ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. Clinically significant adverse reactions are described elsewhere in the labeling:Cardiovascular Reactions [see Warnings and Precautions (5.1)] Hypersensitivity Reactions [see Warnings and Precautions (5.2)] Cardiovascular Reactions [see Warnings and Precautions (5.1)] Hypersensitivity Reactions [see Warnings and Precautions (5.2)] Adverse reactions (>= 1%) are constipation, nausea, vomiting, abdominal pain, pyrexia, ALT increase, and dysuria. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact PROVEPHARM Inc at 1-833-727-6556 or 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 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 BLUDIGO was evaluated in randomized, intra-patient controlled, blind to dose of BLUDIGO, clinical trial. total of 118 adult patients undergoing endoscopic urological or gynecological procedures were treated intravenously; 58 (49%) of these patients received one dose of BLUDIGO 2.5 mL and 60 (51%) of patients received one dose of BLUDIGO mL. The 2.5 mL dose is not approved [see Dosage and Administration (2.1)]. The mean age of patients was 51 years and 35 (30%) patients were 65 years of age or older. The majority of patients were White 105 (89%) and female 87 (74%).The adverse reactions (>=1%) reported in the clinical trial are provided in Table 1.Table 1. Adverse Reactions Reported at >=1% of Patients Receiving BLUDIGO mL Intravenously BLUDIGO mL(N=60)n (%) Constipation (5.0) Nausea (3.3) Vomiting (3.3) Abdominal Pain (3.3) Pyrexia (3.3) ALT increase (3.3) Dysuria (1.7). 6.2 Postmarketing Experience. The following adverse reactions have been identified following the use of indigotindisulfonate sodium injection products.Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. Cardiovascular disorders: cardiac arrest, arrhythmia, asystole, atrioventricular block second degree, hypotension, elevation in blood pressure, bradycardia, tachycardia General disorders and administration site conditions: injection site discoloration Immune system disorders: anaphylactic reactions with hypotension, dyspnea, bronchospasm, urticaria, erythema.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenicityCarcinogenicity studies in animals have not been conducted with indigotindisulfonate sodium using the intravenous route of administration.Long-term studies in mice with oral and subcutaneous administration of indigotindisulfonate sodium revealed no carcinogenic effects.MutagenesisAlthough indigotindisulfonate sodium has been evaluated in number of Ames assay studies, an Ames assay study that follows all currently recommended guidelines has not been performed. Indigotindisulfonate was not genotoxic in all those Ames assays.The mutagenicity of indigotindisulfonate was inconclusive in the in vitro mouse L5187Y Lymphoma TK +/- assay. Orally administered indigotindisulfonate was not mutagenic in the in vivo mouse micronucleus test. An in vivo micronucleus test with indigotindisulfonate sodium using the intravenous route of administration has not been conducted.FertilityFertility studies with indigotindisulfonate sodium using the intravenous route of administration have not been conducted.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Indigotindisulfonate is dye excreted by the kidney through tubular secretion and enhances visualization of the ureteral orifices by its deep blue color.. 12.2 Pharmacodynamics. The blue color is detectable at the ureteral orifices within minutes to minutes after the intravenous injection.. 12.3 Pharmacokinetics. The pharmacokinetic properties of BLUDIGO are presented in Table 2.Table 2. Pharmacokinetics of Indigotindisulfonate in Healthy Adults Following Intravenous Administration ofBLUDIGO mL (40 mg)BLUDIGO5 mL (40 mg)General InformationCmax (CV%), ug/mL6.33 (58.4)AUC0-INF (CV%), ug.h/mL1.15 (36.4)DistributionMean (CV%) Volume of Distribution, L10.7 (36.1)Protein Binding, in vitroAbout 90%EliminationMean (CV%) Elimination Half-life, minutes12 (34.1)Mean (CV%) Clearance, L/hourUrinary7.08 (66.3)Total40.2 (45.1)MetabolismPrimary Metabolic PathwaysOxidative metabolismExcretionUrine (CV%)a 16.0% (44.0)Feces<2%aUnchanged drugCmax= maximum plasma concentration; AUC0-INF=area under the plasma concentration-time curve from time of administration extrapolated to infinity; CV=coefficient of variation.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. The safety and efficacy of BLUDIGO were evaluated in randomized intra-patient controlled, blind to dose of BLUDIGO, multi-center study (NCT04228445) in 118 adult patients undergoing endoscopic urological or gynecological surgical procedures including cystoscopic (58%), robotic (28%), and transvaginal (14%) approaches.The majority of patients were white (89%), female (74%), and younger than 65 years of age (70%). Mean age was 51 years, and age ranged from 20 to 88 years.Patients were randomized in 1:1 ratio to receive 2.5 mL or mL of BLUDIGO intravenously prior to the end of the surgical procedure. Each patient underwent cystoscopy and received mL of sodium chloride injection 0.9% followed by the randomized BLUDIGO dose for visualization of urinary flow from the ureteral orifices. The 2.5 mL dose is not approved [see Dosage and Administration (2.1)]. The ureteral orifices and urine flow were observed and video recorded from to 10 minutes post injection, with separate recordings made following sodium chloride injection and BLUDIGO. The conspicuity of the urine flow from the ureteral orifices was assessed in randomized, blinded fashion by two independent central reviewers using 5-point scale (1 no urine flow observed; = weak urine flow, little color contrast; = Color contrast or significant urine flow; = strong urine flow with good color contrast; and = strong urine flow with striking contrast in color) once after sodium chloride injection and twice after BLUDIGO resulting in paired data. The surgeons also reviewed and scored conspicuity of the urine flow from the ureteral orifices. The responder for ureter is defined as the difference in conspicuity score between BLUDIGO and sodium chloride injection being at least one point difference and the conspicuity score following BLUDIGO alone being greater than or equal to three. The reviewer agreement with the responder endpoint is acceptable. The proportion of responders along with its 95% confidence interval by ureter and reviewer or surgeon is summarized in Table 3.Table 3. Summary of Proportion of Responders by Ureter and Reviewer or Surgeon in Patients Receiving BLUDIGO mLBLUDIGO mLLeft Ureter (n=49)Right Ureter (n=49)Reviewer 1% Responder95% CL63%(48%, 77%)76%(61%, 87%)Reviewer 2% responder95% CL78%(63%, 88%)82%(68%, 91%)Surgeon% responder95% CL71%(57%, 83%)82%(68%, 91%)responder: IC conspicuity score >= and difference (IC Saline) in conspicuity score >=1, missing data is imputed as non-responder two-sided 95% confidence limits for the proportion of responder, calculated using the Clopper-Pearson (Exact) method.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 BLUDIGO was evaluated in randomized, intra-patient controlled, blind to dose of BLUDIGO, clinical trial. total of 118 adult patients undergoing endoscopic urological or gynecological procedures were treated intravenously; 58 (49%) of these patients received one dose of BLUDIGO 2.5 mL and 60 (51%) of patients received one dose of BLUDIGO mL. The 2.5 mL dose is not approved [see Dosage and Administration (2.1)]. The mean age of patients was 51 years and 35 (30%) patients were 65 years of age or older. The majority of patients were White 105 (89%) and female 87 (74%).The adverse reactions (>=1%) reported in the clinical trial are provided in Table 1.Table 1. Adverse Reactions Reported at >=1% of Patients Receiving BLUDIGO mL Intravenously BLUDIGO mL(N=60)n (%) Constipation (5.0) Nausea (3.3) Vomiting (3.3) Abdominal Pain (3.3) Pyrexia (3.3) ALT increase (3.3) Dysuria (1.7).

DESCRIPTION SECTION.

11 DESCRIPTION. BLUDIGO (indigotindisulfonate sodium injection, USP) is sterile deep blue or bluish-purple diagnostic dye for intravenous use.Each mL contains mg indigotindisulfonate sodium (equivalent to 7.2 mg indigotindisulfonate) and may also contain citric acid and sodium citrate to adjust pH value between and 6.5 and has an osmolality <= 0.05 osmol/kg. Indigotindisulfonate sodium is also known as indigo carmine.The chemical name of indigotindisulfonate sodium is Disodium 3,3-dioxo-[2,2-biindoline]-5,5-disulfonate. Its molecular formula is C16H8N2Na2O8S2 and its molecular weight is 466.35 g/mol. Its structural formula is:indigotindisulfonate sodium. image description.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Recommended dose is mL given intravenously over minute. (2.1)Monitor blood pressure and heart rhythm during and after injection. (2.2) Recommended dose is mL given intravenously over minute. (2.1). Monitor blood pressure and heart rhythm during and after injection. (2.2) 2.1 Recommended Dosage. The recommended dose of BLUDIGO is mL given as an intravenous injection over minute.The blue color is detectable at the ureteral orifices within minutes to minutes after the intravenous injection.. 2.2 Important Administration Instructions. Monitor blood pressure and cardiac rhythm during and following the injection [see Warnings and Precautions (5.1)]. Use immediately after opening ampule.Withdraw the contents of the ampule through 5 micron or smaller filter straw/filter needle to ensure that the withdrawn solution contains no particulates. The withdrawn solution should be inspected visually for particulate matter and discoloration prior to administration.Do not administer with infusion assemblies used with other diluents or drugs.Discard any unused portion.. Monitor blood pressure and cardiac rhythm during and following the injection [see Warnings and Precautions (5.1)]. Use immediately after opening ampule.. Withdraw the contents of the ampule through 5 micron or smaller filter straw/filter needle to ensure that the withdrawn solution contains no particulates. The withdrawn solution should be inspected visually for particulate matter and discoloration prior to administration.. Do not administer with infusion assemblies used with other diluents or drugs.. Discard any unused portion.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Cardiovascular ReactionsAdvise the patient of the possibility of developing elevated blood pressure, hypotension, bradycardia, tachycardia, or atrioventricular block during or after the administration of BLUDIGO [see Warnings and Precautions (5.1)].Injection Site and Urine DiscolorationInform the patient that BLUDIGO may cause blue discoloration of injection site and urine and that the discoloration should resolve within 48 hours. Advise the patient to inform the healthcare provider if the discoloration of the injection site is associated with other symptoms [see Adverse Reactions (6.2)].. Manufactured for:PROVEPHARM SAS13013 Marseille, FRANCEManufactured by:CENEXI52 rue Marcel et Jacques Gaucher94120 Fontenay sous Bois, FRANCEDistributed by:PROVEPHARM INC.Collegeville, PA 19426, USA.

LACTATION SECTION.

8.2 Lactation. Risk SummaryIt is not known if indigotindisulfonate is present in animal or human milk. The transfer of indigotindisulfonate into breastmilk is likely to be low and adverse effects on the breastfed infant are not expected [see Clinical Pharmacology (12.3)]. There are no data on the effect of indigotindisulfonate on the breastfed infant or milk production. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for BLUDIGO and any potential adverse effects on the breastfed infant from BLUDIGO or from the underlying maternal condition.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenicityCarcinogenicity studies in animals have not been conducted with indigotindisulfonate sodium using the intravenous route of administration.Long-term studies in mice with oral and subcutaneous administration of indigotindisulfonate sodium revealed no carcinogenic effects.MutagenesisAlthough indigotindisulfonate sodium has been evaluated in number of Ames assay studies, an Ames assay study that follows all currently recommended guidelines has not been performed. Indigotindisulfonate was not genotoxic in all those Ames assays.The mutagenicity of indigotindisulfonate was inconclusive in the in vitro mouse L5187Y Lymphoma TK +/- assay. Orally administered indigotindisulfonate was not mutagenic in the in vivo mouse micronucleus test. An in vivo micronucleus test with indigotindisulfonate sodium using the intravenous route of administration has not been conducted.FertilityFertility studies with indigotindisulfonate sodium using the intravenous route of administration have not been conducted.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The pharmacokinetic properties of BLUDIGO are presented in Table 2.Table 2. Pharmacokinetics of Indigotindisulfonate in Healthy Adults Following Intravenous Administration ofBLUDIGO mL (40 mg)BLUDIGO5 mL (40 mg)General InformationCmax (CV%), ug/mL6.33 (58.4)AUC0-INF (CV%), ug.h/mL1.15 (36.4)DistributionMean (CV%) Volume of Distribution, L10.7 (36.1)Protein Binding, in vitroAbout 90%EliminationMean (CV%) Elimination Half-life, minutes12 (34.1)Mean (CV%) Clearance, L/hourUrinary7.08 (66.3)Total40.2 (45.1)MetabolismPrimary Metabolic PathwaysOxidative metabolismExcretionUrine (CV%)a 16.0% (44.0)Feces<2%aUnchanged drugCmax= maximum plasma concentration; AUC0-INF=area under the plasma concentration-time curve from time of administration extrapolated to infinity; CV=coefficient of variation.

POSTMARKETING EXPERIENCE SECTION.

6.2 Postmarketing Experience. The following adverse reactions have been identified following the use of indigotindisulfonate sodium injection products.Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. Cardiovascular disorders: cardiac arrest, arrhythmia, asystole, atrioventricular block second degree, hypotension, elevation in blood pressure, bradycardia, tachycardia General disorders and administration site conditions: injection site discoloration Immune system disorders: anaphylactic reactions with hypotension, dyspnea, bronchospasm, urticaria, erythema.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryAvailable data from case reports, case series, observational studies and clinical experience with indigotindisulfonate sodium injection use in pregnant women over several decades have not identified drug associated risk of adverse maternal and fetal adverse effects. Indigotindisulfonate sodium injection use during the first trimester of pregnancy is rare; thus, the data are insufficient to evaluate for drug associated risk of major birth defects and miscarriage. The majority of the published data were from intra-amniotic injections. Animal reproduction studies using the intravenous route of administration have not been conducted. Oral administration of indigotindisulfonate sodium to pregnant rats and rabbits produced no evidence of fetal harm.However, oral availability is low (3%) so that the risk of intravenous administration of indigotindisulfonate sodium during pregnancy cannot be evaluated from the data available .The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Renal Impairment: BLUDIGO is not recommended for use in patients with eGFR<30 mL/min. (8.6). Renal Impairment: BLUDIGO is not recommended for use in patients with eGFR<30 mL/min. (8.6). 8.1 Pregnancy. Risk SummaryAvailable data from case reports, case series, observational studies and clinical experience with indigotindisulfonate sodium injection use in pregnant women over several decades have not identified drug associated risk of adverse maternal and fetal adverse effects. Indigotindisulfonate sodium injection use during the first trimester of pregnancy is rare; thus, the data are insufficient to evaluate for drug associated risk of major birth defects and miscarriage. The majority of the published data were from intra-amniotic injections. Animal reproduction studies using the intravenous route of administration have not been conducted. Oral administration of indigotindisulfonate sodium to pregnant rats and rabbits produced no evidence of fetal harm.However, oral availability is low (3%) so that the risk of intravenous administration of indigotindisulfonate sodium during pregnancy cannot be evaluated from the data available .The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively.. 8.2 Lactation. Risk SummaryIt is not known if indigotindisulfonate is present in animal or human milk. The transfer of indigotindisulfonate into breastmilk is likely to be low and adverse effects on the breastfed infant are not expected [see Clinical Pharmacology (12.3)]. There are no data on the effect of indigotindisulfonate on the breastfed infant or milk production. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for BLUDIGO and any potential adverse effects on the breastfed infant from BLUDIGO or from the underlying maternal condition.. 8.4 Pediatric Use. The safety and effectiveness of BLUDIGO have not been established in pediatric patients.. 8.5 Geriatric Use. Of the total number of subjects in the clinical study of BLUDIGO, 23 (20%) were 65 to 74 years of age, and 12 (10%) were 75 and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.. 8.6 Renal Impairment. Indigotindisulfonate is known to be excreted by the kidney through tubular secretion. No dedicated pharmacokinetic study using BLUDIGO in patients with varying degree of renal impairment has been conducted. Based on subgroup analyses in the randomized clinical trial, dose adjustment is not needed in patients with mild to moderate renal impairment (estimated glomerular filtration rate (eGFR) 30 to 89 mL/min derived from the Modification of Diet in Renal Disease formula). BLUDIGO has not been studied in patients with eGFR 30 mL/min and is not recommended for use in these patients.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Cardiovascular Reactions: Severe or life-threatening cardiovascular reactions including cardiac arrest, arrhythmia, asystole, atrioventricular block second degree, hypotension, elevation in blood pressure, bradycardia, and tachycardia have been reported. Closely monitor blood pressure and cardiac rhythm during and following the BLUDIGO injection. Interrupt administration if reactions are observed. (5.1)Hypersensitivity Reactions: Serious anaphylactic reactions with hypotension, dyspnea, bronchospasm, urticaria, or erythema have been reported. Monitor patients for anaphylactic reactions and have emergency equipment and trained personnel readily available. (5.2)Interference with Oximetry Measurements:Anesthesiologists should be aware of the potential for artifactual reduction in SpO2 when anesthetized patients are administered BLUDIGO. (5.3). Cardiovascular Reactions: Severe or life-threatening cardiovascular reactions including cardiac arrest, arrhythmia, asystole, atrioventricular block second degree, hypotension, elevation in blood pressure, bradycardia, and tachycardia have been reported. Closely monitor blood pressure and cardiac rhythm during and following the BLUDIGO injection. Interrupt administration if reactions are observed. (5.1). Hypersensitivity Reactions: Serious anaphylactic reactions with hypotension, dyspnea, bronchospasm, urticaria, or erythema have been reported. Monitor patients for anaphylactic reactions and have emergency equipment and trained personnel readily available. (5.2). Interference with Oximetry Measurements:Anesthesiologists should be aware of the potential for artifactual reduction in SpO2 when anesthetized patients are administered BLUDIGO. (5.3). 5.1 Cardiovascular Reactions. Severe or life-threatening cardiovascular reactions including cardiac arrest, arrhythmia, asystole, second degree atrioventricular block, hypotension, elevation in blood pressure, bradycardia, and tachycardia have been reported generally within 60 minutes following administration of indigotindisulfonate sodium injection products and required urgent intervention [see Adverse Reactions (6.2)]. Indigotindisulfonate may cause vasoconstriction by interference with vasodilation mediated by nitric oxide dependent mechanisms and by direct vasoconstriction. Indigotindisulfonate may also cause hypotension. Patients with hypertension, heart rate and conduction disorders, or medications causing bradycardia may be at increased risk for elevated blood pressure, hypotension, and bradycardia.Closely monitor blood pressure and cardiac rhythm during and following the injection of BLUDIGO. Interrupt administration if reactions are observed.. 5.2 Hypersensitivity Reactions. Serious anaphylactic reactions with hypotension, dyspnea, bronchospasm, urticaria, or erythema have been reported with the use of indigotindisulfonate sodium injection products [see Adverse Reactions (6.2)]. BLUDIGO is contraindicated in patients with known hypersensitivity to indigotindisulfonate [see Contraindications (4)]. Monitor patients for anaphylactic reactions and have emergency equipment and trained personnel readily available.. 5.3 Interference with Oximetry Measurements. Indigotindisulfonate has been reported to interfere with light absorption and transiently interfere with pulse oximetric methods. Anesthesiologists should be aware of the potential for artifactual reduction in SpO2 when anesthetized patients are administered BLUDIGO.