndrome, coadministration of dextromethorphan and IV methylene blue should be avoided if possible. Methylene blue has been demonstrated to be a potent monoamine oxidase inhibitor (MAOI) and may cause potentially fatal serotonin toxicity (serotonin syndrome) when combined with serotonin reuptake inhibitors (SRIs). Dextromethorphan increases central serotonin effects. If methylene blue is judged to be indicated, all SRIs, including dextromethorphan, must be ceased prior to treatment/procedure/surgery. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Dextromethorphan; Quinidine: (Major) Because of the potential risk and severity of serotonin syndrome, coadministration of dextromethorphan and IV methylene blue should be avoided if possible. Methylene blue has been demonstrated to be a potent monoamine oxidase inhibitor (MAOI) and may cause potentially fatal serotonin toxicity (serotonin syndrome) when combined with serotonin reuptake inhibitors (SRIs). Dextromethorphan increases central serotonin effects. If methylene blue is judged to be indicated, all SRIs, including dextromethorphan, must be ceased prior to treatment/procedure/surgery. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Dihydroergotamine: (Moderate) Theoretically, concurrent use of methylene blue and ergot alkaloids may increase the risk of serotonin syndrome. Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A) and ergot alkaloids increase central serotonin effects. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Serotonin syndrome is characterized by rapid development of various symptoms such as hyperthermia, hypertension, myoclonus, rigidity, hyperhidrosis, incoordination, diarrhea, mental status changes (e.g., confusion, delirium, or coma), and in rare cases, death.
Dolasetron: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering dolasetron with other drugs that have serotonergic properties such as methylene blue. If serotonin syndrome is suspected, discontinue dolasetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
Doxepin: (Contraindicated) According to the manufacturer, treatment initiation with doxepin is contraindicated in patients currently receiving intravenous (IV) methylene blue due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than doxepin (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving doxepin and requiring urgent treatment with IV methylene blue, doxepin should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits outweigh the risks. The patient should be monitored for serotonin syndrome for 2 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Doxepin may be re-initiated 24 hours after the last dose of methylene blue. Results from an in vitro study indicate that methylene blue is a potent, reversible inhibitor of the monoamine oxidase type A enzyme (MAO-A). MAO-A is responsible for the metabolism of serotonin. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent, in patients receiving serotonergic agents. It is not known if patients receiving other serotonergic psychiatric agents with IV methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between IV methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Signs and symptoms o

f serotonin syndrome include fever, diaphoresis, shivering, myoclonus, tremor, tachycardia, diarrhea, nausea, headache, incoordination, mental status changes (e.g., agitation, confusion), hyperreflexia, seizures, and coma.
Duloxetine: (Contraindicated) Concurrent use of methylene blue and serotonin norepinephrine reuptake inhibitors (SNRIs) (e.g., venlafaxine, duloxetine, desvenlafaxine, milnacipran) should generally be avoided due to the potential for serotonin syndrome. Results from an in vitro study indicate that methylene blue is a potent, reversible inhibitor of the monoamine oxidase type A enzyme (MAO-A). MAO-A is responsible for the metabolism of serotonin; therefore, concurrent use of an MAO-A inhibitor with serotonergic agents such as SNRIs may result in a clinically significant interaction. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, SNRIs, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. One case report suggests that serotonin toxicity may have occurred post-operatively following administration of standard infusions of methylene blue in a patient receiving duloxetine. The patient experienced disorientation, a mildly elevated temperature, tachycardia, elevated blood pressure, mild agitation, and nystagmus. In a separate case, a patient who had been receiving venlafaxine developed expressive aphasia, confusion, and disinhibition following a methylene blue infusion. The authors concluded that methylene blue toxicity had occurred; however, they did not exclude the possibility of a drug interaction based upon previous reports of an interaction between injectable methylene blue and selective serotonin reuptake inhibitors (SSRIs). Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Signs and symptoms of serotonin syndrome include fever, diaphoresis, shivering, myoclonus, tremor, tachycardia, diarrhea, nausea, headache, incoordination, mental status changes (e.g., agitation, confusion), hyperreflexia, seizures, and coma. If emergent treatment with methylene blue is required in a patient receiving an SNRI, the SNRI must be stopped immediately and the patient should be monitored for symptoms of CNS toxicity for two weeks or until 24 hours after the last dose of methylene blue, whichever comes first. During non-emergent use of methylene blue, the SNRI should be stopped at least 2 weeks prior to methylene blue treatment, but also taking into consideration the half-life of the SNRI being discontinued.
Ergoloid Mesylates: (Moderate) Theoretically, concurrent use of methylene blue and ergot alkaloids may increase the risk of serotonin syndrome. Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A) and ergot alkaloids increase central serotonin effects. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Serotonin syndrome is characterized by rapid development of various symptoms such as hyperthermia, hypertension, myoclonus, rigidity, hyperhidrosis, incoordination, diarrhea, mental status changes (e.g., confusion, delirium, or coma), and in rare cases, death.
Ergot alkaloids: (Moderate) Theoretically, concurrent use of methylene blue and ergot alkaloids may increase the risk of serotonin syndrome. Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A) and ergot alkaloids increase central serotonin effects. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Serotonin syndrome is characterized by rapid development of various symptoms such as hyperthermia, hypertension, myoclonus, rigidity, hyperhidrosis, incoordination, diarrhea, mental status changes (e.g., confusion, delirium, or coma), and in rare cases, death.
Ergotamine: (Moderate) Theoretically, concurrent use of methylene blue and ergot alkaloids may increase the risk of serotonin syndrome. Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A) and ergot alkaloids increase central serotonin effects. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Serotonin syndrome is characterized by rapid development of various symptoms such as hyperthermia, hypertension, myoclonus, rigidity, hyperhidrosis, incoordination, diarrhea, mental status changes (e.g., confusion, delirium, or coma), and in rare cases, death.
Ergotamine; Caffeine: (Moderate) Theoretically, concurrent use of methylene blue and ergot alkaloids may increase the risk of serotonin syndrome. Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A) and ergot alkaloids increase central serotonin effects. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Serotonin syndrome is characterized by rapid development of various symptoms such as hyperthermia, hypertension, myoclonus, rigidity, hyperhidrosis, incoordination, diarrhea, mental status changes (e.g., confusion, delirium, or coma), and in rare cases, death.
Escitalopram: (Contraindicated) According to the manufacturer of escitalopram, treatment initiation with escitalopram is contraindicated in patients currently receiving intravenous (IV) methylene blue due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than escitalopram (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving escitalopram and requiring urgent treatment with IV methylene blue, escitalopram should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits outweigh the risks. The patient should be monitored for serotonin syndrome for 2 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Escitalopram may be re-initiated 24 hours after the last dose of methylene blue. Results from an in vitro study indicate that methylene blue is a potent, reversible inhibitor of the monoamine oxidase type A enzyme (MAO-A). MAO-A is responsible for the metabolism of serotonin; therefore, concurrent use of an MAO-A inhibitor with a serotonergic agent may result in a clinically significant interaction. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent, in patients receiving SSRIs, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with IV methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. One case describes a patient receiving citalopram who experienced agitation, restlessness, pupil dilation with sluggish response to light, myoclonic movements of the lower limbs, and brisk reflexes following an infusion of methylene blue, while another patient receiving paroxetine developed tachycardia, agitation, dystonia and abnormal eye movements. During a retrospective study of 193 surgical patients who had received a methylene blue injection, it was found that all 12 of the patients who experienced postoperative neurological sequelae had been taking a serotonin reuptake inhibitor preoperatively. One of the 12 patients experienced cardiopulmonary arrest and died. Of the remaining 181 patients who did not experience neurological sequelae, 8.8% were taking a serotonin reuptake inhibitor. Published interaction reports between IV methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and coma. Signs and symptoms of serotonin syndrome include fever, diaphoresis, shivering, myoclonus, tremor, tachycardia, diarrhea, nausea, headache, incoordination, mental status changes (e.g., agitation, confusion), hyperreflexia, seizures, and coma.
Fenfluramine: (Contraindicated) Coadministration of fenfluramine with monoamine oxidase inhibitors (MAOIs), such as methylene blue, or within 14 days after discontinuation of treatment with methylene blue is contraindicated due to the risk of serotonin syndrome.
Fentanyl: (Major) Avoid concomitant use of fentanyl in patients receiving methylene blue or within 14 days of stopping treatment with methylene blue due to the risk of serotonin syndrome or opioid toxicity, including respiratory depression. If cannot avoid use, choose the lowest possible methylene blue dose and observe the patient closely for up to 4 hours after administration.
Fluoxetine: (Contraindicated) According to the manufacturer of fluoxetine, treatment initiation with fluoxetine is contraindicated in patients currently receiving intravenous (IV) methylene blue due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than fluoxetine (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving fluoxetine and requiring urgent treatment with IV methylene blue, fluoxetine should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits outweigh the risks. The patient should be monitored for serotonin syndrome for 5 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Fluoxetine may be re-initiated 24 hours after the last dose of methylene blue. Results from an in vitro study indicate that methylene blue is a potent, reversible inhibitor of the monoamine oxidase type A enzyme (MAO-A). MAO-A is responsible for the metabolism of serotonin; therefore, concurrent use of an MAO-A inhibitor with a serotonergic agent may result in a clinically significant interaction. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent, in patients receiving SSRIs, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with IV methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. One case describes a patient receiving citalopram who experienced agitation, restlessness, pupil dilation with sluggish response to light, myoclonic movements of the lower limbs, and brisk reflexes following an infusion of methylene blue, while another patient receiving paroxetine developed tachycardia, agitation, dystonia and abnormal eye movements. During a retrospective study of 193 surgical patients who had received a methylene blue injection, it was found that all 12 of the patients who experienced postoperative neurological sequelae had been taking a serotonin reuptake inhibitor preoperatively. One of the 12 patients experienced cardiopulmonary arrest and died. Of the remaining 181 patients who did not experience neurological sequelae, 8.8% were taking a serotonin reuptake inhibitor. Published interaction reports between IV methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and coma. Signs and symptoms of serotonin syndrome include fever, diaphoresis, shivering, myoclonus, tremor, tachycardia, diarrhea, nausea, headache, incoordination, mental status changes (e.g., agitation, confusion), hyperreflexia, seizures, and coma.
Fluvoxamine: (Contraindicated) According to the manufacturer of fluvoxamine, treatment initiation with fluvoxamine is contraindicated in patients currently receiving intravenous (IV) methylene blue due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than fluvoxamine (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving fluvoxamine and requiring urgent treatment with IV methylene blue, fluvoxamine should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits outweigh the risks. The patient should be monitored for serotonin syndrome for 2 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Fluvoxamine may be re-initiated 24 hours after the last dose of methylene blue. MAO-A is responsible for the metabolism of serotonin; therefore, concurrent use of an MAO-A inhibitor with a serotonergic agent may result in a clinically significant interaction. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving SSRIs, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with IV methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. One case describes a patient receiving citalopram who experienced agitation, restlessness, pupil dilation with sluggish response to light, myoclonic movements of the lower limbs, and brisk reflexes following an infusion of methylene blue, while another patient receiving paroxetine developed tachycardia, agitation, dystonia and abnormal eye movements. During a retrospective study of 193 surgical patients who had received a methylene blue injection, it was found that all 12 of the patients who experienced postoperative neurological sequelae had been taking a serotonin reuptake inhibitor preoperatively. One of the 12 patients experienced cardiopulmonary arrest and died. Of the remaining 181 patients who did not experience neurological sequelae, 8.8% were taking a serotonin reuptake inhibitor. Published interaction reports between IV methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and coma. Signs and symptoms of serotonin syndrome include fever, diaphoresis, shivering, myoclonus, tremor, tachycardia, diarrhea, nausea, headache, incoordination, mental status changes (e.g., agitation, confusion), hyperreflexia, seizures, and coma.
Granisetron: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering granisetron with other drugs that have serotonergic properties such as methylene blue. If serotonin syndrome is suspected, discontinue granisetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
Guaifenesin; Hydrocodone: (Major) Avoid concomitant use of hydrocodone in patients receiving methylene blue or within 14 days of stopping treatment with methylene blue due to the risk of serotonin syndrome or opioid toxicity, including respiratory depression. If cannot avoid use, choose the lowest possible methylene blue dose and observe the patient closely for up to 4 hours after administration.
Homatropine; Hydrocodone: (Major) Avoid concomitant use of hydrocodone in patients receiving methylene blue or within 14 days of stopping treatment with methylene blue due to the risk of serotonin syndrome or opioid toxicity, including respiratory depression. If cannot avoid use, choose the lowest possible methylene blue dose and observe the patient closely for up to 4 hours after administration.
Hydrocodone: (Major) Avoid concomitant use of hydrocodone in patients receiving methylene blue or within 14 days of stopping treatment with methylene blue due to the risk of serotonin syndrome or opioid toxicity, including respiratory depression. If cannot avoid use, choose the lowest possible methylene blue dose and observe the patient closely for up to 4 hours after administration.
Hydrocodone; Ibuprofen: (Major) Avoid concomitant use of hydrocodone in patients receiving methylene blue or within 14 days of stopping treatment with methylene blue due to the risk of serotonin syndrome or opioid toxicity, including respiratory depression. If cannot avoid use, choose the lowest possible methylene blue dose and observe the patient closely for up to 4 hours after administration.
Hydrocodone; Pseudoephedrine: (Major) Avoid concomitant use of hydrocodone in patients receiving methylene blue or within 14 days of stopping treatment with methylene blue due to the risk of serotonin syndrome or opioid toxicity, including respiratory depression. If cannot avoid use, choose the lowest possible methylene blue dose and observe the patient closely for up to 4 hours after administration.
Hydromorphone: (Major) Avoid concomitant use of hydromorphone in patients receiving methylene blue or within 14 days of stopping treatment with methylene blue due to the risk of serotonin syndrome or opioid toxicity, including respiratory depression. If cannot avoid use, choose the lowest possible methylene blue dose and observe the patient closely for up to 4 hours after administration. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.
Ibuprofen; Oxycodone: (Major) Avoid concomitant use of oxycodone in patients receiving methylene blue or within 14 days of stopping treatment with methylene blue due to the risk of serotonin syndrome or opioid toxicity, including respiratory depression. If cannot avoid use, choose the lowest possible methylene blue dose and observe the patient closely for up to 4 hours after administration.
Imipramine: (Contraindicated) According to the manufacturer, treatment initiation with imipramine is contraindicated in patients currently receiving intravenous (IV) methylene blue due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than imipramine (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving imipramine and requiring urgent treatment with IV methylene blue, imipramine should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits outweigh the risks. The patient should be monitored for serotonin syndrome for 2 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Imipramine may be re-initiated 24 hours after the last dose of methylene blue. Results from an in vitro study indicate that methylene blue is a potent, reversible inhibitor of the monoamine oxidase type A enzyme (MAO-A). MAO-A is responsible for the metabolism of serotonin. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent, in patients receiving serotonergic agents. It is not known if patients receiving other serotonergic psychiatric agents with IV methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between IV methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Signs and symptoms of serotonin syndrome include fever, diaphoresis, shivering, myoclonus, tremor, tachycardia, diarrhea, nausea, headache, incoordination, mental status changes (e.g., agitation, confusion), hyperreflexia, seizures, and coma.
Isocarboxazid: (Contraindicated) Avoid concomitant use with monoamine oxidase inhibitors (MAOIs); Methylene Blue injection may cause serious or fatal serotonergic syndrome when used in combination with serotonergic drugs. Methylene blue has been demonstrated to be a potent MAOI. Whenever possible, a washout period should elapse between the use of the MAOI and Methylene Blue injection. Patients treated with Methylene Blue injection should be monitored for serotonin syndrome. If symptoms of serotonin syndrome occur, discontinue use, and initiate supportive treatment. Inform patients of the increased risk of serotonin syndrome and advise them to not to take any serotonergic drugs within 72 hours after the last dose of Methylene Blue. If the IV use of Methylene Blue cannot be avoided, choose the lowest possible dose and closely observe the patient for CNS and serotonin-related effects for up to 4 hours after Methylene Blue is given.
Isoniazid, INH: (Major) Concurrent use of methylene blue and drugs that possess MAOI-like activity (e.g., isoniazid, INH) should generally be avoided due to the potential for serotonin syndrome. Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A). Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving serotonergic agents such as selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clompiramine. It is not known if patients receiving intravenous methylene blue with other serotonergic psychiatric agents are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Serotonin syndrome is characterized by rapid development of various symptoms such as hyperthermia, hypertension, myoclonus, rigidity, hyperhidrosis, incoordination, diarrhea, mental status changes (e.g., confusion, delirium, or coma), and in rare cases, death.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Concurrent use of methylene blue and drugs that possess MAOI-like activity (e.g., isoniazid, INH) should generally be avoided due to the potential for serotonin syndrome. Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A). Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving serotonergic agents such as selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clompiramine. It is not known if patients receiving intravenous methylene blue with other serotonergic psychiatric agents are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Serotonin syndrome is characterized by rapid development of various symptoms such as hyperthermia, hypertension, myoclonus, rigidity, hyperhidrosis, incoordination, diarrhea, mental status changes (e.g., confusion, delirium, or coma), and in rare cases, death.
Isoniazid, INH; Rifampin: (Major) Concurrent use of methylene blue and drugs that possess MAOI-like activity (e.g., isoniazid, INH) should generally be avoided due to the potential for serotonin syndrome. Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A). Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving serotonergic agents such as selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clompiramine. It is not known if patients receiving intravenous methylene blue with other serotonergic psychiatric agents are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Serotonin syndrome is characterized by rapid development of various symptoms such as hyperthermia, hypertension, myoclonus, rigidity, hyperhidrosis, incoordination, diarrhea, mental status changes (e.g., confusion, delirium, or coma), and in rare cases, death.
Lasmiditan: (Moderate) Serotonin syndrome may occur during coadministration of lasmiditan and methylene blue. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management.
Levomilnacipran: (Contraindicated) Concurrent use of methylene blue and serotonin norepinephrine reuptake inhibitors (SNRIs) (e.g., venlafaxine, duloxetine, desvenlafaxine, milnacipran) should generally be avoided due to the potential for serotonin syndrome. Results from an in vitro study indicate that methylene blue is a potent, reversible inhibitor of the monoamine oxidase type A enzyme (MAO-A). MAO-A is responsible for the metabolism of serotonin; therefore, concurrent use of an MAO-A inhibitor with serotonergic agents such as SNRIs may result in a clinically significant interaction. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, SNRIs, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. One case report suggests that serotonin toxicity may have occurred post-operatively following administration of standard infusions of methylene blue in a patient receiving duloxetine. The patient experienced disorientation, a mildly elevated temperature, tachycardia, elevated blood pressure, mild agitation, and nystagmus. In a separate case, a patient who had been receiving venlafaxine developed expressive aphasia, confusion, and disinhibition following a methylene blue infusion. The authors concluded that methylene blue toxicity had occurred; however, they did not exclude the possibility of a drug interaction based upon previous reports of an interaction between injectable methylene blue and selective serotonin reuptake inhibitors (SSRIs). Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Signs and symptoms of serotonin syndrome include fever, diaphoresis, shivering, myoclonus, tremor, tachycardia, diarrhea, nausea, headache, incoordination, mental status changes (e.g., agitation, confusion), hyperreflexia, seizures, and coma. If emergent treatment with methylene blue is required in a patient receiving an SNRI, the SNRI must be stopped immediately and the patient should be monitored for symptoms of CNS toxicity for two weeks or until 24 hours after the last dose of methylene blue, whichever comes first. During non-emergent use of methylene blue, the SNRI should be stopped at least 2 weeks prior to methylene blue treatment, but also taking into consideration the half-life of the SNRI being discontinued.
Levorphanol: (Major) Avoid concomitant use of methylene blue with levorphanol due to risk of serotonin syndrome. If cannot avoid use, choose the lowest possible methylene blue dose and observe the patient closely for up to 4 hours after administration. Do not administer levorphanol within 72 hours of the last dose of methylene blue.
Linezolid: (Major) Concurrent use of methylene blue and medications with serotonergic effects, such as linezolid, should be avoided if possible. Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A) and linezolid is an antibiotic with reversible, non-selective MAO inhibitor activity. Since MAO type A deaminates serotonin, administration of linezolid concurrently with another agent with MAO-A inhibiting activity can potentially increase serotonin. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonergic agents. It is not known if patients receiving intravenous methylene blue with linezolid are at a comparable risk. Serotonin syndrome is characterized by rapid development of various symptoms such as hyperthermia, hypertension, myoclonus, rigidity, hyperhidrosis, incoordination, diarrhea, mental status changes (e.g., confusion, delirium, or coma), and in rare cases, death.
Lisdexamfetamine: (Contraindicated) Amphetamines should not be administered during or within 14 days after the use of methylene blue. Methylene blue is a potent, reversible monoamine oxidase inhibitor (MAOI) which can prolong and intensify the cardiac stimulation and vasopressor effects of amphetamines, potentially resulting in hypertensive crisis. Methylene blue also has the potential to interact with serotonergic agents, such as amphetamines, which may increase the risk for serotonin syndrome. Serotonin syndrome is characterized by mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea), and in rare instances, death. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents, such as amphetamines, with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma.
Lithium: (Major) Theoretically, concurrent use of methylene blue and lithium may increase the risk of serotonin syndrome. Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A) and lithium is thought to increase central serotonin effects by various mechanisms. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other psychiatric serotonergic agents with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Serotonin syndrome is characterized by rapid development of various symptoms such as hyperthermia, hypertension, myoclonus, rigidity, hyperhidrosis, incoordination, diarrhea, mental status changes (e.g., confusion, delirium, or coma), and in rare cases, death. If serotonin syndrome is suspected, serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
Lorcaserin: (Major) Theoretically, concurrent use of methylene blue and lorcaserin may increase the risk of serotonin syndrome. Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A) and lorcaserin increases central serotonin effects). Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Serotonin syndrome is characterized by rapid development of various symptoms such as hyperthermia, hypertension, myoclonus, rigidity, hyperhidrosis, incoordination, diarrhea, mental status changes (e.g., confusion, delirium, or coma), and in rare cases, death.
Maprotiline: (Moderate) Maprotiline should be used cautiously with intravenous methylene blue. Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin and norepinephrine in the brain (MAO-A). Maprotiline is a selective norepinephrine reuptake inhibitor. Therefore, the potential for serotonin syndrome during coadministration of maprotiline and methylene blue is unclear. Monitoring for potential increases in blood pressure is advised.
Meperidine: (Contraindicated) Meperidine use in patients taking methylene blue or within 14 days of stopping such treatment is contraindicated due to the risk of serotonin syndrome or precipitation of other unpredictable, severe, and occasionally fatal reactions, possibly related to preexisting hyperphenylalaninemia.
Metaxalone: (Moderate) Concomitant use of IV methylene blue and metaxalone may increase the risk for serotonin syndrome. Consult the IV methylene blue product label for management. Monitor patients for serotonin syndrome if concomitant use is necessary.
Methadone: (Major) Avoid concomitant use of methadone in patients receiving methylene blue or within 14 days of stopping treatment with methylene blue due to the risk of serotonin syndrome or opioid toxicity, including respiratory depression. If cannot avoid use, choose the lowest possible methylene blue dose and observe the patient closely for up to 4 hours after administration.
Methamphetamine: (Contraindicated) Amphetamines should not be administered during or within 14 days after the use of methylene blue. Methylene blue is a potent, reversible monoamine oxidase inhibitor (MAOI) which can prolong and intensify the cardiac stimulation and vasopressor effects of amphetamines, potentially resulting in hypertensive crisis. Methylene blue also has the potential to interact with serotonergic agents, such as amphetamines, which may increase the risk for serotonin syndrome. Serotonin syndrome is characterized by mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea), and in rare instances, death. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents, such as amphetamines, with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma.
Methoxsalen: (Moderate) Use methoxsalen and methylene blue together with caution; the risk of severe burns/photosensitivity may be additive. If concurrent use is necessary, closely monitor patients for signs or symptoms of skin toxicity.
Methylergonovine: (Moderate) Theoretically, concurrent use of methylene blue and ergot alkaloids may increase the risk of serotonin syndrome. Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A) and ergot alkaloids increase central serotonin effects. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Serotonin syndrome is characterized by rapid development of various symptoms such as hyperthermia, hypertension, myoclonus, rigidity, hyperhidrosis, incoordination, diarrhea, mental status changes (e.g., confusion, delirium, or coma), and in rare cases, death.
Methylphenidate Derivatives: (Moderate) Theoretically, concurrent use of methylene blue and methylphenidate derivatives may increase the risk of serotonin syndrome. Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A) and methylphenidate increases central serotonin effects. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Serotonin syndrome is characterized by the rapid development of various symptoms such as hyperthermia, hypertension, myoclonus, rigidity, hyperhidrosis, incoordination, diarrhea, mental status changes (e.g., confusion, delirium, or coma), and in rare cases, death. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical management should be implemented.
Milnacipran: (Contraindicated) Concurrent use of methylene blue and serotonin norepinephrine reuptake inhibitors (SNRIs) (e.g., venlafaxine, duloxetine, desvenlafaxine, milnacipran) should generally be avoided due to the potential for serotonin syndrome. Results from an in vitro study indicate that methylene blue is a potent, reversible inhibitor of the monoamine oxidase type A enzyme (MAO-A). MAO-A is responsible for the metabolism of serotonin; therefore, concurrent use of an MAO-A inhibitor with serotonergic agents such as SNRIs may result in a clinically significant interaction. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, SNRIs, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. One case report suggests that serotonin toxicity may have occurred post-operatively following administration of standard infusions of methylene blue in a patient receiving duloxetine. The patient experienced disorientation, a mildly elevated temperature, tachycardia, elevated blood pressure, mild agitation, and nystagmus. In a separate case, a patient who had been receiving venlafaxine developed expressive aphasia, confusion, and disinhibition following a methylene blue infusion. The authors concluded that methylene blue toxicity had occurred; however, they did not exclude the possibility of a drug interaction based upon previous reports of an interaction between injectable methylene blue and selective serotonin reuptake inhibitors (SSRIs). Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Signs and symptoms of serotonin syndrome include fever, diaphoresis, shivering, myoclonus, tremor, tachycardia, diarrhea, nausea, headache, incoordination, mental status changes (e.g., agitation, confusion), hyperreflexia, seizures, and coma. If emergent treatment with methylene blue is required in a patient receiving an SNRI, the SNRI must be stopped immediately and the patient should be monitored for symptoms of CNS toxicity for two weeks or until 24 hours after the last dose of methylene blue, whichever comes first. During non-emergent use of methylene blue, the SNRI should be stopped at least 2 weeks prior to methylene blue treatment, but also taking into consideration the half-life of the SNRI being discontinued.
Mirtazapine: (Contraindicated) According to the manufacturer of mirtazapine, treatment initiation with mirtazapine is contraindicated in patients currently receiving intravenous methylene blue due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than mirtazapine (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving mirtazapine and requiring urgent treatment with intravenous methylene blue, mirtazapine should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits of methylene blue outweigh the risks. The patient should be monitored for serotonin syndrome for 2 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Mirtazapine may be re-initiated 24 hours after the last dose of methylene blue Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A) and mirtazapine increases central serotonin effects. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving serotonergic agents such as selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving intravenous methylene blue with other serotonergic psychiatric agents are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Serotonin syndrome is characterized by rapid development of various symptoms such as hyperthermia, hypertension, myoclonus, rigidity, hyperhidrosis, incoordination, diarrhea, mental status changes (e.g., confusion, delirium, or coma), and in rare cases, death.
Monoamine oxidase inhibitors: (Contraindicated) Avoid concomitant use with monoamine oxidase inhibitors (MAOIs); Methylene Blue injection may cause serious or fatal serotonergic syndrome when used in combination with serotonergic drugs. Methylene blue has been demonstrated to be a potent MAOI. Whenever possible, a washout period should elapse between the use of the MAOI and Methylene Blue injection. Patients treated with Methylene Blue injection should be monitored for serotonin syndrome. If symptoms of serotonin syndrome occur, discontinue use, and initiate supportive treatment. Inform patients of the increased risk of serotonin syndrome and advise them to not to take any serotonergic drugs within 72 hours after the last dose of Methylene Blue. If the IV use of Methylene Blue cannot be avoided, choose the lowest possible dose and closely observe the patient for CNS and serotonin-related effects for up to 4 hours after Methylene Blue is given.
Morphine: (Contraindicated) Morphine use in patients taking methylene blue or within 14 days of stopping such treatment is contraindicated due to the risk of serotonin syndrome or opioid toxicity.
Morphine; Naltrexone: (Contraindicated) Morphine use in patients taking methylene blue or within 14 days of stopping such treatment is contraindicated due to the risk of serotonin syndrome or opioid toxicity.
Nalbuphine: (Major) Avoid concomitant use of nalbuphine in patients receiving methylene blue or within 14 days of stopping treatment with methylene blue due to the risk of serotonin syndrome or opioid toxicity, including respiratory depression. If cannot avoid use, choose the lowest possible methylene blue dose and observe the patient closely for up to 4 hours after administration. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.
Nefazodone: (Major) Concurrent use of intravenous methylene blue with nefazodone may increase the risk of serotonin syndrome. Methylene blue is a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A) and nefazodone increases central serotonin effects. Cases of serotonin syndrome have been reported with IV methylene blue given as a visualizing agent in patients receiving serotonergic agents like SSRIs, SNRIs, and clomipramine. It is not known if patients receiving other serotonergic psychiatric agents are at a comparable risk. Serotonin syndrome is characterized by rapid development of various symptoms such as hyperthermia, hypertension, myoclonus, rigidity, hyperhidrosis, incoordination, diarrhea, mental status changes (e.g., confusion, delirium, or coma), and in rare cases, death. For patients requiring urgent treatment with IV methylene blue, it may be wise to discontinue nefazodone and monitor the patient until 24 hours after the last dose of methylene blue IV; nefazodone can then be re-initiated 24 hours after the last dose of methylene blue.
Netupitant, Fosnetupitant; Palonosetron: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering palonosetron with other drugs that have serotonergic properties such as methylene blue. If serotonin syndrome is suspected, discontinue palonosetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
Nortriptyline: (Contraindicated) According to the manufacturer of nortriptyline, treatment initiation with nortriptyline is contraindicated in patients currently receiving intravenous (IV) methylene blue due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than nortriptyline (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving nortriptyline and requiring urgent treatment with IV methylene blue, nortriptyline should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits outweigh the risks. The patient should be monitored for serotonin syndrome for 2 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Nortriptyline may be re-initiated 24 hours after the last dose of methylene blue. Results from an in vitro study indicate that methylene blue is a potent, reversible inhibitor of the monoamine oxidase type A enzyme (MAO-A). MAO-A is responsible for the metabolism of serotonin. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent, in patients receiving serotonergic agents. It is not known if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between IV methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Signs and symptoms of serotonin syndrome include fever, diaphoresis, shivering, myoclonus, tremor, tachycardia, diarrhea, nausea, headache, incoordination, mental status changes (e.g., agitation, confusion), hyperreflexia, seizures, and coma.
Olanzapine; Fluoxetine: (Contraindicated) According to the manufacturer of fluoxetine, treatment initiation with fluoxetine is contraindicated in patients currently receiving intravenous (IV) methylene blue due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than fluoxetine (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving fluoxetine and requiring urgent treatment with IV methylene blue, fluoxetine should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits outweigh the risks. The patient should be monitored for serotonin syndrome for 5 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Fluoxetine may be re-initiated 24 hours after the last dose of methylene blue. Results from an in vitro study indicate that methylene blue is a potent, reversible inhibitor of the monoamine oxidase type A enzyme (MAO-A). MAO-A is responsible for the metabolism of serotonin; therefore, concurrent use of an MAO-A inhibitor with a serotonergic agent may result in a clinically significant interaction. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent, in patients receiving SSRIs, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with IV methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. One case describes a patient receiving citalopram who experienced agitation, restlessness, pupil dilation with sluggish response to light, myoclonic movements of the lower limbs, and brisk reflexes following an infusion of methylene blue, while another patient receiving paroxetine developed tachycardia, agitation, dystonia and abnormal eye movements. During a retrospective study of 193 surgical patients who had received a methylene blue injection, it was found that all 12 of the patients who experienced postoperative neurological sequelae had been taking a serotonin reuptake inhibitor preoperatively. One of the 12 patients experienced cardiopulmonary arrest and died. Of the remaining 181 patients who did not experience neurological sequelae, 8.8% were taking a serotonin reuptake inhibitor. Published interaction reports between IV methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and coma. Signs and symptoms of serotonin syndrome include fever, diaphoresis, shivering, myoclonus, tremor, tachycardia, diarrhea, nausea, headache, incoordination, mental status changes (e.g., agitation, confusion), hyperreflexia, seizures, and coma.
Oliceridine: (Moderate) If concomitant use of oliceridine and methylene blue is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Ondansetron: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering ondansetron with other drugs that have serotonergic properties such as methylene blue. If serotonin syndrome is suspected, discontinue ondansetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
Oxycodone: (Major) Avoid concomitant use of oxycodone in patients receiving methylene blue or within 14 days of stopping treatment with methylene blue due to the risk of serotonin syndrome or opioid toxicity, including respiratory depression. If cannot avoid use, choose the lowest possible methylene blue dose and observe the patient closely for up to 4 hours after administration.
Oxymorphone: (Major) Avoid concomitant use of oxymorphone in patients receiving methylene blue or within 14 days of stopping treatment with methylene blue due to the risk of serotonin syndrome or opioid toxicity, including respiratory depression. If cannot avoid use, choose the lowest possible methylene blue dose and observe the patient closely for up to 4 hours after administration.
Ozanimod: (Major) Concurrent use of intravenous (IV) methylene blue and drugs with selective MAOI activity, such as ozanimod, should generally be avoided due to the potential for serotonin syndrome. If emergent treatment with methylene blue is required in a patient receiving an MAOI it is advisable to discontinue the MAOI and monitor the patient for symptoms of CNS toxicity for two weeks or until 24 hours after the last dose of methylene blue, whichever comes first. During non-emergent use of methylene blue, it is advisable to discontinue ozanimod at least 2 weeks prior to methylene blue treatment, taking into consideration the half-life of ozanimod. Because the metabolites of ozanimod inhibit primarily monoamine oxidase-B (MAO-B), an interaction may be less likely to occur than with other traditional MAOIs. Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the c atabolism of serotonin in the brain (MAO-A). Cases of serotonin syndrome have been reported, primarily following administration of IV methylene blue (1 to 8 mg/kg) as a visualizing agent in patients receiving serotonergic agents.
Palonosetron: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering palonosetron with other drugs that have serotonergic properties such as methylene blue. If serotonin syndrome is suspected, discontinue palonosetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
Paroxetine: (Contraindicated) According to the manufacturer of paroxetine, treatment initiation with paroxetine is contraindicated in patients currently receiving intravenous (IV) methylene blue due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than paroxetine (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving paroxetine and requiring urgent treatment with IV methylene blue, paroxetine should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits outweigh the risks. The patient should be monitored for serotonin syndrome for 2 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Paroxetine may be re-initiated 24 hours after the last dose of methylene blue. Results from an in vitro study indicate that methylene blue is a potent, reversible inhibitor of the monoamine oxidase type A enzyme (MAO-A). MAO-A is responsible for the metabolism of serotonin; therefore, concurrent use of an MAO-A inhibitor with a serotonergic agent may result in a clinically significant interaction. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent, in patients receiving SSRIs, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with IV methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. One case describes a patient receiving citalopram who experienced agitation, restlessness, pupil dilation with sluggish response to light, myoclonic movements of the lower limbs, and brisk reflexes following an infusion of methylene blue, while another patient receiving paroxetine developed tachycardia, agitation, dystonia and abnormal eye movements. During a retrospective study of 193 surgical patients who had received a methylene blue injection, it was found that all 12 of the patients who experienced postoperative neurological sequelae had been taking a serotonin reuptake inhibitor preoperatively. One of the 12 patients experienced cardiopulmonary arrest and died. Of the remaining 181 patients who did not experience neurological sequelae, 8.8% were taking a serotonin reuptake inhibitor. Published interaction reports between IV methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and coma. Signs and symptoms of serotonin syndrome include fever, diaphoresis, shivering, myoclonus, tremor, tachycardia, diarrhea, nausea, headache, incoordination, mental status changes (e.g., agitation, confusion), hyperreflexia, seizures, and coma.
Pentazocine: (Moderate) Theoretically, concurrent use of methylene blue and pentazocine may increase the risk of serotonin syndrome. Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A) and pentazocine increases central serotonin effects. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Serotonin syndrome is characterized by rapid development of various symptoms such as hyperthermia, hypertension, myoclonus, rigidity, hyperhidrosis, incoordination, diarrhea, mental status changes (e.g., confusion, delirium, or coma), and in rare cases, death.
Pentazocine; Naloxone: (Moderate) Theoretically, concurrent use of methylene blue and pentazocine may increase the risk of serotonin syndrome. Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A) and pentazocine increases central serotonin effects. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Serotonin syndrome is characterized by rapid development of various symptoms such as hyperthermia, hypertension, myoclonus, rigidity, hyperhidrosis, incoordination, diarrhea, mental status changes (e.g., confusion, delirium, or coma), and in rare cases, death.
Perphenazine; Amitriptyline: (Contraindicated) Per the manufacturer, treatment initiation with amitriptyline is contraindicated in patients currently receiving intravenous (IV) methylene blue due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than amitriptyline (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving amitriptyline and requiring urgent treatment with IV methylene blue, amitriptyline should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits outweigh the risks. The patient should be monitored for serotonin syndrome for 2 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Amitriptyline may be re-initiated 24 hours after the last dose of methylene blue. Results from an in vitro study indicate that methylene blue is a potent, reversible inhibitor of the monoamine oxidase type A enzyme (MAO-A). MAO-A is responsible for the metabolism of serotonin. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent, in patients receiving serotonergic agents. It is not known if patients receiving other serotonergic psychiatric agents with IV methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between IV methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Signs and symptoms of serotonin syndrome include fever, diaphoresis, shivering, myoclonus, tremor, tachycardia, diarrhea, nausea, headache, incoordination, mental status changes (e.g., agitation, confusion), hyperreflexia, seizures, and coma.
Phenelzine: (Contraindicated) Avoid concomitant use with monoamine oxidase inhibitors (MAOIs); Methylene Blue injection may cause serious or fatal serotonergic syndrome when used in combination with serotonergic drugs. Methylene blue has been demonstrated to be a potent MAOI. Whenever possible, a washout period should elapse between the use of the MAOI and Methylene Blue injection. Patients treated with Methylene Blue injection should be monitored for serotonin syndrome. If symptoms of serotonin syndrome occur, discontinue use, and initiate supportive treatment. Inform patients of the increased risk of serotonin syndrome and advise them to not to take any serotonergic drugs within 72 hours after the last dose of Methylene Blue. If the IV use of Methylene Blue cannot be avoided, choose the lowest possible dose and closely observe the patient for CNS and serotonin-related effects for up to 4 hours after Methylene Blue is given.
Porfimer: (Major) Avoid coadministration of porfimer with methylene blue due to the risk of increased photosensitivity. All patients treated with porfimer will be photosensitive. Concomitant use of other photosensitizing agents like methylene blue may increase the risk of a photosensitivity reaction.
Procarbazine: (Major) Concurrent use of methylene blue and MAOIs or drugs that possess MAOI-like activity (e.g., procarbazine) should generally be avoided due to the potential for serotonin syndrome. Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A). Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving serotonergic agents such as selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clompiramine. It is not known if patients receiving intravenous methylene blue with other serotonergic psychiatric agents are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Serotonin syndrome is characterized by rapid development of various symptoms such as hyperthermia, hypertension, myoclonus, rigidity, hyperhidrosis, incoordination, diarrhea, mental status changes (e.g., confusion, delirium, or coma), and in rare cases, death.
Promethazine; Dextromethorphan: (Major) Because of the potential risk and severity of serotonin syndrome, coadministration of dextromethorphan and IV methylene blue should be avoided if possible. Methylene blue has been demonstrated to be a potent monoamine oxidase inhibitor (MAOI) and may cause potentially fatal serotonin toxicity (serotonin syndrome) when combined with serotonin reuptake inhibitors (SRIs). Dextromethorphan increases central serotonin effects. If methylene blue is judged to be indicated, all SRIs, including dextromethorphan, must be ceased prior to treatment/procedure/surgery. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Protriptyline: (Contraindicated) According to the manufacturer, treatment initiation with protriptyline is contraindicated in patients currently receiving intravenous (IV) methylene blue due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than protriptyline (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving protriptyline and requiring urgent treatment with IV methylene blue, protriptyline should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits outweigh the risks. The patient should be monitored for serotonin syndrome for 2 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Protriptyline may be re-initiated 24 hours after the last dose of methylene blue. Results from an in vitro study indicate that methylene blue is a potent, reversible inhibitor of the monoamine oxidase type A enzyme (MAO-A). MAO-A is responsible for the metabolism of serotonin. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent, in patients receiving serotonergic agents. It is not known if patients receiving other serotonergic psychiatric agents with IV methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between IV methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Signs and symptoms of serotonin syndrome include fever, diaphoresis, shivering, myoclonus, tremor, tachycardia, diarrhea, nausea, headache, incoordination, mental status changes (e.g., agitation, confusion), hyperreflexia, seizures, and coma.
Rasagiline: (Major) Concurrent use of intravenous (IV) methylene blue and MAOIs such as rasagiline should generally be avoided due to the potential for serotonin syndrome. If emergent treatment with methylene blue is required in a patient receiving an MAOI it is advisable to discontinue the MAOI and monitor the patient for symptoms of CNS toxicity for two weeks or until 24 hours after the last dose of methylene blue, whichever comes first. During non-emergent use of methylene blue, it is advisable to discontinue the MAOI at least 2 weeks prior to methylene blue treatment, but also taking into consideration the half-life of the MAOI being discontinued. Because rasagiline is a selective monoamine oxidase-B (MAO-B) inhibitor at manufacturer recommended doses, an interaction may be less likely to occur than with other traditional MAOIs. Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A). Cases of serotonin syndrome have been reported, primarily following administration of IV methylene blue (1 to 8 mg/kg) as a visualizing agent in patients receiving serotonergic agents.
Remifentanil: (Major) Avoid concomitant use of remifentanil in patients receiving methylene blue or within 14 days of stopping treatment with methylene blue due to the risk of serotonin syndrome or opioid toxicity, including respiratory depression. If cannot avoid use, choose the lowest possible methylene blue dose and observe the patient closely for up to 4 hours after administration.
Safinamide: (Major) Concurrent use of intravenous (IV) methylene blue and MAOIs such as safinamide should generally be avoided due to the potential for serotonin syndrome. If emergent treatment with methylene blue is required in a patient receiving an MAOI it is advisable to discontinue the MAOI and monitor the patient for symptoms of CNS toxicity for two weeks or until 24 hours after the last dose of methylene blue, whichever comes first. During non-emergent use of methylene blue, it is advisable to discontinue the MAOI at least 2 weeks prior to methylene blue treatment, but also taking into consideration the half-life of the MAOI being discontinued. Because safinamide is a selective monoamine oxidase-B (MAO-B) inhibitor at manufacturer recommended doses, an interaction may be less likely to occur than with other traditional MAOIs. Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A). Cases of serotonin syndrome have been reported, primarily following administration of IV methylene blue (1 to 8 mg/kg) as a visualizing agent in patients receiving serotonergic agents.
Selegiline: (Major) Concurrent use of intravenous (IV) methylene blue and MAOIs such as selegiline should generally be avoided due to the potential for serotonin syndrome. If emergent treatment with methylene blue is required in a patient receiving an MAOI, it is advisable to discontinue the MAOI and monitor the patient for symptoms of CNS toxicity for two weeks or until 24 hours after the last dose of methylene blue, whichever comes first. During non-emergent use of methylene blue, it is advisable to discontinue the MAOI at least 2 weeks prior to methylene blue treatment, but also taking into consideration the half-life of selegiline. Because selegiline is a selective monoamine oxidase-B (MAO-B) inhibitor, an interaction may be less likely to occur than with other traditional MAOIs. Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A). Cases of serotonin syndrome have been reported, primarily following administration of IV methylene blue (1 to 8 mg/kg) as a visualizing agent in patients receiving serotonergic agents.
Serotonin norepinephrine reuptake inhibitors: (Contraindicated) Concurrent use of methylene blue and serotonin norepinephrine reuptake inhibitors (SNRIs) (e.g., venlafaxine, duloxetine, desvenlafaxine, milnacipran) should generally be avoided due to the potential for serotonin syndrome. Results from an in vitro study indicate that methylene blue is a potent, reversible inhibitor of the monoamine oxidase type A enzyme (MAO-A). MAO-A is responsible for the metabolism of serotonin; therefore, concurrent use of an MAO-A inhibitor with serotonergic agents such as SNRIs may result in a clinically significant interaction. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, SNRIs, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. One case report suggests that serotonin toxicity may have occurred post-operatively following administration of standard infusions of methylene blue in a patient receiving duloxetine. The patient experienced disorientation, a mildly elevated temperature, tachycardia, elevated blood pressure, mild agitation, and nystagmus. In a separate case, a patient who had been receiving venlafaxine developed expressive aphasia, confusion, and disinhibition following a methylene blue infusion. The authors concluded that methylene blue toxicity had occurred; however, they did not exclude the possibility of a drug interaction based upon previous reports of an interaction between injectable methylene blue and selective serotonin reuptake inhibitors (SSRIs). Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Signs and symptoms of serotonin syndrome include fever, diaphoresis, shivering, myoclonus, tremor, tachycardia, diarrhea, nausea, headache, incoordination, mental status changes (e.g., agitation, confusion), hyperreflexia, seizures, and coma. If emergent treatment with methylene blue is required in a patient receiving an SNRI, the SNRI must be stopped immediately and the patient should be monitored for symptoms of CNS toxicity for two weeks or until 24 hours after the last dose of methylene blue, whichever comes first. During non-emergent use of methylene blue, the SNRI should be stopped at least 2 weeks prior to methylene blue treatment, but also taking into consideration the half-life of the SNRI being discontinued.
Serotonin-Receptor Agonists: (Major) Theoretically, concurrent use of methylene blue and serotonin-receptor agonists may increase the risk of serotonin syndrome. Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A) and serotonin-receptor agonists increase central serotonin effects. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic agents with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Serotonin syndrome is characterized by rapid development of various symptoms such as hyperthermia, hypertension, myoclonus, rigidity, hyperhidrosis, incoordination, diarrhea, mental status changes (e.g., confusion, delirium, or coma), and in rare cases, death.
Sertraline: (Contraindicated) According to the manufacturer of sertraline, treatment initiation with sertraline is contraindicated in patients currently receiving intravenous (IV) methylene blue due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than sertraline (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving sertraline and requiring urgent treatment with IV methylene blue, sertraline should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits outweigh the risks. The patient should be monitored for serotonin syndrome for 2 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Sertraline may be re-initiated 24 hours after the last dose of methylene blue. Results from an in vitro study indicate that methylene blue is a potent, reversible inhibitor of the monoamine oxidase type A enzyme (MAO-A). MAO-A is responsible for the metabolism of serotonin; therefore, concurrent use of an MAO-A inhibitor with a serotonergic agent may result in a clinically significant interaction. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent, in patients receiving SSRIs, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with IV methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. One case describes a patient receiving citalopram who experienced agitation, restlessness, pupil dilation with sluggish response to light, myoclonic movements of the lower limbs, and brisk reflexes following an infusion of methylene blue, while another patient receiving paroxetine developed tachycardia, agitation, dystonia and abnormal eye movements. During a retrospective study of 193 surgical patients who had received a methylene blue injection, it was found that all 12 of the patients who experienced postoperative neurological sequelae had been taking a serotonin reuptake inhibitor preoperatively. One of the 12 patients experienced cardiopulmonary arrest and died. Of the remaining 181 patients who did not experience neurological sequelae, 8.8% were taking a serotonin reuptake inhibitor. Published interaction reports between IV methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and coma. Signs and symptoms of serotonin syndrome include fever, diaphoresis, shivering, myoclonus, tremor, tachycardia, diarrhea, nausea, headache, incoordination, mental status changes (e.g., agitation, confusion), hyperreflexia, seizures, and coma.
St. John's Wort, Hypericum perforatum: (Contraindicated) Concurrent use of methylene blue and St. John's Wort, hypericum perforatum should generally be avoided due to the potential for serotonin syndrome. Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A) and St. John's Wort increases central serotonin effects. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Serotonin syndrome is characterized by rapid development of various symptoms such as hyperthermia, hypertension, myoclonus, rigidity, hyperhidrosis, incoordination, diarrhea, mental status changes (e.g., confusion, delirium, or coma), and in rare cases, death. If emergent treatment with methylene blue is required in a patient receiving St. John's Wort, it is advisable to discontinue the St. John's Wort and monitor the patient for symptoms of CNS toxicity for two weeks or until 24 hours after the last dose of methylene blue, whichever comes first. During non-emergent use of methylene blue, it is advisable to stop the St. John's Wort for at least 2 weeks prior to methylene blue treatment.
Sufentanil: (Major) Avoid concomitant use of sufentanil in patients receiving methylene blue or within 14 days of stopping treatment with methylene blue due to the risk of serotonin syndrome or opioid toxicity, including respiratory depression. If cannot avoid use, choose the lowest possible methylene blue dose and observe the patient closely for up to 4 hours after administration.
Tapentadol: (Contraindicated) Tapentadol use in patients taking methylene blue or within 14 days of stopping such treatment is contraindicated due to the risk of serotonin syndrome or opioid toxicity. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses of another opioid to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.
Tramadol: (Contraindicated) Tramadol use is contraindicated in patients who are receiving or who have received monoamine oxidase inhibitors (MAOIs) within the previous 14 days. Methylene blue is a reversible inhibitor of MAO. Concomitant use of tramadol with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome or seizures. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as tramadol.
Tramadol; Acetaminophen: (Contraindicated) Tramadol use is contraindicated in patients who are receiving or who have received monoamine oxidase inhibitors (MAOIs) within the previous 14 days. Methylene blue is a reversible inhibitor of MAO. Concomitant use of tramadol with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome or seizures. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as tramadol.
Tranylcypromine: (Contraindicated) Avoid concomitant use with monoamine oxidase inhibitors (MAOIs); Methylene Blue injection may cause serious or fatal serotonergic syndrome when used in combination with serotonergic drugs. Methylene blue has been demonstrated to be a potent MAOI. Whenever possible, a washout period should elapse between the use of the MAOI and Methylene Blue injection. Patients treated with Methylene Blue injection should be monitored for serotonin syndrome. If symptoms of serotonin syndrome occur, discontinue use, and initiate supportive treatment. Inform patients of the increased risk of serotonin syndrome and advise them to not to take any serotonergic drugs within 72 hours after the last dose of Methylene Blue. If the IV use of Methylene Blue cannot be avoided, choose the lowest possible dose and closely observe the patient for CNS and serotonin-related effects for up to 4 hours after Methylene Blue is given.
Trazodone: (Contraindicated) According to the manufacturer of trazodone, treatment initiation with trazodone is contraindicated in patients currently receiving intravenous methylene blue due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than trazodone (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving trazodone and requiring urgent treatment with intravenous methylene blue, trazodone should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits of methylene blue outweigh the risks. The patient should be monitored for serotonin syndrome for 2 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Trazodone may be re-initiated 24 hours after the last dose of methylene blue. Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A) and trazodone increases central serotonin effects. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving serotonergic agents such as selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving intravenous methylene blue with other serotonergic psychiatric agents are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Serotonin syndrome is characterized by rapid development of various symptoms such as hyperthermia, hypertension, myoclonus, rigidity, hyperhidrosis, incoordination, diarrhea, mental status changes (e.g., confusion, delirium, or coma), and in rare cases, death.
Trimipramine: (Contraindicated) According to the manufacturer, treatment initiation with trimipramine is contraindicated in patients currently receiving intravenous (IV) methylene blue due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than trimipramine (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving trimipramine and requiring urgent treatment with IV methylene blue, trimipramine should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits outweigh the risks. The patient should be monitored for serotonin syndrome for 2 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Trimipramine may be re-initiated 24 hours after the last dose of methylene blue. Results from an in vitro study indicate that methylene blue is a potent, reversible inhibitor of the monoamine oxidase type A enzyme (MAO-A). MAO-A is responsible for the metabolism of serotonin. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent, in patients receiving serotonergic agents. It is not known if patients receiving other serotonergic psychiatric agents with IV methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between IV methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Signs and symptoms of serotonin syndrome include fever, diaphoresis, shivering, myoclonus, tremor, tachycardia, diarrhea, nausea, headache, incoordination, mental status changes (e.g., agitation, confusion), hyperreflexia, seizures, and coma.
Tryptophan, 5-Hydroxytryptophan: (Major) Concurrent use of intravenous (IV) methylene blue and dietary supplements of tryptophan should be avoided if possible due to a risk for serotonin syndrome. Although the mechanism is not clearly understood, literature reports suggest inhibition of MAO by methylene blue may be involved in increasing a risk for serotonin syndrome when methylene blue is combined with serotonergic agents. Tryptophan is a serotonin precursor. If co-use of methylene blue and a serotonergic agent cannot be avoided, choose the lowest possible dose and monitor the patient for CNS effects for up to 4 hours after administration of IV methylene blue.
Venlafaxine: (Contraindicated) Concurrent use of methylene blue and serotonin norepinephrine reuptake inhibitors (SNRIs) (e.g., venlafaxine, duloxetine, desvenlafaxine, milnacipran) should generally be avoided due to the potential for serotonin syndrome. Results from an in vitro study indicate that methylene blue is a potent, reversible inhibitor of the monoamine oxidase type A enzyme (MAO-A). MAO-A is responsible for the metabolism of serotonin; therefore, concurrent use of an MAO-A inhibitor with serotonergic agents such as SNRIs may result in a clinically significant interaction. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, SNRIs, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. One case report suggests that serotonin toxicity may have occurred post-operatively following administration of standard infusions of methylene blue in a patient receiving duloxetine. The patient experienced disorientation, a mildly elevated temperature, tachycardia, elevated blood pressure, mild agitation, and nystagmus. In a separate case, a patient who had been receiving venlafaxine developed expressive aphasia, confusion, and disinhibition following a methylene blue infusion. The authors concluded that methylene blue toxicity had occurred; however, they did not exclude the possibility of a drug interaction based upon previous reports of an interaction between injectable methylene blue and selective serotonin reuptake inhibitors (SSRIs). Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Signs and symptoms of serotonin syndrome include fever, diaphoresis, shivering, myoclonus, tremor, tachycardia, diarrhea, nausea, headache, incoordination, mental status changes (e.g., agitation, confusion), hyperreflexia, seizures, and coma. If emergent treatment with methylene blue is required in a patient receiving an SNRI, the SNRI must be stopped immediately and the patient should be monitored for symptoms of CNS toxicity for two weeks or until 24 hours after the last dose of methylene blue, whichever comes first. During non-emergent use of methylene blue, the SNRI should be stopped at least 2 weeks prior to methylene blue treatment, but also taking into consideration the half-life of the SNRI being discontinued.
Verteporfin: (Moderate) Use caution if coadministration of verteporfin with methylene blue is necessary due to the risk of increased photosensitivity. Verteporfin is a light-activated drug used in photodynamic therapy; all patients treated with verteporfin will be photosensitive. Concomitant use of other photosensitizing agents like methylene blue may increase the risk of a photosensitivity reaction.
Vilazodone: (Contraindicated) According to the manufacturer of vilazodone, treatment initiation with vilazodone is contraindicated in patients currently receiving intravenous (IV) methylene blue due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than vilazodone (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients requiring urgent treatment with IV methylene blue, vilazodone should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits outweigh the risks. The patient should be monitored for serotonin syndrome for 2 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Vilazodone may be re-initiated 24 hours after the last dose of methylene blue. Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A) and vilazodone is a selective serotonin reuptake inhibitor and partial 5-HT1 agonist. Concurrent use of an MAO-A inhibitor with a serotonergic agent may result in a clinically significant interaction. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving serotonin-augmenting agents. It is not known if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between IV methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Serotonin syndrome is characterized by rapid development of various symptoms such as hyperthermia, hypertension, myoclonus, rigidity, hyperhidrosis, incoordination, diarrhea, mental status changes (e.g., confusion, delirium, or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
Vortioxetine: (Contraindicated) Treatment initiation with vortioxetine is contraindicated in patients currently receiving intravenous methylene blue due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than vortioxetine (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving vortioxetine and requiring urgent treatment with intravenous methylene blue, vortioxetine should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits of methylene blue outweigh the risks. The patient should be monitored for serotonin syndrome for 21 days or until 24 hours after the last dose of methylene blue, whichever comes first. Vortioxetine may be re-initiated 24 hours after the last dose of methylene blue. Results from an in vitro study indicate that methylene blue is a potent, reversible inhibitor of the monoamine oxidase type A enzyme (MAO-A). MAO-A is responsible for the metabolism of serotonin; therefore, concurrent use of an MAO-A inhibitor with a serotonergic agent may result in a clinically significant interaction. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving SSRIs, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. One case describes a patient receiving citalopram who experienced agitation, restlessness, pupil dilation with sluggish response to light, myoclonic movements of the lower limbs, and brisk reflexes following an infusion of methylene blue, while another patient receiving paroxetine developed tachycardia, agitation, dystonia and abnormal eye movements During a retrospective study of 193 surgical patients who had received a methylene blue injection, it was found that all 12 of the patients who experienced postoperative neurological sequelae had been taking a serotonin reuptake inhibitor preoperatively. One of the 12 patients experienced cardiopulmonary arrest and died. Of the remaining 181 patients who did not experience neurological sequelae, 8.8% were taking a serotonin reuptake inhibitor. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and coma. Signs and symptoms of serotonin syndrome include fever, diaphoresis, shivering, myoclonus, tremor, tachycardia, diarrhea, nausea, headache, incoordination, mental status changes (e.g., agitation, confusion), and hyperreflexia.

Methylene Blue/PROVAYBLUE Intravenous Inj Sol: 1%, 1mL, 5mg

Adults

2 mg/kg/day IV.

Geriatric

2 mg/kg/day IV.

Adolescents

2 mg/kg/day IV.

Children

2 mg/kg/day IV.

Infants

2 mg/kg/day IV.

Neonates

2 mg/kg/day IV.

Methemoglobinemia occurs when hemoglobin is oxidized to form methemoglobin. Unlike hemoglobin, methemoglobin is incapable of oxygen transport which can lead to tissue hypoxia. Methylene blue is a water soluble thiazine dye. Methylene blue is converted to leucomethylene blue by NADPH reductase. Leucomethylene blue accelerates the reduction of the ferric iron of methemoglobin to the ferrous state of normal hemoglobin, allowing for oxygen delivery to tissues.

Methylene blue is administered intravenously. Methylene blue is highly protein bound (94%) and exhibits concentration-dependent partitioning into blood cells. Methylene blue is metabolized by CYP1A2, CYP2C19, and CYP2D6; however the predominant pathway is mediated by UDP-galactose transporter (UGT) conjugation by multiple UGT enzymes, including UGT1A4 and UGT1A9. Approximately 40% of methylene blue is excreted unchanged by the kidneys. Low concentrations of methylene blue increase the conversion of methemoglobin to hemoglobin. The exposure-response or exposure-safety relationship for methylene blue is unknown.
 
Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4/5, UGT1A4, UGT1A9, P-gp, OCT2, MATE1, and MATE2-K.
Methylene blue is primarily metabolized by UGT1A4 and UGT1A9 and to a lesser extent by CYP1A2, CYP2C19, and CYP2D6. Methylene blue inhibits CYP1A2, CYP2B6, CYP2C8, CYP2C19, CYP2D6, CYP3A4/5 in vitro (CYP2C9, CYP2D6, and CYP3A4/5 may be time-dependent inhibition), UGT1A9, UGT1A4, P-glycoprotein (P-gp), organic cation transporter (OCT) 2, multidrug and toxin extrusion (MATE) 1, and MATE2-K. Methylene blue induces CYP1A2.

Pregnancy

Methylene blue is contraindicated in women who are or may become pregnant. Methylene blue may cause fetal harm when administered during pregnancy. Epidemiologic evidence exists that methylene blue is a teratogen. Intra-amniotic injection of pregnant women with methylene blue during the second trimester was associated with neonatal intestinal atresia and fetal death. Methylene blue should not be administered during amniocentesis due to the risk of teratogenicity and other newborn adverse effects. Intra-amniotic injection of methylene blue hours to days prior to birth can result in hyperbilirubinemia, hemolytic anemia, skin staining, methemoglobinemia, respiratory distress, and photosensitivity in the neonate. If methylene blue is administered to a pregnant woman at term, monitor the neonate for adverse reactions. If methylene blue is used during pregnancy or if the patient becomes pregnant while taking this drug, advise the woman of the potential risk to the fetus.

There is no information regarding the presence of methylene blue in human milk, the effects on the breast-fed infant, or the effects on milk production. Discontinue breast-feeding during methylene blue administration and for up to 8 days after treatment with methylene blue due to the potential for serious adverse effects, including genotoxicity.