{"id":"methylthioninium-chloride","rwe":[],"_fda":{"id":"420bd985-ac55-44b9-b8a0-a5098220575b","set_id":"4f6848e5-35ed-4046-b13c-3032b5ba3232","openfda":{"unii":["T42P99266K"],"route":["INTRAVENOUS"],"rxcui":["1788984","1788989","2199323","2199324"],"spl_id":["420bd985-ac55-44b9-b8a0-a5098220575b"],"brand_name":["PROVAYBLUE"],"spl_set_id":["4f6848e5-35ed-4046-b13c-3032b5ba3232"],"package_ndc":["0517-0374-01","0517-0374-05","0517-0381-01","0517-0381-05","0517-0125-01","0517-0125-05","0517-0371-01","0517-0371-05"],"product_ndc":["0517-0125","0517-0374","0517-0381","0517-0371"],"generic_name":["METHYLENE BLUE"],"product_type":["HUMAN PRESCRIPTION DRUG"],"substance_name":["METHYLENE BLUE"],"manufacturer_name":["American Regent, Inc."],"application_number":["NDA204630"],"is_original_packager":[true]},"version":"28","pregnancy":["8.1 Pregnancy Risk Summary PROVAYBLUE may cause fetal harm when administered to a pregnant woman. Intra-amniotic injection of pregnant women with a methylene blue class product during the second trimester was associated with neonatal intestinal atresia and fetal death. Methylene blue produced adverse developmental outcomes in rats and rabbits when administered orally during organogenesis at doses at least 32 and 16 times, respectively, the clinical dose of 1 mg/kg (see Data ) . Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2-4% and 15-20%, respectively. Clinical Considerations Fetal/neonatal adverse reactions Intra-amniotic injection of a methylene blue class product hours to days prior to birth can result hyperbilirubinemia, hemolytic anemia, skin staining, methemoglobinemia, respiratory distress and photosensitivity in the newborn. Following administration of PROVAYBLUE to a pregnant woman at term, observe the newborn for these adverse reactions and institute supportive care. Data Animal Data Methylene blue was administered orally to pregnant rats at doses of 50 to 350 mg/kg/day, during the period of organogenesis. Maternal and embryofetal toxicities were observed at all doses of methylene blue and were most evident at the 200 and 350 mg/kg/day doses. Maternal toxicity consisted of increased spleen weight. Embryo-fetal toxicities included reduced fetal weight, post-implantation loss, edema, and malformations including enlarged lateral ventricles. The dose of 200 mg/kg (1200 mg/m 2 ) in rats is approximately 32 times a clinical dose of 1 mg/kg based on body surface area. Methylene blue was administered orally to pregnant rabbits at doses of 50, 100, or 150 mg/kg/day, during the period of organogenesis. Maternal death was observed at the methylene blue dose of 100 mg/kg. Embryofetal toxicities included spontaneous abortion at all dose levels and a malformation (umbilical hernia) at the 100 and 150 mg/kg/day doses. The dose of 50 mg/kg (600 mg/m 2 ) in rabbits is approximately 16 times a clinical dose of 1 mg/kg based on body surface area."],"overdosage":["10 OVERDOSAGE Hypotension, wheezing and reduced oxygenation have been reported in patients who received methylene blue class products in single doses of 3 mg/kg or more. Administration of large intravenous doses (cumulative dose ≥ 7 mg/kg ) of a methylene blue class product caused nausea, vomiting, precordial pain, dyspnea, tachypnea, chest tightness, tachycardia, apprehension, tremor, mydriasis, blue staining of the urine, the skin and mucous membranes, abdominal pain, dizziness, paresthesia, headache, confusion, mild methemoglobinemia (up to 7%) and electrocardiogram changes (T-wave flattening or inversion). These effects lasted 2-12 hours following administration. A severe overdosage (single dose of 20 mg/kg or more) of a methylene blue class product caused severe intravascular hemolysis, hyperbilirubinemia and death. In case of overdose of PROVAYBLUE, maintain the patient under observation until signs and symptoms have resolved, monitor for cardiopulmonary, hematologic and neurologic toxicities, and institute supportive measures as necessary."],"description":["11 DESCRIPTION Methylene blue is an oxidation-reduction agent. Its chemical name is 3,7-bis(dimethylamino)phenothiazin-5-ium, chloride hydrate. The molecular formula of methylene blue is C 16 H 18 ClN 3 S.xH 2 O and its molecular weight of 319.86 g/mol for the anhydrous form. The structural formula of methylene blue is: PROVAYBLUE (methylene blue) injection USP is a sterile solution intended for intravenous administration. Each mL of solution contains 5 mg methylene blue and water for injection. PROVAYBLUE (methylene blue) injection, USP: is a clear dark blue solution with a pH value between 3.0 and 4.5. The osmolality is between 10 and 15 mOsm/kg. PROVAYBLUE (methylene blue) injection strength is expressed in terms of trihydrate. Figure"],"how_supplied":["16 HOW SUPPLIED/STORAGE AND HANDLING PROVAYBLUE (methylene blue) injection, USP : is supplied in 10 mL and 2 mL single-dose ampules or single-dose vials. Each 10 mL ampule and vial contains 50 mg of methylene blue as a clear dark blue solution. Each 2 mL ampule and vial contains 10 mg of methylene blue as a clear dark blue solution. A box contains five ampules or vials. Box of 5 ampules of 50 mg/10 mL: NDC 0517-0374-05 Box of 5 ampules of 10 mg/2 mL: NDC 0517-0125-05 Box of 5 vials of 50 mg/10 mL: NDC 0517-0381-05 Box of 5 vials of 10 mg/2 mL: NDC 0517-0371-05 Storage: Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). [See USP Controlled Room Temperature] Any unused product or waste material should be disposed of in accordance with local practice. Do not refrigerate or freeze . Keep the ampule or the vial in the original package to protect from light."],"boxed_warning":["WARNING: SEROTONIN SYNDROME WITH CONCOMITANT USE OF SEROTONERGIC DRUGS AND OPIOIDS PROVAYBLUE may cause serious or fatal serotonergic syndrome when used in combination with serotonergic drugs and opioids. Avoid concomitant use of PROVAYBLUE with selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs) and opioids. [see Warnings and Precautions ( 5.1 ) and Drug Interactions ( 7.1 )]. WARNING: SEROTONIN SYNDROME WITH CONCOMITANT USE OF SEROTONERGIC DRUGS AND OPIOIDS See full prescribing information for complete boxed warning. PROVAYBLUE may cause serious or fatal serotonergic syndrome when used in combination with serotonergic drugs and opioids. Avoid concomitant use of PROVAYBLUE with selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs) and opioids. ( 5.1 , 7.1 )"],"geriatric_use":["8.5 Geriatric Use Clinical studies of PROVAYBLUE did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. PROVAYBLUE is known to be substantially excreted by the kidney, so the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, treatment of methemoglobinemia in these patients should use the lowest number of doses needed to achieve a response [see Dosage and Administration ( 2 )] ."],"pediatric_use":["8.4 Pediatric Use The safety and effectiveness of PROVAYBLUE for the treatment of acquired methemoglobinemia have been established in pediatric patients. Use of PROVAYBLUE is supported by two retrospective case series that included 2 pediatric patients treated with PROVAYBLUE and 12 treated with another methylene blue class product. The case series included pediatric patients in the following age groups: 3 neonates (less than 1 month), 4 infants (1 month up to less than 2 years), 4 children (2 years up to less than 12 years), and 3 adolescents (12 years to less than 17 years). The efficacy outcomes were consistent across pediatric and adult patients in both case series [see Clinical Studies ( 14 )]."],"effective_time":"20250528","clinical_studies":["14 CLINICAL STUDIES 14.1 Treatment of Acquired Methemoglobinemia The efficacy of PROVAYBLUE in the treatment of patients with methemoglobinemia was evaluated in 31 adult patients with acquired methemoglobinemia across two studies: NCT03395223 , a prospective, interventional, open-label, single-arm study, and NCT03542760 , a prospective, multicenter, observational registry. Of the 31 subjects enrolled 90% were white, 10% were black, 58% were female, and 42% were male. Hispanic or Latino was 9.7%; non-Hispanic or Latino was 67.7%, and ethnicity data were missing for 22.6%. The mean age was 45.6 years, and the ages ranged from 19 to 72 years. Each individual received at least 1 intravenous dose of PROVAYBLUE; two received 2 doses and one received 3 doses. Most doses administered were 1 mg/kg (82.9%), but doses from 0.78 mg/kg to 2 mg/kg were administered. The recommended PROVAYBLUE dose is 1 mg/kg; lower or greater doses are not recommended. The maximum recommended number of doses is two , a prospective, interventional, open-label, single-arm study, and NCT03542760, a prospective, multicenter, observational registry. Of the 31 subjects enrolled 90% were white, 10% were black, 58% were female, and 42% were male. Hispanic or Latino was 9.7%; non-Hispanic or Latino was 67.7%, and ethnicity data were missing for 22.6%. The mean age was 45.6 years, and the ages ranged from 19 to 72 years. Each individual received at least 1 intravenous dose of PROVAYBLUE; two received 2 doses and one received 3 doses. Most doses administered were 1 mg/kg (82.9%), but doses from 0.78 mg/kg to 2 mg/kg were administered. The recommended PROVAYBLUE dose is 1 mg/kg; lower or greater doses are not recommended. The maximum recommended number of doses is two [see Dosage and Administration ( 2.1 )] . In total, 29 of the 31 (93.5%) subjects had post treatment methemoglobin (metHb) assessment; 28 of the 29 subjects had baseline metHb with a mean concentration of 18.4% and a range of 4.1% to 74.4%. Twenty-six of the 28 (92.9%) subjects who had baseline metHb had at least a 50% reduction in metHB from baseline in their first assessment post baseline. This first post dosing assessment occurred from 0.2 to 27.3 hours from the end of first PROVAYBLUE infusion with a median time of 2.7 hours. There were 12 subjects that had baseline metHb and had metHb assessed within 2 hours of the end of the first PROVAYBLUE treatment; 9 of the 12 (75%; 95% CI (42.8%,93.3%)) had at least a 50% reduction in metHb at 1 hour postdosing. Available vital sign data including blood pressure, heart rate and respiratory rate were reviewed at baseline and compared to data collected within 2 hours post PROVAYBLUE infusion. Prior to treatment with PROVAYBLUE, 16 of the 23 (70%) of patients had a respiratory rate exceeding the upper limit of normal (≥ 20 bpm). Of these, 10 of the 16 (63%) experienced a normalization of respiratory rate within 2 hours post ProvayBlue infusion. There was minimal impact on other vital signs. At baseline, the most common prespecified signs and symptoms of methemoglobinemia (reported by ≥2 subjects [6.5%] overall) were cyanosis (32.3%), dyspnea (25.8%), fatigue (25.8%), depressed CNS (9.7%), headache (6.5%), weakness (6.5%), and dizziness (6.5%). Following treatment with PROVAYBLUE, signs and symptoms of methemoglobinemia improved. The efficacy of PROVAYBLUE in the treatment of methemoglobinemia in pediatric patients was assessed in 14 patients in two retrospective case series (2 patients received PROVAYBLUE and 12 who received another methylene blue product). The ages ranged from 6 days to 16 years. The efficacy outcomes were consistent across the pediatric and adult populations."],"laboratory_tests":["5.7 Interference with Laboratory Tests PROVAYBLUE is a blue dye which passes freely into the urine and may interfere with the interpretation of any urine test which relies on a blue indicator, such as the dipstick test for leucocyte esterase."],"pharmacodynamics":["12.2 Pharmacodynamics Low concentrations of methylene blue speeds up the in vivo conversion of methemoglobin to hemoglobin. Methylene blue has been observed to stain tissues selectively. The exposure-response or –safety relationship for methylene is unknown. Cardiac Electrophysiology The results of a thorough QT study demonstrated PROVAYBLUE at an intravenous dose of 2 mg/kg as a 5-minute intravenous infusion had no effect on the QT, PR or QRS intervals."],"pharmacokinetics":["12.3 Pharmacokinetics The mean (CV%) Cmax and AUC of methylene blue 2,917 ng/mL (39%) and 13977 ng.hr/mL (21%) following a 2 mg/kg dose administered as a 5-minute intravenous infusion. Distribution The mean± standard deviation steady state volume of distribution of a 2 mg/kg dose of PROVAYBLUE was 255 L ± 58. The mean plasma protein binding of methylene blue is approximately 94% in vitro. Methylene blue exhibits concentration-dependent partitioning into blood cells in vitro. The blood-to-plasma ratio was 5.1±2.8 at 5 minutes from the start of a 2 mg/kg dose administered as a 5-minute intravenous infusion and reached a plateau of 0.6 at 4 hours in a clinical study. Methylene Blue is a substrate for the P-glycoprotein (P-gp, ABCB1) transporter, but not for BCRP or OCT2 in vitro. Elimination Methylene blue has a half-life of approximately 24 hours in humans. Metabolism Methylene blue is metabolized by CYPs 1A2, 2C19 and 2D6 in vitro; however, the predominant in vitro pathway appears to be UGT-mediated conjugation by multiple UGT enzymes, including UGT1A4 and UGT1A9. Azure B, which is a minor impurity in methylene blue, is also formed in humans as a metabolite of methylene blue, with an overall drug/metabolite AUC ratio of greater than 6:1. Azure B has 8-fold lower potency than methylene blue. Excretion Approximately 40% of methylene blue is excreted into the urine unchanged. Specific Populations Renal Impairment After a single 1 mg/kg dose of PROVAYBLUE, AUC 0-96h increased by 52%, 116%, and 192% in subjects with mild (estimated glomerular filtration rate (eGFR) 60 – 89 mL/min/1.73 m 2 ), moderate (eGFR 30-59 mL/min/1.73m 2 ), and severe (eGFR 15-29 mL/min/1.732m 2 ) renal impairment, respectively. Cmax increased by 42%, 34%, and 15% in subjects with mild, moderate, and severe renal impairment respectively [see Dosage and Administration ( 2.2 ) and Use in Specific Populations ( 8.6 )] . The half-life was unchanged in patients with mild to moderate renal impairment. The AUC 0-96h of Azure B after a single 1 mg/kg dose increased by 29%, 94%, and 339% in subjects with mild (estimated glomerular filtration rate (eGFR) 60 – 89 mL/min/1.73 m 2 ), moderate (eGFR 30-59 mL/min/1.73m 2 ), and severe (eGFR 15-29 mL/min/1.732m 2 ) renal impairment, respectively. C max increased by 23%, 13%, and 65% in subjects with mild, moderate, and severe renal impairment, respectively [see Dosage and Administration ( 2.2 ) and Use in Specific Populations ( 8.6 )] Drug Interactions Studies Clinical Studies: The coadministration of 2 mg/kg dose of PROVAYBLUE with midazolam (a CYP3A4 substrate), caffeine (a CYP1A2 substrate), warfarin (a CYP2C9 substrate), and dextromethorphan (a CYP2D6 substrate) in a cocktail study did not affect the exposure of these substrates compared to their exposure without PROVAYBLUE administration. In Vitro Studies: Cytochrome P450 (CYP450) Enzymes : Methylene blue inhibits CYP isozymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4/5. Possible time-dependent inhibition of CYP2C9, CYP2D6 and CYP3A4/5 (testosterone as substrate) was also observed. Methylene blue induces CYP1A2 but does not induce CYP2B6 or CYP3A4. UDP-Glucuronosyltransferase (UGT): Methylene blue inhibits UGT1A9 and UGT1A4, but did not significantly inhibit UGTs 1A1, 1A3, 1A6, 2B7 or 2B15. Transporter: Methylene blue is both a substrate for and an inhibitor of P-gp but is not a substrate for BCRP or OCT2 in vitro. Methylene blue is not a significant inhibitor of BCRP, OAT1, OAT3, OAT1B1 or OAT1B3. Methylene blue inhibits OCT2, MATE1 and MATE2-K."],"adverse_reactions":["6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: Serotonin Syndrome with Concomitant Use of Serotonergic Drugs [see Warnings and Precautions ( 5.1 )] Anaphylaxis [see Warnings and Precautions ( 5.2 )] Lack of Effectiveness [see Warnings and Precautions ( 5.3 )] Hemolytic Anemia [see Warnings and Precautions ( 5.4 )] Interference with In-Vivo Monitoring Devices [see Warnings and Precautions ( 5.5 )] Effects on Ability to Drive and Operate Machinery [see Warnings and Precautions ( 5.6 )] Interference with Laboratory Tests [see Warnings and Precautions ( 5.7 )] The most commonly reported adverse reactions (>2%) included headache, hypokalemia, diarrhea, hypomagnesemia, myoclonus, nausea, and seizure-like phenomena. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact American Regent at 1-800-734-9236, FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of PROVAYBLUE in adults with acquired methemoglobinemia was assessed in 31 patients who received at least 1 dose of PROVAYBLUE [see Clinical Studies ( 14 )] . Most doses administered were 1 mg/kg (82.9%), but doses from 0.78 mg/kg to 2 mg/kg were administered. All patients received at least one dose of PROVAYBLUE; two received two doses, and one received three doses. Serious adverse reactions occurred in 3.2% of patients who received PROVAYBLUE. A serious adverse reaction of seizure-like phenomenon was reported in one patient. Adverse reactions (≥2%) included headache, hypokalemia, diarrhea, hypomagnesemia, myoclonus, nausea, and seizure-like phenomena. The safety of PROVAYBLUE in pediatric patients with acquired methemoglobinemia was assessed in two retrospective case series that included two pediatric patients treated with PROVAYBLUE and 12 treated with another methylene blue product. The case series included patients in the following age groups: 3 neonates (<1 month), 4 infants (1 month to <2 years), 4 children (2 years to <12 years), and 3 adolescents (12 years to <17 years). The safety profile in pediatric patients was similar to that in adult patients. Other adverse reactions reported to occur following the administration of methylene blue class products include the following: Blood and lymphatic system disorders : hemolytic anemia, hemolysis, hyperbilirubinemia Cardiac disorders : palpitations, tachycardia Eye disorders : eye pruritus, ocular hyperemia, vision blurred Gastrointestinal disorders : abdominal pain lower, dry mouth, flatulence, glossodynia, tongue eruption General disorders and administration site conditions : death, infusion site extravasation, infusion site induration, infusion site pruritus, infusion site swelling, infusion site urticaria, peripheral swelling, thirst Investigations : elevated liver enzymes Musculoskeletal and connective tissue disorders : myalgia Renal and urinary disorders : dysuria Respiratory, thoracic and mediastinal disorders : nasal congestion, oropharyngeal pain, rhinorrhea, sneezing Skin and subcutaneous tissue disorders : necrotic ulcer, papule, phototoxicity Vascular disorders : hypertension"],"contraindications":["4 CONTRAINDICATIONS PROVAYBLUE is contraindicated in the following conditions: Severe hypersensitivity reactions to methylene blue or any other thiazine dye [see Warnings and Precautions ( 5.2 )] . Patients with glucose-6-phosphate dehydrogenase deficiency (G6PD) due to the risk of hemolytic anemia [see Warnings and Precautions ( 5.3 , 5.4 )]. PROVAYBLUE is contraindicated in the following conditions ( 4 ): Severe hypersensitivity to methylene blue Patients with glucose-6-phosphate dehydrogenase deficiency (G6PD) due to the risk of hemolytic anemia"],"drug_interactions":["7 DRUG INTERACTIONS Clinically significant drug interactions with PROVAYBLUE are described below: The concomitant use of PROVAYBLUE with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Although the mechanism is not clearly understood, literature reports suggest PROVAYBLUE is a potent reversible inhibitor of monoamine oxidase. Avoid concomitant use of PROVAYBLUE with medicinal products that enhance serotonergic transmission including antidepressants like SSRIs (selective serotonin reuptake inhibitors), SNRIs (serotonin and norepinephrine reuptake inhibitors), MAOIs (monoamine oxidase inhibitors), bupropion, buspirone, clomipramine, mirtazapine, linezolid, opioids, and dextromethorphan because of the potential for serious CNS reactions, including potentially fatal serotonin syndrome. If the intravenous use of PROVAYBLUE cannot be avoided in patients treated with serotonergic medicinal products, choose the lowest possible dose and observe the patient closely for CNS effects for up to 4 hours after administration [see Warning and Precautions ( 5.1 ) and Clinical Pharmacology ( 12.3 )]."],"mechanism_of_action":["12.1 Mechanism of Action Methylene blue is a water soluble thiazine dye that promotes a non-enyzmatic redox conversion of metHb to hemoglobin. In situ, methylene blue is first converted to leucomethylene blue (LMB) via NADPH reductase. It is the LMB molecule which then reduces the ferric iron of metHb to the ferrous state of normal hemoglobin."],"recent_major_changes":["Boxed Warning 11/2023 Indications and Usage ( 1 ) 01/2024 Warnings and Precautions ( 5 ) 11/2023"],"clinical_pharmacology":["12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Methylene blue is a water soluble thiazine dye that promotes a non-enyzmatic redox conversion of metHb to hemoglobin. In situ, methylene blue is first converted to leucomethylene blue (LMB) via NADPH reductase. It is the LMB molecule which then reduces the ferric iron of metHb to the ferrous state of normal hemoglobin. 12.2 Pharmacodynamics Low concentrations of methylene blue speeds up the in vivo conversion of methemoglobin to hemoglobin. Methylene blue has been observed to stain tissues selectively. The exposure-response or –safety relationship for methylene is unknown. Cardiac Electrophysiology The results of a thorough QT study demonstrated PROVAYBLUE at an intravenous dose of 2 mg/kg as a 5-minute intravenous infusion had no effect on the QT, PR or QRS intervals. 12.3 Pharmacokinetics The mean (CV%) Cmax and AUC of methylene blue 2,917 ng/mL (39%) and 13977 ng.hr/mL (21%) following a 2 mg/kg dose administered as a 5-minute intravenous infusion. Distribution The mean± standard deviation steady state volume of distribution of a 2 mg/kg dose of PROVAYBLUE was 255 L ± 58. The mean plasma protein binding of methylene blue is approximately 94% in vitro. Methylene blue exhibits concentration-dependent partitioning into blood cells in vitro. The blood-to-plasma ratio was 5.1±2.8 at 5 minutes from the start of a 2 mg/kg dose administered as a 5-minute intravenous infusion and reached a plateau of 0.6 at 4 hours in a clinical study. Methylene Blue is a substrate for the P-glycoprotein (P-gp, ABCB1) transporter, but not for BCRP or OCT2 in vitro. Elimination Methylene blue has a half-life of approximately 24 hours in humans. Metabolism Methylene blue is metabolized by CYPs 1A2, 2C19 and 2D6 in vitro; however, the predominant in vitro pathway appears to be UGT-mediated conjugation by multiple UGT enzymes, including UGT1A4 and UGT1A9. Azure B, which is a minor impurity in methylene blue, is also formed in humans as a metabolite of methylene blue, with an overall drug/metabolite AUC ratio of greater than 6:1. Azure B has 8-fold lower potency than methylene blue. Excretion Approximately 40% of methylene blue is excreted into the urine unchanged. Specific Populations Renal Impairment After a single 1 mg/kg dose of PROVAYBLUE, AUC 0-96h increased by 52%, 116%, and 192% in subjects with mild (estimated glomerular filtration rate (eGFR) 60 – 89 mL/min/1.73 m 2 ), moderate (eGFR 30-59 mL/min/1.73m 2 ), and severe (eGFR 15-29 mL/min/1.732m 2 ) renal impairment, respectively. Cmax increased by 42%, 34%, and 15% in subjects with mild, moderate, and severe renal impairment respectively [see Dosage and Administration ( 2.2 ) and Use in Specific Populations ( 8.6 )] . The half-life was unchanged in patients with mild to moderate renal impairment. The AUC 0-96h of Azure B after a single 1 mg/kg dose increased by 29%, 94%, and 339% in subjects with mild (estimated glomerular filtration rate (eGFR) 60 – 89 mL/min/1.73 m 2 ), moderate (eGFR 30-59 mL/min/1.73m 2 ), and severe (eGFR 15-29 mL/min/1.732m 2 ) renal impairment, respectively. C max increased by 23%, 13%, and 65% in subjects with mild, moderate, and severe renal impairment, respectively [see Dosage and Administration ( 2.2 ) and Use in Specific Populations ( 8.6 )] Drug Interactions Studies Clinical Studies: The coadministration of 2 mg/kg dose of PROVAYBLUE with midazolam (a CYP3A4 substrate), caffeine (a CYP1A2 substrate), warfarin (a CYP2C9 substrate), and dextromethorphan (a CYP2D6 substrate) in a cocktail study did not affect the exposure of these substrates compared to their exposure without PROVAYBLUE administration. In Vitro Studies: Cytochrome P450 (CYP450) Enzymes : Methylene blue inhibits CYP isozymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4/5. Possible time-dependent inhibition of CYP2C9, CYP2D6 and CYP3A4/5 (testosterone as substrate) was also observed. Methylene blue induces CYP1A2 but does not induce CYP2B6 or CYP3A4. UDP-Glucuronosyltransferase (UGT): Methylene blue inhibits UGT1A9 and UGT1A4, but did not significantly inhibit UGTs 1A1, 1A3, 1A6, 2B7 or 2B15. Transporter: Methylene blue is both a substrate for and an inhibitor of P-gp but is not a substrate for BCRP or OCT2 in vitro. Methylene blue is not a significant inhibitor of BCRP, OAT1, OAT3, OAT1B1 or OAT1B3. Methylene blue inhibits OCT2, MATE1 and MATE2-K."],"indications_and_usage":["1 INDICATIONS AND USAGE PROVAYBLUE is indicated for the treatment of pediatric and adult patients with acquired methemoglobinemia. PROVAYBLUE (methylene blue) is an oxidation-reduction agent indicated for the treatment of pediatric and adult patients with acquired methemoglobinemia."],"warnings_and_cautions":["5 WARNINGS AND PRECAUTIONS Hypersensitivity: If severe or life threatening allergic reaction occurs, discontinue PROVAYBLUE, treat the allergic reaction, and monitor until signs and symptoms resolve ( 5.2 ) Lack of Effectiveness: Consider alternative treatments if there is no resolution of methemoglobinemia after 2 doses ( 2.1 , 5.3 ) Hemolytic Anemia: Discontinue PROVAYBLUE and transfuse ( 5.4 ) Interference with In-Vivo Monitoring Devices: Use methods other than pulse oximetry to assess oxygen saturation ( 5.5 ) Effects on Ability to Drive and Operate Machinery: Advise patients to refrain from these activities until neurologic and visual symptoms have resolved ( 5.6 ) 5.1 Serotonin Syndrome with Concomitant Use of Serotonergic Drugs and Opioids The development of serotonin syndrome has been reported with the use of methylene blue class products. Most reports have been associated with concomitant use of serotonergic drugs (e.g., selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs). Opioids and dextromethorphan may increase the risk of developing serotonin syndrome. Some of the reported cases were fatal. Symptoms associated with serotonin syndrome may include the following combination of signs and symptoms: mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, and hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, and incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Avoid concomitant use of PROVAYBLUE with serotonergic drugs and opioids. Patients treated with PROVAYBLUE should be monitored for the emergence of serotonin syndrome. If symptoms of serotonin syndrome occur, discontinue use of PROVAYBLUE, and initiate supportive treatment. Inform patients of the increased risk of serotonin syndrome and advise them to not to take serotonergic drugs within 72 hours after the last dose of PROVAYBLUE [see Drug Interactions ( 7 ), Patient Counseling Information ( 17 )] . 5.2 Hypersensitivity Anaphylactic reactions to methylene blue class products have been reported. Patients treated with PROVAYBLUE should be monitored for anaphylaxis. If anaphylaxis or other severe hypersensitivity reactions (e.g., angioedema, urticaria, bronchospasm) should occur, discontinue use of PROVAYBLUE and initiate supportive treatment. PROVAYBLUE is contraindicated in patients who have experienced anaphylaxis or other severe hypersensitivity reactions to a methylene blue class product in the past. 5.3 Lack of Effectiveness Methemoglobinemia may not resolve or may rebound after response to treatment with PROVAYBLUE in patients with methemoglobinemia due to aryl amines such as aniline or sulfa drugs such as dapsone. Monitor response to therapy with PROVAYBLUE through resolution of methemoglobinemia. If methemoglobinemia does not respond to 2 doses of PROVAYBLUE or if methemoglobinemia rebounds after a response, consider additional treatment options [see Dosage and Administration ( 2.2 )] . Patients with glucose-6-phosphate dehydrogenase deficiency may not reduce PROVAYBLUE to its active form in vivo . PROVAYBLUE may not be effective in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. 5.4 Hemolytic Anemia Hemolysis can occur during treatment of methemoglobinemia with PROVAYBLUE. Laboratory testing may show Heinz bodies, elevated indirect bilirubin and low haptoglobin, but the Coombs test is negative. The onset of anemia may be delayed 1 or more days after treatment with PROVAYBLUE. The anemia may require red blood cell transfusions [see Adverse Reactions ( 6.1 )]. Use the lowest effective number of doses of PROVAYBLUE to treat methemoglobinemia. Discontinue PROVAYBLUE and consider alternative treatments of methemoglobinemia if severe hemolysis occurs. Treatment of patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency with PROVAYBLUE may result in severe hemolysis and severe anemia. PROVAYBLUE is contraindicated for use in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency [see Contraindications ( 4 )]. 5.5 Interference with In Vivo Monitoring Devices Inaccurate Pulse Oximeter Readings The presence of methylene blue in the blood may result in an underestimation of the oxygen saturation reading by pulse oximetry. If a measure of oxygen saturation is required during or shortly after infusion of PROVAYBLUE, it is advisable to obtain an arterial blood sample for testing by an alternative method. Bispectral index monitor A fall in the Bispectral Index (BIS) has been reported following administration of methylene blue class products. If PROVAYBLUE is administered during surgery, alternative methods for assessing the depth of anesthesia should be employed. 5.6 Effects on Ability to Drive and Operate Machinery Treatment with PROVAYBLUE may cause confusion, dizziness and disturbances in vision [see Adverse Reactions ( 6 )] . Advise patients to refrain from driving or engaging in hazardous occupations or activities such as operating heavy or potentially dangerous machinery until such adverse reactions to PROVAYBLUE have resolved. 5.7 Interference with Laboratory Tests PROVAYBLUE is a blue dye which passes freely into the urine and may interfere with the interpretation of any urine test which relies on a blue indicator, such as the dipstick test for leucocyte esterase."],"nonclinical_toxicology":["13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility In a two-year carcinogenicity study, rats were administered oral doses of methylene blue at 5, 25, or 50 mg/kg. Methylene blue caused pancreatic islet adenomas or carcinomas (combined) in male rats. In a two-year carcinogenicity study, mice were administered oral doses of methylene blue at 2.5, 12.5, or 25 mg/kg. There were no drug-related neoplastic findings in mice. Methylene blue was genotoxic in gene mutation assays in bacteria (Ames test), and in an in vitro sister chromatid exchange test and an in vitro chromosomal aberration test in Chinese hamster ovary (CHO) cells. Methylene blue was negative for micronucleus induction in bone marrow or peripheral blood collected from mice treated with methylene blue. Fertility studies with methylene blue have not been conducted. In vitro, methylene blue reduced motility of human sperm in a concentration dependent manner."],"information_for_patients":["17 PATIENT COUNSELING INFORMATION Serotonin Syndrome Advise patients of the possibility of serotonin syndrome, especially with concomitant use of serotonergic agents such as medications to treat depression and migraines. Advise patients to seek immediate medical attention if the following symptoms occur after treatment with PROVAYBLUE: changes in mental status, autonomic instability, or neuromuscular symptoms with or without gastrointestinal symptoms [see Warnings and Precautions ( 5.1 )]. Pregnancy Advise pregnant women of the potential risk to the fetus with the use of PROVAYBLUE during pregnancy [see Use in Specific populations ( 8.1 )]. Breastfeeding Advise patients to discontinue breast-feeding for up to 8 days after treatment with PROVAYBLUE [see Use in Specific populations ( 8.2 )] . Driving and Using Machines Advise patients to avoid driving and use of machines during treatment with PROVAYBLUE. Driving can be affected as a result of a confusional state, dizziness and possible eye disturbances [see Warnings and Precautions ( 5.6 )] . Phototoxicity Advise patients to take protective measures against exposure to light, because phototoxicity may occur after administration of methylene blue [see Adverse Reactions ( 6.1 )] . Skin and Body Fluid Blue Discoloration Advise patients that PROVAYBLUE may cause a blue discoloration of the skin and body fluids [see Adverse Reactions ( 6.1 )]. Manufactured for: PROVEPHARM SAS 22 rue Marc Donadille 13013 Marseille, France Ampules manufactured by: CENEXI 52 rue Marcel et Jacques Gaucher 94120 Fontenay sous Bois, France Vials manufactured by: CENEXI HSC 2 rue Louis Pasteur 14200 Hérouville-Saint-Clair, France Distributed by: American Regent, Inc. Shirley, NY 11967 Questions? : 1-800-734-9236"],"dosage_and_administration":["2 DOSAGE AND ADMINISTRATION Administer 1 mg/kg intravenously over 5-30 minutes. ( 2.1 ) If methemoglobin level remains above 30% or if clinical symptoms persist, give a repeat dose of up to 1 mg/kg one hour after the first dose. ( 2.1 ) Administer a single dose of 1 mg/kg in patients with moderate or severe renal impairment. ( 2.2 ) 2.1 Dosage and Administration Ensure patent venous access prior to administration of PROVAYBLUE. Do not administer PROVAYBLUE subcutaneously. Administer PROVAYBLUE 1 mg/kg intravenously over 5-30 minutes. If the methemoglobin level remains greater than 30% or if clinical signs and symptoms persist, a repeat dose of PROVAYBLUE 1 mg/kg may be given one hour after the first dose. If methemoglobinemia does not resolve after 2 doses of PROVAYBLUE, consider initiating alternative interventions for treatment of methemoglobinemia. 2.2 Recommended Dosage for Renal Impairment The recommended dosage of PROVAYBLUE in patients with moderate or severe renal impairment (eGFR 15-59 mL/min/1.73 m 2 ) is a single dose of 1 mg/kg. If the methemoglobin level remains greater than 30% or if the clinical symptoms persist 1 hour after dosing, consider initiating alternative interventions for the treatment of methemoglobinemia. 2.3 Preparation PROVAYBLUE is hypotonic and may be diluted before use in a solution of 50 mL 5% Dextrose Injection in order to avoid local pain, particularly in the pediatric population. Use the diluted solution immediately after preparation. Avoid diluting with sodium chloride solutions, because it has been demonstrated that chloride reduces the solubility of methylene blue. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard unused portion."],"spl_product_data_elements":["PROVAYBLUE methylene blue WATER METHYLENE BLUE METHYLENE BLUE CATION PROVAYBLUE methylene blue WATER METHYLENE BLUE METHYLENE BLUE CATION PROVAYBLUE methylene blue WATER METHYLENE BLUE METHYLENE BLUE CATION PROVAYBLUE methylene blue WATER METHYLENE BLUE METHYLENE BLUE CATION"],"dosage_forms_and_strengths":["3 DOSAGE FORMS AND STRENGTHS PROVAYBLUE (methylene blue) injection, USP : 50 mg/10 mL (5 mg/mL) or 10 mg/2 mL (5 mg/mL) clear dark blue solution in single-dose ampules or single-dose vials. 50 mg/10 mL (5 mg/mL) single-dose ampule. ( 3 ) 10 mg/2 mL (5 mg/mL) single-dose ampule. ( 3 ) 50 mg/10 mL (5 mg/mL) single-dose vial. ( 3 ) 10 mg/2 mL (5 mg/mL) single-dose vial. ( 3 )"],"use_in_specific_populations":["8 USE IN SPECIFIC POPULATIONS Pregnancy: Only use during pregnancy if the potential benefit justifies the potential risk to the fetus. ( 8.1 ) Lactation: Discontinue breast-feeding for up to 8 days after treatment. ( 8.2 ) Hepatic Impairment: Monitor patients longer for toxicity and drug interactions due to delayed clearance. ( 8.7 ) 8.1 Pregnancy Risk Summary PROVAYBLUE may cause fetal harm when administered to a pregnant woman. Intra-amniotic injection of pregnant women with a methylene blue class product during the second trimester was associated with neonatal intestinal atresia and fetal death. Methylene blue produced adverse developmental outcomes in rats and rabbits when administered orally during organogenesis at doses at least 32 and 16 times, respectively, the clinical dose of 1 mg/kg (see Data ) . Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2-4% and 15-20%, respectively. Clinical Considerations Fetal/neonatal adverse reactions Intra-amniotic injection of a methylene blue class product hours to days prior to birth can result hyperbilirubinemia, hemolytic anemia, skin staining, methemoglobinemia, respiratory distress and photosensitivity in the newborn. Following administration of PROVAYBLUE to a pregnant woman at term, observe the newborn for these adverse reactions and institute supportive care. Data Animal Data Methylene blue was administered orally to pregnant rats at doses of 50 to 350 mg/kg/day, during the period of organogenesis. Maternal and embryofetal toxicities were observed at all doses of methylene blue and were most evident at the 200 and 350 mg/kg/day doses. Maternal toxicity consisted of increased spleen weight. Embryo-fetal toxicities included reduced fetal weight, post-implantation loss, edema, and malformations including enlarged lateral ventricles. The dose of 200 mg/kg (1200 mg/m 2 ) in rats is approximately 32 times a clinical dose of 1 mg/kg based on body surface area. Methylene blue was administered orally to pregnant rabbits at doses of 50, 100, or 150 mg/kg/day, during the period of organogenesis. Maternal death was observed at the methylene blue dose of 100 mg/kg. Embryofetal toxicities included spontaneous abortion at all dose levels and a malformation (umbilical hernia) at the 100 and 150 mg/kg/day doses. The dose of 50 mg/kg (600 mg/m 2 ) in rabbits is approximately 16 times a clinical dose of 1 mg/kg based on body surface area. 8.2 Lactation Risk Summary There is no information regarding the presence of methylene blue in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions including genotoxicity, discontinue breast-feeding during and for up to 8 days after treatment with PROVAYBLUE [see Clinical Pharmacology ( 12.3 )] . 8.4 Pediatric Use The safety and effectiveness of PROVAYBLUE for the treatment of acquired methemoglobinemia have been established in pediatric patients. Use of PROVAYBLUE is supported by two retrospective case series that included 2 pediatric patients treated with PROVAYBLUE and 12 treated with another methylene blue class product. The case series included pediatric patients in the following age groups: 3 neonates (less than 1 month), 4 infants (1 month up to less than 2 years), 4 children (2 years up to less than 12 years), and 3 adolescents (12 years to less than 17 years). The efficacy outcomes were consistent across pediatric and adult patients in both case series [see Clinical Studies ( 14 )]. 8.5 Geriatric Use Clinical studies of PROVAYBLUE did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. PROVAYBLUE is known to be substantially excreted by the kidney, so the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, treatment of methemoglobinemia in these patients should use the lowest number of doses needed to achieve a response [see Dosage and Administration ( 2 )] . 8.6 Renal Impairment Methylene blue concentrations increased in subjects with renal impairment (eGFR 15 to 89 mL/min/1.73m 2 ) significantly [see Clinical Pharmacology ( 12.3 )] . Adjust PROVAYBLUE dosage in patients with moderate or severe renal impairment (eGFR 15 to 59 mL/min/1.73 m 2 ) [see Dosage and Administration ( 2.2 )] . No dose adjustment is recommended in patients with mild renal impairment (eGFR 60 – 89 mL/min/1.73 m 2 ). 8.7 Hepatic Impairment Methylene blue is extensively metabolized in the liver. Monitor patients with any hepatic impairment for toxicities and potential drug interactions for an extended period of time following treatment with PROVAYBLUE."],"package_label_principal_display_panel":["Principal Display Panel - 50 mg/10 mL (5 mg/mL) Ampule Label NDC 0517 -0374- 01 Rx Only ProvayBlue ® (methylene blue) Injection USP 50 mg/10 mL (5 mg/mL) (0.5%) Intravenous use only Use 5% Dextrose Injection When Diluting Single-Dose Ampule Discard Unused Portion Manufactured by Cenexi for: Provepharm SAS Distributed by: American Regent, INC. Shirley, NY 11967 Ampule Label 10 mL","Principal Display Panel - 50 mg/10 mL (5 mg/mL) Carton Label Rx only NDC 0517 -0374- 05 ProvayBlue ® (methylene blue) Injection USP 5 Single-Dose Ampules. Discard Unused Portion 50 mg/10 mL (5 mg/mL) (0.5%) Intravenous use only For slow intravenous injection Use 5% Dextrose Injection When Diluting Distributed by: AMERICAN REGENT PROVEPHARM 10 mL Carton","Principal Display Panel - 10 mg/2 mL (5 mg/mL) Ampule Label NDC 0517 -0125- 01 Rx Only ProvayBlue ® (methylene blue) Injection USP 10 mg/2 mL (5 mg/mL) (0.5%) Intravenous use only Use 5% Dextrose Injection When Diluting Single Dose Ampule Discard Unused Portion Manufactured by Cenexi for: Provepharm SAS Distributed by: American Regent, INC. Shirley, NY 11967 2 mL Ampule Label","Principal Display Panel - 10 mg/2 mL (5 mg/mL) Carton Label Rx only NDC 0517 -0125- 05 ProvayBlue ® (methylene blue) Injection USP 5 Single-Dose Ampules. Discard Unused Portion 10 mg/2 mL (5 mg/mL) (0.5%) Intravenous use only For slow intravenous injection Use 5% Dextrose Injection When Diluting Distributed by: AMERICAN REGENT PROVEPHARM 2 mL Carton","Principal Display Panel - 50 mg/10 mL (5 mg/mL) Single-Dose Vial Label NDC 0517 -0381- 01 ProvayBlue ® (methylene blue) Injection USP 50 mg/10 mL (5 mg/mL) (0.5%) Rx only Intravenous use only Use 5% Dextrose Injection When Diluting Single-Dose Vial Discard Unused Portion Manufactured by Cenexi for: Provepharm SAS Distributed by: American Regent, Inc. Shirley, NY 11967 Single-Dose Vial Label 10 mL","Principal Display Panel - 50 mg/10 mL (5 mg/mL) Single-Dose Vial Carton Label NDC 0517 -0381- 05 ProvayBlue ® (methylene blue) Injection USP 50 mg/10 mL (5 mg/mL) (0.5%) 5 Single-Dose Vials Discard Unused Portion Intravenous use only For slow intravenous injection Use 5% Dextrose Injection When Diluting Distributed by: AMERICAN REGENT PROVEPHARM Single-Dose Vial Carton Label 10 mL","Principal Display Panel - 10 mg/2 mL (5 mg/mL) Single-Dose Vial Label NDC 0517 -0371- 01 ProvayBlue ® (methylene blue) Injection USP 10 mg/2 mL (5 mg/mL) (0.5%) Rx only Intravenous use only Use 5% Dextrose Injection When Diluting Single-Dose Vial. Discard Unused Portion Manufactured by Cenexi for: Provepharm SAS Distributed by: American Regent, Inc. Shirley, NY 11967 Single-Dose Vial Label 2 mL","Principal Display Panel - 10 mg/2 mL (5 mg/mL) Single-Dose Vial Carton Label Rx only NDC 0517 -0371- 05 ProvayBlue ® (methylene blue) Injection USP 10 mg/2 mL (5 mg/mL) (0.5%) 5 Single-Dose Vials Discard Unused Portion Intravenous use only For slow intravenous injection Use 5% Dextrose Injection When Diluting Distributed by: AMERICAN REGENT PROVEPHARM Single-Dose Vial Carton Label 2 mL"],"carcinogenesis_and_mutagenesis_and_impairment_of_fertility":["13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility In a two-year carcinogenicity study, rats were administered oral doses of methylene blue at 5, 25, or 50 mg/kg. Methylene blue caused pancreatic islet adenomas or carcinomas (combined) in male rats. In a two-year carcinogenicity study, mice were administered oral doses of methylene blue at 2.5, 12.5, or 25 mg/kg. There were no drug-related neoplastic findings in mice. Methylene blue was genotoxic in gene mutation assays in bacteria (Ames test), and in an in vitro sister chromatid exchange test and an in vitro chromosomal aberration test in Chinese hamster ovary (CHO) cells. Methylene blue was negative for micronucleus induction in bone marrow or peripheral blood collected from mice treated with methylene blue. Fertility studies with methylene blue have not been conducted. In vitro, methylene blue reduced motility of human sperm in a concentration dependent manner."]},"tags":[{"label":"Monoamine Oxidase Inhibitors","category":"class"},{"label":"Small Molecule","category":"modality"},{"label":"Amine oxidase [flavin-containing] A","category":"target"},{"label":"MAOA","category":"gene"},{"label":"APP","category":"gene"},{"label":"MAPT","category":"gene"},{"label":"V03AB17","category":"atc"},{"label":"Oral","category":"route"},{"label":"Intravenous","category":"route"},{"label":"Capsule","category":"form"},{"label":"Injection","category":"form"},{"label":"Tablet","category":"form"},{"label":"Active","category":"status"},{"label":"Methemoglobinemia","category":"indication"},{"label":"Enzyme Inhibitors","category":"pharmacology"}],"phase":"marketed","safety":{"boxedWarnings":["WARNING: SEROTONIN SYNDROME WITH CONCOMITANT USE OF SEROTONERGIC DRUGS AND OPIOIDS PROVAYBLUE may cause serious or fatal serotonergic syndrome when used in combination with serotonergic drugs and opioids. Avoid concomitant use of PROVAYBLUE with selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs) and opioids. [see Warnings and Precautions ( 5.1 ) and Drug Interactions ( 7.1 )]. WARNING: SEROTONIN SYNDROME WITH CONCOMITANT USE OF SEROTONERGIC DRUGS AND OPIOIDS See full prescribing information for complete boxed warning. PROVAYBLUE may cause serious or fatal serotonergic syndrome when used in combination with serotonergic drugs and opioids. Avoid concomitant use of PROVAYBLUE with selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs) and opioids. ( 5.1 , 7.1 )"],"safetySignals":[{"llr":1802.228,"date":"","count":417,"signal":"Serotonin syndrome","source":"DrugCentral FAERS","actionTaken":"Reported 417 times (LLR=1802)"},{"llr":523.304,"date":"","count":294,"signal":"Drug interaction","source":"DrugCentral FAERS","actionTaken":"Reported 294 times (LLR=523)"},{"llr":324.343,"date":"","count":53,"signal":"Myoglobin urine present","source":"DrugCentral FAERS","actionTaken":"Reported 53 times (LLR=324)"},{"llr":267.539,"date":"","count":69,"signal":"Toxic encephalopathy","source":"DrugCentral FAERS","actionTaken":"Reported 69 times (LLR=268)"},{"llr":189.865,"date":"","count":53,"signal":"Amylase increased","source":"DrugCentral FAERS","actionTaken":"Reported 53 times (LLR=190)"},{"llr":163.025,"date":"","count":53,"signal":"Troponin increased","source":"DrugCentral FAERS","actionTaken":"Reported 53 times (LLR=163)"},{"llr":157.162,"date":"","count":41,"signal":"Clonus","source":"DrugCentral FAERS","actionTaken":"Reported 41 times (LLR=157)"},{"llr":151.475,"date":"","count":35,"signal":"Vasoplegia syndrome","source":"DrugCentral FAERS","actionTaken":"Reported 35 times (LLR=151)"},{"llr":140.622,"date":"","count":54,"signal":"Blood potassium increased","source":"DrugCentral FAERS","actionTaken":"Reported 54 times (LLR=141)"},{"llr":140.288,"date":"","count":39,"signal":"Hyperreflexia","source":"DrugCentral FAERS","actionTaken":"Reported 39 times (LLR=140)"},{"llr":140.096,"date":"","count":67,"signal":"Blood creatine phosphokinase increased","source":"DrugCentral FAERS","actionTaken":"Reported 67 times (LLR=140)"},{"llr":128.117,"date":"","count":63,"signal":"Encephalopathy","source":"DrugCentral FAERS","actionTaken":"Reported 63 times (LLR=128)"},{"llr":122.54,"date":"","count":53,"signal":"Blood lactate dehydrogenase increased","source":"DrugCentral FAERS","actionTaken":"Reported 53 times (LLR=123)"},{"llr":106.296,"date":"","count":33,"signal":"Nystagmus","source":"DrugCentral FAERS","actionTaken":"Reported 33 times (LLR=106)"},{"llr":105.271,"date":"","count":64,"signal":"Coma","source":"DrugCentral FAERS","actionTaken":"Reported 64 times (LLR=105)"}],"drugInteractions":[{"url":"/drug/alpha/beta-agonists","drug":"Alpha/Beta Agonists","action":"Use caution","effect":"MAO Inhibitors may enhance the hypertensive effect of Alpha/Beta-Agonists","source":"DrugCentral","drugSlug":"alpha/beta-agonists"},{"url":"/drug/amphetamines","drug":"Amphetamines","action":"Use caution","effect":"MAO Inhibitors may enhance the hypertensive effect of amphetamines","source":"DrugCentral","drugSlug":"amphetamines"},{"url":"/drug/indirectly-acting-sympathomimetic-amines","drug":"Indirectly Acting Sympathomimetic Amines","action":"Contraindicated","effect":"potentially fatal hypertensive crisis","source":"DrugCentral","drugSlug":"indirectly-acting-sympathomimetic-amines"},{"url":"/drug/selective-serotonin-reuptake-inhibitors","drug":"Selective Serotonin Reuptake Inhibitors","action":"Contraindicated","effect":"serotonin syndrome","source":"DrugCentral","drugSlug":"selective-serotonin-reuptake-inhibitors"},{"url":"/drug/serotonin/norepinephrine-reuptake-inhibitors","drug":"Serotonin/Norepinephrine Reuptake Inhibitors","action":"Contraindicated","effect":"serotonin syndrome","source":"DrugCentral","drugSlug":"serotonin/norepinephrine-reuptake-inhibitors"},{"url":"/drug/tricyclic-antidepressants","drug":"Tricyclic Antidepressants","action":"Contraindicated","effect":"very toxic and sometimes fatal reactions the serotonin syndrome or similar","source":"DrugCentral","drugSlug":"tricyclic-antidepressants"},{"url":"/drug/almotriptan","drug":"almotriptan","action":"Avoid combination","effect":"May interact with Almotriptan, Methylene Blue","source":"DrugCentral","drugSlug":"almotriptan"},{"url":"/drug/bupivacaine","drug":"bupivacaine","action":"Avoid combination","effect":"May interact with Bupivacaine, Methylene Blue","source":"DrugCentral","drugSlug":"bupivacaine"},{"url":"/drug/buspirone","drug":"buspirone","action":"Use caution","effect":"May increase blood pressure","source":"DrugCentral","drugSlug":"buspirone"},{"url":"/drug/dextromethorphan","drug":"dextromethorphan","action":"Contraindicated","effect":"fatal/non-fatal reactions","source":"DrugCentral","drugSlug":"dextromethorphan"},{"url":"/drug/eletriptan","drug":"eletriptan","action":"Avoid combination","effect":"May interact with Eletriptan, Methylene Blue","source":"DrugCentral","drugSlug":"eletriptan"},{"url":"/drug/frovatriptan","drug":"frovatriptan","action":"Avoid combination","effect":"May interact with Frovatriptan, Methylene Blue","source":"DrugCentral","drugSlug":"frovatriptan"},{"url":"/drug/isocarboxazid","drug":"isocarboxazid","action":"Avoid combination","effect":"May interact with Isocarboxazid, Methylene Blue","source":"DrugCentral","drugSlug":"isocarboxazid"},{"url":"/drug/levodopa","drug":"levodopa","action":"Contraindicated","effect":"life-threatening hypertensive reaction","source":"DrugCentral","drugSlug":"levodopa"},{"url":"/drug/linezolid","drug":"linezolid","action":"Avoid combination","effect":"May interact with Linezolid, Methylene Blue","source":"DrugCentral","drugSlug":"linezolid"},{"url":"/drug/mepivacaine","drug":"mepivacaine","action":"Avoid combination","effect":"May interact with Mepivacaine, Methylene Blue","source":"DrugCentral","drugSlug":"mepivacaine"},{"url":"/drug/methyldopa","drug":"methyldopa","action":"Use caution","effect":"hypertension may occur","source":"DrugCentral","drugSlug":"methyldopa"},{"url":"/drug/mirtazapine","drug":"mirtazapine","action":"Contraindicated","effect":"Label warning","source":"DrugCentral","drugSlug":"mirtazapine"},{"url":"/drug/naratriptan","drug":"naratriptan","action":"Avoid combination","effect":"May interact with Methylene Blue, Naratriptan Hydrochloride","source":"DrugCentral","drugSlug":"naratriptan"},{"url":"/drug/pargyline","drug":"pargyline","action":"Avoid combination","effect":"May interact with Methylene Blue, Pargyline","source":"DrugCentral","drugSlug":"pargyline"}],"commonSideEffects":[{"effect":"headache","drugRate":">2%","_validated":true,"placeboRate":""},{"effect":"hypokalemia","drugRate":">2%","_validated":true,"placeboRate":""},{"effect":"diarrhea","drugRate":">2%","_validated":true,"placeboRate":""},{"effect":"hypomagnesemia","drugRate":">2%","_validated":true,"placeboRate":""},{"effect":"myoclonus","drugRate":">2%","_validated":true,"placeboRate":""},{"effect":"nausea","drugRate":">2%","_validated":true,"placeboRate":""},{"effect":"seizure-like phenomena","drugRate":">2%","_validated":true,"placeboRate":""}],"contraindications":["Achalasia of esophagus","Acute nephropathy","Anemia","Anemia due to enzyme deficiency","Atony of colon","Benign prostatic hyperplasia","Bladder outflow obstruction","Blood coagulation disorder","Body fluid retention","Breastfeeding (mother)","Cardiovascular event risk","Chronic heart failure","Cirrhosis of liver","Conduction disorder of the heart","Deficiency of glucose-6-phosphate dehydrogenase","Diabetes mellitus","Disease of liver","Disorder of autonomic nervous system","Disorder of cardiovascular system","Disorder of coronary artery","Edema","Factor II deficiency","Fever greater than 100.4 Fahrenheit","Gastritis","Gastroesophageal reflux disease"],"specialPopulations":{"Pregnancy":"Only use during pregnancy if the potential benefit justifies the potential risk to the fetus. May cause fetal harm when administered to pregnant woman. Intra-amniotic injection of pregnant women with methylene blue class product during the second trimester was associated with neonatal intestinal atresia and fetal death. Methylene blue produced adverse developmental outcomes in rats and rabbits when administered orally during organogenesis at doses at least 32 and 16 times, respectively, the clinical dose of mg/kg. Risk Summary: PROVAYBLUE (R) may cause fetal harm when administered to pregnant woman. Intra-amniotic injection of pregnant women with methylene blue class product during the second trimester was associated with neonatal intestinal atresia and fetal death. Methylene blue produced adverse developmental outcomes in rats and rabbits when administered orally during organogenesis at doses at least 32 and 16 times, respectively, the clinical dose of mg/kg [see Data] Advise pregnant women of the potential risk to fetus. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2-4% and 15-20%, respectively.","Geriatric use":"The retrospective case series included patients age 65 years and over treated with PROVAYBLUE (R) (or bioequivalent formulation) and treated with another methylene blue class product. The efficacy outcomes were consistent across adult and elderly patients in both case series [see Clinical Studies 14)] This drug is known to be substantially excreted by the kidney, so the risk of adverse reactions to this drug may be greater in patients with impaired renal function.","Paediatric use":"The safety and effectiveness of PROVAYBLUE (R) have been established in pediatric patients. Use of PROVAYBLUE (R) is supported by two retrospective case series that included pediatric patients treated with PROVAYBLUE (R) and 12 treated with another methylene blue class product. The case series included pediatric patients in the following age groups: neonates (less than month), infants (1 month up to less than years), children (2 years up to less than 12 years), and adolescents","Renal impairment":"This drug is known to be substantially excreted by the kidney, so the risk of adverse reactions to this drug may be greater in patients with impaired renal function.","Hepatic impairment":"Monitor patients longer for toxicity and drug interactions due to delayed clearance."},"seriousAdverseEvents":[{"event":"seizure-like phenomenon","detail":"reported in one patient","severity":"serious","incidence":"1 patient"}]},"trials":[],"aliases":[],"patents":[],"pricing":[],"_sources":{"trials":{"url":"https://clinicaltrials.gov/search?intr=methylthioninium chloride","method":"api_direct","source":"ClinicalTrials.gov","rawText":"","confidence":1,"sourceType":"ctgov","retrievedAt":"2026-04-20T01:03:53.834026+00:00"},"timeline":{"url":"https://en.wikipedia.org/wiki/Methylthioninium Chloride","method":"deterministic","source":"Wikipedia","rawText":"","confidence":0.8,"sourceType":"wikipedia","retrievedAt":"2026-04-20T01:04:03.516390+00:00"},"regulatory.ca":{"url":"","method":"api_direct","source":"Health Canada DPD","rawText":"","confidence":1,"sourceType":"health_canada_dpd","retrievedAt":"2026-04-20T01:04:00.674657+00:00"},"publicationCount":{"url":"https://pubmed.ncbi.nlm.nih.gov/?term=methylthioninium chloride","method":"api_direct","source":"PubMed/NCBI","rawText":"","confidence":1,"sourceType":"pubmed","retrievedAt":"2026-04-20T01:04:01.821613+00:00"},"administration.route":{"url":"","method":"deterministic","source":"FDA Label","rawText":"","confidence":1,"sourceType":"fda_label","retrievedAt":"2026-04-20T01:03:51.609399+00:00"},"safety.boxedWarnings":{"url":"","method":"deterministic","source":"FDA Label (boxed_warning)","rawText":"WARNING: SEROTONIN SYNDROME WITH CONCOMITANT USE OF SEROTONERGIC DRUGS AND OPIOIDS PROVAYBLUE may cause serious or fatal serotonergic syndrome when used in combination with serotonergic drugs and opioids. Avoid concomitant use of PROVAYBLUE with selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs) and opioids. [see Warnings and Precautions ( 5.1 ) and Drug Interactions ( 7.1 )]. WARNING: SEROTONIN SYNDROME WIT","confidence":1,"sourceType":"fda_label","retrievedAt":"2026-04-20T01:03:51.617746+00:00"},"mechanism.target_chembl":{"url":"","method":"api_direct","source":"ChEMBL mechanism: Soluble guanylate cyclase inhibitor","rawText":"","confidence":1,"sourceType":"chembl","retrievedAt":"2026-04-20T01:04:03.516287+00:00"},"crossReferences.chemblId":{"url":"https://www.ebi.ac.uk/chembl/compound_report_card/CHEMBL405110/","method":"api_direct","source":"ChEMBL (EMBL-EBI)","rawText":"","confidence":1,"sourceType":"chembl","retrievedAt":"2026-04-20T01:04:03.410682+00:00"},"safety.commonSideEffects":{"url":"","method":"ai_extraction","source":"FDA Label + AI","aiModel":"featherless","rawText":"6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: Serotonin Syndrome with Concomitant Use of Serotonergic Drugs [see Warnings and Precautions ( 5.1 )] Anaphylaxis [see Warnings and Precautions ( 5.2 )] Lack of Effectiveness [see Warnings and Precautions ( 5.3 )] Hemolytic Anemia [see Warnings and Precautions ( 5.4 )] Interference with In-Vivo Monitoring Devices [see Warnings and Precautions ( 5.5 )] Effects on Ability to Drive ","confidence":0.95,"sourceType":"fda_label","retrievedAt":"2026-04-20T01:04:18.574908+00:00"},"regulatory.fda_application":{"url":"","method":"deterministic","source":"FDA Label","rawText":"NDA204630","confidence":1,"sourceType":"fda_label","retrievedAt":"2026-04-20T01:03:51.617758+00:00"}},"allNames":"provayblue","offLabel":[],"synonyms":["methylthioninium benzalkonium chloride hydrate","methylthioninium chloride hydrate","methylenum coeruleum","methylthioninium chloratum","methylene blue","methylthioninium chloride","aizen methylene blue","proveblue"],"timeline":[],"approvals":[{"date":"","orphan":false,"company":"","regulator":"FDA"}],"brandName":"Provayblue","ecosystem":[{"indication":"Methemoglobinemia","otherDrugs":[],"globalPrevalence":null}],"mechanism":{"target":"Amine oxidase [flavin-containing] A","novelty":"First-in-class","targets":[{"gene":"MAOA","source":"DrugCentral","target":"Amine oxidase [flavin-containing] A","protein":"Amine oxidase [flavin-containing] A"},{"gene":"APP","source":"DrugCentral","target":"Amyloid beta A4 protein","protein":"Amyloid beta A4 protein"},{"gene":"MAPT","source":"DrugCentral","target":"Microtubule-associated protein tau","protein":"Microtubule-associated protein tau"},{"gene":"MAOB","source":"DrugCentral","target":"Amine oxidase [flavin-containing] B","protein":"Amine oxidase [flavin-containing] B"},{"gene":"GSR","source":"DrugCentral","target":"Glutathione reductase, mitochondrial","protein":"Glutathione reductase, mitochondrial"},{"gene":"TXNRD1","source":"DrugCentral","target":"Thioredoxin reductase 1, cytoplasmic","protein":"Thioredoxin reductase 1, cytoplasmic"}],"modality":"Small Molecule","drugClass":"Monoamine Oxidase Inhibitors","explanation":"Methylene blue is water soluble thiazine dye that promotes non-enzymatic redox conversion of metHb to hemoglobin. In situ, methylene blue is first converted to leucomethylene blue (LMB) via NADPH reductase. It is the LMB molecule which then reduces the ferric iron of metHb to the ferrous state of normal hemoglobin.","oneSentence":"Provayblue works by inhibiting the enzyme amine oxidase [flavin-containing] A, which is involved in the breakdown of certain amines in the body.","technicalDetail":"Provayblue (methylthioninium chloride) competitively inhibits the flavin-containing amine oxidase enzyme, preventing the oxidation of certain amines and thereby reducing the formation of methemoglobin.","_target_confidence":0.5},"_wikipedia":{"url":"https://en.wikipedia.org/wiki/Methylene_blue","title":"Methylene blue","extract":"Methylthioninium chloride, commonly called methylene blue, is a salt used as a dye and as a medication. As a medication, it is mainly used to treat methemoglobinemia. It has previously been used for treating cyanide poisoning and urinary tract infections, but this use is no longer recommended. It has also been used to treat cases of malaria for over a century.","wiki_history":"==History==\nMethylene blue has been described as \"the first fully synthetic drug used in medicine\". Methylene blue was first prepared in 1876 by German chemist Heinrich Caro.\n\nIts use in the treatment of malaria was pioneered by Paul Guttmann and Paul Ehrlich in 1891. During this period before World War I, researchers like Ehrlich believed that drugs and dyes worked in the same way, by preferentially staining pathogens and possibly harming them. Changing the cell membrane of pathogens is how various drugs work, so the theory was partially correct, although far from complete. Methylene blue continued to be used in World War II, where it was not well-liked by soldiers, who observed, \"Even at the loo, we see, we pee, navy blue.\"\n\nIt was discovered to be an antidote to carbon monoxide poisoning and cyanide poisoning in 1933 by Matilda Brooks.\n\nMethylene blue was the original prototype or lead compound for the design of many antimalarials including chloroquine, antihistamines, and antipsychotics including chlorpromazine.","wiki_society_and_culture":"== Society and culture ==\nIn the late 2010s and early 2020s, a social media trend emerged promoting the use of methylene blue for various medical purposes, including anti-aging, metabolism enhancement, cognitive improvement, cancer treatment, and COVID-19 treatment. Currently there is no scientific consensus on, and no FDA approval for, its effectiveness and safety for these purposes. and skin aging. It was also explored as part of anticancer photodynamic therapy using lasers. One systematic review of the studies expresses optimism but emphasizes the need for more extensive research to confirm methylene blue's clinical applications. Another review takes a more critical stance, stating that \"it is obvious that the clinical use of [methylene blue] represents a rather controversial problem given the heterogeneity of available data and the lack of preclinical data, which is in conflict with standards of safe use of such substances in human medicinal practice\".\n\nIn January 2025, Robert F. Kennedy Jr, then the U.S. health secretary nominee, was filmed adding droplets of an unidentified blue liquid to his drink during a flight. While many have speculated that it was methylene blue, Kennedy has not addressed the claims."},"commercial":{},"references":[{"id":1,"url":"https://drugcentral.org/drugcard/1763","fields":["approvals","synonyms","ATC","PK","indications","contraindications","DDIs","targets","patents","FAERS"],"source":"DrugCentral"},{"id":2,"url":"https://clinicaltrials.gov/search?intr=methylthioninium%20chloride","fields":["trials"],"source":"ClinicalTrials.gov"},{"id":3,"url":"https://pubmed.ncbi.nlm.nih.gov/?term=methylthioninium chloride","fields":["publications"],"source":"PubMed/NCBI"},{"id":4,"url":"https://en.wikipedia.org/wiki/Methylene_blue","fields":["history","overview"],"source":"Wikipedia"}],"_enrichedAt":"2026-03-30T14:26:38.038699","_validation":{"fieldsValidated":1,"lastValidatedAt":"2026-04-20T01:04:21.634070+00:00","fieldsConflicting":1,"overallConfidence":0.8},"biosimilars":[],"competitors":[{"drugName":"nalorphine","drugSlug":"nalorphine","fdaApproval":"","relationship":"same-class"},{"drugName":"pralidoxime","drugSlug":"pralidoxime","fdaApproval":"1964-03-11","patentStatus":"Unknown","relationship":"same-class"},{"drugName":"prednisolone","drugSlug":"prednisolone","fdaApproval":"1955-06-21","genericCount":42,"patentStatus":"Off-patent — generic available","relationship":"same-class"},{"drugName":"promethazine","drugSlug":"promethazine","fdaApproval":"1951-03-29","genericCount":48,"patentStatus":"Off-patent — generic available","relationship":"same-class"},{"drugName":"sodium nitrite","drugSlug":"sodium-nitrite","fdaApproval":"2011-01-14","patentExpiry":"Feb 10, 2030","patentStatus":"Patent protected","relationship":"same-class"},{"drugName":"dimercaprol","drugSlug":"dimercaprol","fdaApproval":"1946-05-06","patentStatus":"Unknown","relationship":"same-class"},{"drugName":"protamine sulfate","drugSlug":"protamine-sulfate","fdaApproval":"1969-08-13","genericCount":2,"patentStatus":"Off-patent — generic available","relationship":"same-class"},{"drugName":"naloxone","drugSlug":"naloxone","fdaApproval":"1971-04-13","patentExpiry":"Oct 30, 2028","patentStatus":"Patent protected","relationship":"same-class"},{"drugName":"ethanol","drugSlug":"ethanol","fdaApproval":"1946-01-17","patentStatus":"Unknown","relationship":"same-class"},{"drugName":"copper sulfate","drugSlug":"copper-sulfate","fdaApproval":"1987-05-05","relationship":"same-class"},{"drugName":"potassium iodide","drugSlug":"potassium-iodide","fdaApproval":"1979-11-09","genericCount":3,"patentStatus":"Off-patent — generic available","relationship":"same-class"},{"drugName":"amyl nitrite","drugSlug":"amyl-nitrite","fdaApproval":"","relationship":"same-class"},{"drugName":"acetylcysteine","drugSlug":"acetylcysteine","fdaApproval":"1963-09-14","patentExpiry":"May 8, 2032","patentStatus":"Patent protected","relationship":"same-class"},{"drugName":"flumazenil","drugSlug":"flumazenil","fdaApproval":"1991-12-20","genericCount":8,"patentStatus":"Off-patent — generic available","relationship":"same-class"},{"drugName":"methionine","drugSlug":"methionine","fdaApproval":"","relationship":"same-class"},{"drugName":"prussian blue","drugSlug":"prussian-blue","fdaApproval":"2003-10-02","relationship":"same-class"},{"drugName":"hydroxocobalamin","drugSlug":"hydroxocobalamin","fdaApproval":"1978-08-16","genericCount":5,"patentStatus":"Off-patent — generic available","relationship":"same-class"},{"drugName":"fomepizole","drugSlug":"fomepizole","fdaApproval":"1997-12-04","patentExpiry":"Jun 30, 2027","patentStatus":"Patent protected","relationship":"same-class"},{"drugName":"sugammadex","drugSlug":"sugammadex","fdaApproval":"2015-12-15","patentExpiry":"Jul 27, 2026","patentStatus":"Patent protected","relationship":"same-class"},{"drugName":"phentolamine","drugSlug":"phentolamine","fdaApproval":"1952-01-30","patentExpiry":"Oct 25, 2039","patentStatus":"Patent protected","relationship":"same-class"}],"genericName":"methylthioninium chloride","indications":{"approved":[{"name":"Methemoglobinemia","source":"DrugCentral","snomedId":38959009,"regulator":"FDA","eligibility":"Drug-induced methemoglobinemia"}],"offLabel":[],"pipeline":[]},"drugCategory":"active","labelChanges":[],"relatedDrugs":[{"drugId":"nalorphine","brandName":"nalorphine","genericName":"nalorphine","approvalYear":"","relationship":"same-class"},{"drugId":"pralidoxime","brandName":"pralidoxime","genericName":"pralidoxime","approvalYear":"1964","relationship":"same-class"},{"drugId":"prednisolone","brandName":"prednisolone","genericName":"prednisolone","approvalYear":"1955","relationship":"same-class"},{"drugId":"promethazine","brandName":"promethazine","genericName":"promethazine","approvalYear":"1951","relationship":"same-class"},{"drugId":"sodium-nitrite","brandName":"sodium nitrite","genericName":"sodium nitrite","approvalYear":"2011","relationship":"same-class"},{"drugId":"dimercaprol","brandName":"dimercaprol","genericName":"dimercaprol","approvalYear":"1946","relationship":"same-class"},{"drugId":"protamine-sulfate","brandName":"protamine sulfate","genericName":"protamine sulfate","approvalYear":"1969","relationship":"same-class"},{"drugId":"naloxone","brandName":"naloxone","genericName":"naloxone","approvalYear":"1971","relationship":"same-class"},{"drugId":"ethanol","brandName":"ethanol","genericName":"ethanol","approvalYear":"1946","relationship":"same-class"},{"drugId":"copper-sulfate","brandName":"copper sulfate","genericName":"copper sulfate","approvalYear":"1987","relationship":"same-class"}],"trialDetails":[{"nctId":"NCT07494773","phase":"PHASE1,PHASE2","title":"Topical Methylene Blue-Photodynamic Therapy (MB-PDT) for Burn Wound Infection","status":"NOT_YET_RECRUITING","sponsor":"University of Oklahoma","startDate":"2026-06-01","conditions":["Burns","Wound Infection"],"enrollment":50,"completionDate":"2028-05-31"},{"nctId":"NCT07264543","phase":"PHASE2,PHASE3","title":"Early Methylene Blue in the Microhemodynamics of Septic Patients","status":"RECRUITING","sponsor":"Centro de Estudos e Pesquisa em Emergencias Medicas e Terapia 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Gastrectomy","Obesity & Overweight","Obesity Type 2 Diabetes Mellitus","Obstructive Sleep Apnea (OSA)","Hypertension (HTN)","Osteo Arthritis of the Knee"],"enrollment":60,"completionDate":"2025-09-01"},{"nctId":"NCT06426550","phase":"NA","title":"Clinical and Microbiological Evaluation of Laser Therapy in the Treatment of Periodontal Disease in Stages III and IV","status":"COMPLETED","sponsor":"Universidade Federal Fluminense","startDate":"2024-05-06","conditions":["Periodontitis","Periodontitis, Adult"],"enrollment":20,"completionDate":"2026-02-02"},{"nctId":"NCT06416462","phase":"NA","title":"Action of Photodynamic Therapy on Wound Quality and Tissue Repair in the Diabetic Foot","status":"COMPLETED","sponsor":"University of Nove de Julho","startDate":"2024-07-30","conditions":["Diabetic Foot Ulcer"],"enrollment":94,"completionDate":"2024-12-01"},{"nctId":"NCT04234971","phase":"PHASE4","title":"Cost Effectiveness in Alveolar Bone Grafting in Patients With Cleft Lip and Palate","status":"RECRUITING","sponsor":"The University of Texas Health Science Center, Houston","startDate":"2021-06-14","conditions":["Cleft Lip and Palate"],"enrollment":40,"completionDate":"2028-01-01"},{"nctId":"NCT05894954","phase":"PHASE3","title":"Precision Medicine Approach for Early Dementia & Mild Cognitive Impairment","status":"COMPLETED","sponsor":"Alzheimer's Prevention and Reversal Project, Inc.","startDate":"2023-07-31","conditions":["Mild Cognitive Impairment","Dementia, Mild"],"enrollment":73,"completionDate":"2026-02-09"},{"nctId":"NCT06810882","phase":"NA","title":"Intravenous Versus Perineural Ondansetron for Laparoscopic Sleeve Gastrectomy","status":"RECRUITING","sponsor":"Tanta University","startDate":"2025-02-16","conditions":["Ondansetron","Laparoscopic","Gastrectomy"],"enrollment":170,"completionDate":"2026-12-17"},{"nctId":"NCT06052956","phase":"PHASE2","title":"Efficacy of Methylene Blue Photodynamic Therapy for Treatment of Deep Tissue 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Gynaecological Cancer","startDate":"2021-01-18","conditions":["Endometrial Cancer Stage I","Sentinel Lymph Node","Surgery"],"enrollment":760,"completionDate":"2031-02"},{"nctId":"NCT07373015","phase":"NA","title":"Modified Double Snare Assisted EMR (mDS-EMR) VS ESD for Rectal Neuroendocrine Tumors Smaller Than 1cm","status":"NOT_YET_RECRUITING","sponsor":"The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School","startDate":"2026-01-01","conditions":["Rectal Neuroendocrine Tumors"],"enrollment":118,"completionDate":"2028-06-30"},{"nctId":"NCT07040540","phase":"","title":"Hemodynamic Effects of Intradermal Methylene Blue During Breast Surgery Under General Anesthesia","status":"COMPLETED","sponsor":"Dr Abdurrahman Yurtaslan Ankara Oncology Training and Research Hospital","startDate":"2025-07-01","conditions":["Breast Cancer","Breast Surgery","Sentinel Lymph Node Biopsy","Methylene Blue","Hemodynamic Stability","Intraoperative Hypotension"],"enrollment":220,"completionDate":"2026-01-10"},{"nctId":"NCT04854005","phase":"","title":"Use of Sentinel Lymph Node Biopsy in Patients With Early-Stage, Palpable Node-Positive HR+/HER2- Breast Cancer Having Upfront Surgery and Adjuvant Radiation","status":"ACTIVE_NOT_RECRUITING","sponsor":"Memorial Sloan Kettering Cancer Center","startDate":"2021-04-20","conditions":["Breast Cancer"],"enrollment":78,"completionDate":"2026-04"},{"nctId":"NCT07324954","phase":"PHASE1","title":"Methylene Blue in Total Knee Arthroplasty (TKA)","status":"NOT_YET_RECRUITING","sponsor":"University of Miami","startDate":"2026-02-01","conditions":["Total Knee Arthroplasty","Prosthetic-joint Infection","Irrigation"],"enrollment":20,"completionDate":"2027-02-01"},{"nctId":"NCT07311070","phase":"PHASE3","title":"Treatment of Basal Cell Carcinoma (BCC) of the Skin, of the Morpheiform, Infiltrative, and Noduloulcerative Types in Inoperable Patients and Not Suitable for Radiotherapy Using Formulated Methylene Blue","status":"ENROLLING_BY_INVITATION","sponsor":"Daryoush Hamidi Alamdari, PhD","startDate":"2025-10-21","conditions":["Advanced Basal Cell Carcinoma (BCC)","Inoperable Disease","Morpheaform Basal Cell Carcinoma","Noduloulcerative Basal Cell Carcinoma","Infiltrative Basal Cell Carcinoma"],"enrollment":20,"completionDate":"2026-01-20"},{"nctId":"NCT07311057","phase":"PHASE3","title":"Investigation of Effect of Formulated Methylene Blue on Treatment of Squamous Cell Carcinoma Skin Cancer in Inoperable Patients and Not Suitable for Radiotherapy","status":"ENROLLING_BY_INVITATION","sponsor":"Daryoush Hamidi Alamdari, PhD","startDate":"2025-12-20","conditions":["SCC - Squamous Cell Carcinoma","SCC - Squamous Cell Carcinoma of Skin","Inoperable Disease"],"enrollment":20,"completionDate":"2026-01-20"},{"nctId":"NCT03609944","phase":"NA","title":"SpHincterotomy for Acute Recurrent Pancreatitis","status":"COMPLETED","sponsor":"Oregon Health and Science 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