d norepinephrine reuptake inhibitors (snris), monoamine oxidase inhibitors). 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. 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.

s 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 m2) 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 and storage each ml of provayblue ® contains 5 mg methylene blue. each 10 ml ampule and vial of provayblue ® contains 50 mg methylene blue. each 2 ml ampule and vial of provayblue ® contains 10 mg methylene blue. 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. keep the ampule and the vial in the original package to protect from light. discard unused portion.

inical 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 ® was determined in 82 healthy adults of median age of 36 years (range, 19-55 years); 54% were male, and 68% were white. each individual in the safety population received a single dose of provayblue ® 2 mg/kg intravenously. there was one serious adverse reaction reported (syncope due to sinus pauses of 3-14 seconds). the most common (≥2%) moderate or severe adverse reactions were pain in the extremity (56%), headache (7%), feeling hot (6%), syncope (4%), back pain (2%), hyperhidrosis (2%) and nausea (2%). table 1 lists the adverse reactions of any severity that occurred in at least 2% of individuals who received provayblue ® . table 1. adverse reactions following infusion of provayblue ® 2 mg/kg adverse reaction any grade teae (n=82) moderate- severe teae (n=82) pain in extremity 69 84% 46 56% chromaturia 61 74% 0 dysgeusia 16 20% 1 1% feeling hot 14 17% 5 6% dizziness 13 16% 4 5% hyperhidrosis 11 13% 2 2% nausea 11 13% 2 2% skin discoloration 11 13% 0 headache 8 10% 6 7% musculoskeletal pain 7 9% 0 paresthesia oral 7 9% 0 paresthesia 7 9% 0 infusion site pain 5 6% 1 1% feeling cold 5 6% 0 pallor 4 5% 0 dermatitis contact 4 5% 0 syncope 3 4% 3 4% influenza like illness 3 4% 1 1% pruritus 3 4% 1 1% anxiety 3 4% 0 decreased appetite 3 4% 0 chest discomfort 3 4% 0 back pain 2 2% 2 2% cold sweat 2 2% 1 1% dizziness postural 2 2% 1 1% muscle spasms 2 2% 1 1% presyncope 2 2% 1 1% vomiting 2 2% 1 1% arthralgia 2 2% 1 1% chills 2 2% 0 diarrhea 2 2% 0 discomfort 2 2% 0 dyspnea 2 2% 0 erythema 2 2% 0 hypoesthesia oral 2 2% 0 infusion site discomfort 2 2% 0 limb discomfort 2 2% 0 oral discomfort 2 2% 0 catheter site pain 2 2% 0 ecchymosis 2 2% 0 other adverse reactions reported to occur following administration of methylene blue class products include the following: blood and lymphatic system disorders : hemolytic anemia, hemolysis, hyperbilirubinemia, methemoglobinemia 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

ognized 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 ® 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 the retrospective case series included 3 patients age 65 years and over treated with provayblue ® (or a bioequivalent formulation) and 5 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. 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 ® .

rn. 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.

te 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. cmax 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.

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. cmax 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.

at least 50% within 1 hour after intravenous administration of the methylene blue class product. in a combined analysis of all 47 patients treated intravenously with provayblue ® (or a bioequivalent formulation) or with another methylene blue class product, there was no difference in response rate by dose. the methemoglobin decreased by at least 50% within 1 hour of infusion for 15/17 (88%) of patients treated with 1 mg/kg, 12/13 (92%) treated with 2 mg/kg and 16/17 (94%) treated with a different dose or for those whose dose was not reported.

zziness 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