Products Affected - Description

• • Indigo Carmine injection, Akorn, 8 mg/mL, 5 mL ampule, NDC 17478-0508-01

Reason for the Shortage

• • American Regent launched indigo carmine in July 2017.[1]
  • Akorn has discontinued production of indigo carmine due to shortage of raw material.[2]

Available Products

• • Indigo Carmine injection, American Regent, 8 mg/mL, 5 mL ampule, 5 count, NDC 00517-0375-05

• • American Regent has indigo carmine 8 mg/mL 5 mL ampules available.[1]

• • Indigo carmine is indigotindisulfonate sodium, a marker dye used during cystoscopy and ureteral catheterization.[3-4] Indigo carmine is also used in endoscopic procedures, lymph node and vessel delineation, and for tumor localization. Indigo carmine is an unapproved drug without FDA approved labeling.[5]

• • Ensure appropriate dosing and indications when alternative dyes are used.

• • There is no single dye that can replace indigo carmine.[3] Choice of alternative agent will depend on type of procedure and physician discretion, as well as product availability. Many of the marker dyes are on nationwide shortage.[6-7]
  • Table 1 compares indigo carmine, methylene blue, and indocyanine green with regard to indication for use, dosing, metabolism and drug interactions. Table 2 summarizes the published primary literature for intravenous use of marker dyes to evaluate ureter patency during intraoperative cystoscopy. Table 3 summarizes the use of these products given by direct instillation for urologic or gynecologic procedures.
  • Possible oral options for staining the urine during cystoscopy include phenazopyridine and vitamin B complex. Hui et al[8] published a case report of 32 women who received single-dose oral phenazopyridine (100 mg to 200 mg) one hour prior to pelvic reconstructive surgery. Intraoperative cystoscopy was performed to confirm ureteric patency. Bilateral ureteric patency was confirmed in all 32 cases and bladder mucosa was also adequately inspected in all women. No postoperative ureteric injuries were identified. Fernando et al[9] administered 3 tablets of vitamin B complex 1 to 4 hours prior to surgery and cystoscopy. Yellow urine was observed at both ureteric orifices in 72% of patients. Indigo carmine had to be used in 2/69 (2.9%) patients.
  • Amniocentesis with transabdominal instillation of indigo carmine may be used in cases where the diagnosis of suspected premature rupture of membranes remains difficult despite use of standard non-invasive methods.[10-15] There are no studies comparing indigo carmine with alternate dyes for intra-amniotic infusion. There are several case reports of adverse neonatal outcome when methylene blue was given by intra-amniotic injection.[16-21]
  • Sosa et al[14] recently published a comparative trial between intra-amniotic indigo carmine infusion and a noninvasive placental alpha microglobulin-1 immunoassay (AmniSure) in 140 pregnant women who had signs or symptoms suggesting rupture of membranes (ROM) but without obvious leakage of fluid during speculum examination and without confirmation of ROM by methods including pooling, nitrazine, ferning, Valsalva maneuver, or amniotic fluid index measurement by ultrasound. The authors concluded that both intra-amniotic indigo carmine infusion and noninvasive placental alpha microglobulin-1 immunoassay methods were comparable for diagnosing ROM. The indigo dye test unequivocally diagnosed ROM in 27/140 patients. The placental alpha microglobulin-1 immunoassay diagnosed ROM in 28/140 patients [positive predictive value 96.3% (95% CI 0.82-0.99), positive likelihood ratio 74.6 (95% CI 20.31-274.51)]. During the shortage of indigo carmine, use of placental alpha microglobulin-1 immunoassay (AmniSure) may be an option. Consult with a specialist in obstetrics and gynecology.

  Table 1. Comparative Summary of Indications for Use, Dosing, and Pharmacokinetic Properties of Marker Dyes4-522-25

  Properties	Indigo Carmine	Methylene Blue	Indocyanine Green
  FDA approved product	No	No	Yes
  How supplied	8 mg/mL, 5 mL ampule	10 mg/mL, 10 mL vial	25 mg vial
  Package insert indication	Localize ureteral orifices during cystoscopy and ureteral catheterization4	Drug-Induced methemoglobinemia22	To determine cardiac output, liver blood flow and hepatic function, and for use in ophthalmic angiography23
  Common doses	Localizing ureteral orifices: 5 mL intravenous4 Usual dose when used as marker dye: 40 mg or 5 to 10 mL of 0.8% solution.5	Drug induced methemoglobinemia: 1 to 2 mg/kg intravenous slowly over several minutes.5,22 Doses > 7 mg/kg can cause methemoglobinemia24-25	Cardiac output dilution studies: 5 mg via cardiac catheter.11 Hepatic function studies: 0.5 mg/kg intravenous. 23 Ophthalmic angiography: 40 mg intravenous.23
  Drug interactions	No known drug interactions	Methylene blue is a monoamine oxidase inhibitor. Serotonin syndrome can occur in patients taking other serotonergic agents.5	Heparin preparations containing sodium bisulfite reduce peak absorption of indocyanine green in blood.
  Metabolism	Renal excretion	Renal excretion	Not metabolized. Indocyanine green is bound to plasma proteins, taken up by hepatocytes, and excreted unaltered into bile 20 minutes after injection.5
  Metabolites	None	Leukomethylene blue- 75% of oral dose metabolized to leukomethylene blue, which is colorless.	None
  Half-life, intravenous	4 to 5 minutes (blue urine usually appears within 10 minutes of intravenous administration)4	5 to 6.5 hours	3.2 to 3.5 minutes

  
  

  Table 2. Summary of Published Primary Literature for Intravenous Use of Marker Dyes to Evaluate Ureter Patency During Intraoperative Cystoscopy26-35

  Indigo Carmine	Methylene Blue	Indocyanine Green
  There are 7 published reports of intravenous indigo carmine use to confirm ureteral patency.26-32 Dose and timing was not reported in 3 reports.14-16 Indigo carmine dose was 5 mL intravenous in two reports. Harris et al28 used indigo carmine 5 mL intravenously prior to intraoperative cystoscopy in 224 women undergoing reconstructive pelvic surgery. Jelovsek et al30 reported the results of intraoperative cystoscopy with intravenous indigo carmine in 126 patients undergoing total laparoscopic hysterectomy. The dose of indigo carmine was 1 ampule (5 mL) intravenous. Song and Kim31 used indigo carmine 5 mL intravenously one hour prior to operation and then repeated at time of skin incision to help identify ureters in 37 patients with ureteral obstruction.	There are 3 published reports of intravenous methylene blue used to confirm ureteral patency.33-35 The dose of methylene blue in all three studies varied. Joel et al33 published a case report of 2 patients who received methylene blue 1% 10 mL intravenous to confirm ureteral patency. No methylene blue was visualized after administration. Authors speculate the methylene blue was metabolized to leukomethylene, which is colorless. Both patients received subsequent doses of indigo carmine and blue urine was observed. Wang34 reported the use of intravenous 1% methylene blue in 34 women undergoing intraoperative transurethral urethrocystoscopy. The dose was 6 mL (0.1 mL/kg). Delayed emission of the dye was observed in one patient with a right ureter stricture. Verbeek et al35 evaluated the use of methylene blue in 12 patients undergoing lower abdominal surgery exposing the ureters. Methylene blue was given intravenously at a dose of 0.25 mg/kg, 0.5 mg/kg, or 1 mg/kg. Patients underwent near infrared fluorescence imaging for up to 60 minutes after injection. Ureters were visualized within 10 minutes after methylene blue infusion. The authors recommend using methylene blue 0.25 mg/kg, as there were no differences found among the dose groups.	There are no studies describing intravenous indocyanine green to evaluate ureter patency during intraoperative cystoscopy.

  
  

  Table 3. Summary of Published Primary Literature for Direct instillation of Marker Dyes for Urologic or Gynecologic Indications (non-tumor related)36-49

  Indigo Carmine	Methylene Blue	Indocyanine Green
  Rauh-Hain and Laufer36 report one successful case of indigo carmine injected transcervically to confirm patency of fallopian tubes. Indigo carmine dose was not provided. Furuya et al37 injected 1 to 5 mL of indigo carmine into midline cysts of the prostate in 68 patients to aid in the classification of the cysts.	Moore et al38 reported a retrospective review of 5 patients who underwent robot-assisted laparoscopic bladder diverticulectomy. Methylene blue 1% solution was instilled into bladder to aid surgeon in identifying the diverticular neck of the bladder. Hanash et al39 instilled 150 mL to 200 mL of diluted methylene blue solution into the vagina during cystoscopy to aid in the identification of urinary fistulas in two patients. Concentration of methylene blue not provided. Volkmer et al40 used color Doppler ultrasound to identify vesicovaginal fistulas in 12 women. Methylene blue was instilled into the bladder but dosage of methylene blue was not specified. Nyarangi-Dix et al41 evaluated the efficacy of the methylene blue test in 103 men undergoing radical prostatectomy. A solution of methylene blue 5 mL and normal saline 95 mL was instilled into the bladder for 15 seconds. Six studies have reported the use of methylene blue injections into the testicles to assist with artery-sparing or lymphatic vessel-sparing varicocelectomy or hydrocele localization.42-47	Lee et al48 used indocyanine green visualization under near-infrared light to identify ureteral strictures. Indocyanine green 25 mg in 10 mL distilled water was injected via ureteral catheter or nephrostomy tube. In all 7 patients, the surgeon was able to identify the healthy and diseased ureter. Siddighi et al49 used indocyanine green visualization under near-infrared light to identify ureters during robot-assisted laparoscopic pelvic organ prolapse repair. Indocyanine green 25 mg in 10 mL of sterile water was injected into each ureter. Bilateral ureters were visualized in all patients. The specific number of patients who underwent this procedure was not specified but authors indicated > 10 patients.

  
  

• 1. American Regent (personal communications and website). January 10, March 8, May 22, July 25, September 19, October 28, December 9, 2013; January 27, April 24, May 23, October 16 and 21, November 24, December 16, 2014; January 15, March 16, April 30, June 30, September 15, December 22, 2015; March 10, November 11, 2016; February 14, April 7, June 6 and 15, July 13, August 29, October 6, 2017; and January 22, 2018.
  2. Akorn (personal communications). January 19, March 11, May 22, June 15, July 25, September 19, October 28, December 9, 2013; January 27, April 24, May 21, October 16, 2014; March 16, April 30, December 22, 2015; March 10, April 15, June 8, August 15, November 10, 2016; and February 14, 2017.
  3. Indigo Carmine. In McEvoy, GK, Snow EK, et al., Eds. AHFS Drug Information Online. Accessed May 23, 2014.
  4. American Regent. Indigo Carmine injection [product information]. Shirley, NY, American Regent, 2009.
  5. Anon, editor. Drugdex System. Micromedex 2.0 [internet database]. Greenwood Village, CO: Truven Health Analytics; 2014.
  6. Methylene Blue Injection Shortage. American Society of Health-System Pharmacists Drug Shortage Resource Management Center (http://www.ashp.org/menu/DrugShortages/CurrentShortages/Bulletin.aspx?id=27). Accessed May 23, 2014.
  7. Indocyanine Green Shortage. American Society of Health-System Pharmacists Drug Shortage Resource Management Center (http://www.ashp.org/menu/DrugShortages/CurrentShortages/Bulletin.aspx?id=1107). Accessed May 23, 2014.
  8. Hui J, Harvey, MA, Johnston SL. Confirmation of ureteric patency during cystoscopy using phenazopyridine HCL: A Low-Cost Approach. J Obstet Gynaecol Can 2009; 31(9): 845-9.
  9. Fernando S. The role of preoperative oral vitamin B in the cystoscopic assessment of ureteric patency. Int Urogynecol J 2011: 22:947-51.
  10. Practice bulletins No. 139: premature rupture of membranes. Obstet Gynecol 2013;122(4):918-30.
  11. Di Renzo GC, Roura LC, Facchinetti F, et al. Guidelines for the management of spontaneous preterm labor: identification of spontaneous preterm labor, diagnosis of preterm premature rupture of membranes, and preventive tools for preterm birth. J Maternal Fetal Neonatal Med 2011;24(5):659-67.
  12. Mariona FG, Cabero L. Are we ready for a new look at the diagnosis of premature rupture of membranes? J Maternal Fetal Neonatal Med 2012;25(4):403-7.
  13. Ramsauer B, Vidaeff AC, Hosli I, et al. The diagnosis of rupture of fetal membranes (ROM): a meta-analysis. J Perinatal Med 2013;41(3):233-40.
  14. Sosa CG, Herrera E, Restrepo JC, Strauss A, Alonso J. Comparison of placental alpha microglobulin-1 in vaginal fluid with intra-amniotic injection of indigo carmine for the diagnosis of rupture of membranes. J Perinatal Med 2014;42(5):611-6.
  15. van der Ham DP, van Teeffelen A, Mol B. Prelabour rupture of membranes: overview of diagnostic methods. 2012; 24(6):408-12.
  16. Cowett RM, Hakanson DO, Kocon RW, Oh W. Untoward neonatal effect of intraamniotic administration of methylene blue. Obstet Gynecol 1976;48 (1 Suppl):74S-5S.
  17. Dinger J, Autenrieth A, Kamin G, Goebel P, Hinkel GK. Jejunal atresia related to the use of toluidine blue in genetic amniocentesis in twins. J Perinatal Med 2003;31 (3):266-8.
  18. Fribourg S. Safety of intra-amniotic injection of indigo carmine. Am J Obstet Gynecol 1981; 140(3):350-1.
  19. Gluer S. Intestinal atresia following intraamniotic use of dyes. Eur J Ped Surgery 1995; 5 (4):240-2.
  20. McEnerney JK, McEnerney LN. Unfavorable neonatal outcome after intraamniotic injection of methylene blue. Obstet Gynecol 1983;61(3 Suppl):35S-7S.
  21. Spahr RC, Salsburey DJ, Krissberg A, Prin W. Intraamniotic injection of methylene blue leading to methemoglobinemia in one of twins. International J Gynaecol Obstet 1980;17(5):477-8.
  22. Akorn. Methylene Blue Injection [product information]. Lake Forest, IL, Akorn, 2011.
  23. Akorn. IC-Green Injection [product information]. Lake Forest, IL, Akorn, 2011.
  24. Lee M, Sharifi R. Methylene blue versus indigo carmine. Urology 1996;47(5):783-4.
  25. Gilmour D. Urinary tract injury in gynecologic surgery: evaluation and management. In: UpToDate [internet database]. Wolters Kluwer Health, 2014.
  26. Ibeanu OA, Chesson RR, Echols KT, et al. Urinary tract injury during hysterectomy based on universal cystoscopy. Obstet Gynecol 2009; 113:6-10.
  27. Gustilo-Ashby AM, Jelovsek JE, Barber MD, et al. The incidence of ureteral obstruction and the value of intraoperative cystoscopy during vaginal surgery for pelvic organ prolapse. Am J Obstet Gynecol 2006; 194:1478-85.
  28. Harris RL, Cundiff GW, Theofrastous JP, Yoon H, et al. The value of intraoperative cystoscopy in urogynecologic and reconstructive pelvic surgery. Am J Obstet Gynecol 1997; 177:1367-71.
  29. Kwon CH, Goldberg RP, Koduri S et al. The use of intraoperative cystoscopy in major vaginal and urogynecologic surgeries. Am J Obstet Gynecol 2002; 187:1466-72.
  30. Jelovsek JE, Chen G, Roberts SL, et al. Incidence of lower urinary tract injury at the time of total laparoscopic hysterectomy. J Soc Laparoendoscopic Surg 2007; 11:422-27.
  31. Song JE, Kim SK. The use of indigo carmine in ureteral operations. J Urology 1968;98:669-70.
  32. Speights SE, Moore RD, Miklos JR. Frequency of lower urinary tract injury at laparoscopic burch and paravaginal repair. J Am Assoc Gynecol Laparosc. 2000; 7:515-8.
  33. Joel AB, Mueller MD, Pahira JJ, Mordkin RM. Nonvisualization of intravenous methylene blue in patients with clinically normal renal function. Urology 2001; 58: 607vii.
  34. Wang AC. The techniques of trocar insertion and intraoperative urethrocystoscopy in tension-free vaginal taping: an experience of 600 cases. Acta Obstet Gynecol Scand 2004; 83:293-8.
  35. Verbeek FP, van der Vorst JR, Schaafsma BE, et al. Intraoperative near infrared fluorescence guided identification of the ureters using low dose methylene blue: a first in human experience. J Urology 2013; 190:574-9.
  36. Rauh-Hain JA, Laufer MR. Increased diagnostic accuracy of laparoscopy in endometriosis using indigo carmine: a new technique. Fertil Steril 2011; 95:1113-4.
  37. Furuya R, Furuya S, Kato H, et al. New classification of midline cysts of the prostate in adults via a transrectal ultrasonography-guided opacification and dye-injection study. BJU International 2008;102:475-8.
  38. Moore CR, Shirodkar SP, Avallone MA, et al. Intravesical methylene blue facilitates precise identification of the diverticular neck during robot-assisted laparoscopic bladder diverticulectomy. J Laparoendoscopic Adv Surg Tech 2012; 22:492-5.
  39. Hanash KA, Al Zahrani H, Mokhtar AA, Aslam M. Retrograde vaginal methylene blue injection for localization of complex urinary fistulas. J Endourology 2003; 17(10):941-3.
  40. Volkmer BG, Kuefer R, Nesslauer T et al. Colour Doppler ultrasound in vesicovaginal fistulas. Ultrasound Med Biol 2000; 26:771-5.
  41. Nyarangi-Dix, JN, Pahernik S, Bermejo JL et al. Significance of the intraoperative methylene blue test for postoperative evaluation of the vesicourethral anastomosis. Adv Urology 2012:1-6.
  42. Campobasso P. Blue venography in adolescent varicocelectomy: a modified surgical approach. J Pediatr Surg 1997;32:1298-1301.
  43. Barot P, Neff M, Cantor B, et al. Laparoscopic varicocelectomy with lymphatic preservation using methylene blue dye. J Laparoendosc Adv Surg Tech A 2004; 14:183-5.
  44. Sowande OA, Olajide TA. Using methylene blue for perioperative localization of the hydrocele sac in boys. Ann Afr Med 2011; 10:38-40.
  45. Calleary JG, Wiseman O, Masood J et al. Definitive identification of a patent processus vaginalis by intraoperative injection of methylene blue into the hydrocele sac. J Pediat Urol 2008; 4:218-20.
  46. Belloli G, D'Agostinon S, Musi L et al. Adolescent varicocele: operative anatomy and tricks for successful correction. Eur J Pediatr Surg 1995;5:219-21.
  47. Rabah DM, Adwan AA, Seida MA. Lymphatic preservation using methylene blue dye during laparoscopic varicocelectomy: early results. Can J Urol 2009; 16:4826-30.
  48. Lee Z, Simhan J, Parker DC et al. Novel use of indocyanine green for intraoperative, real-time localization of ureteral stenosis during robot-assisted ureteroureterostomy. Urology 2013; 82:729-33.
  49. Siddighi S, Yune JJ, Hardesty J. Indocyanine green for intraoperative localization of ureter. Am J Obstet Gynecol 2014;211: epub.