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Indigo Carmine Injection

[29 August 2014]

Products Affected - Description

Indigo carmine injection, Akorn
8 mg/mL, 5 mL ampule (NDC 17478-0508-01)
 
Indigo carmine injection, American Regent
8 mg/mL, 5 mL ampule (NDC 00517-0375-10)

Reason for the Shortage

  • American Regent has indigo carmine on back order due to manufacturing delays.1
  • Akorn has discontinued production of indigo carmine due to shortage of raw material. Akorn is looking for a new raw material supplier.2

Available Products

There are no presentations available.

Estimated Resupply Dates

  • Akorn has discontinued production of indigo carmine and the company cannot estimate when product will return.2
  • American Regent has indigo carmine 8 mg/mL 5 mL ampules on back order and the company cannot estimate a release date.1

Implications for Patient Care

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

Safety

Ensure appropriate dosing and indications when alternative dyes are used.

Alternative Agents & Management

  • 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 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.8 Fernando et al 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.9
 

Table 1. Comparative Summary of Indications for Use, Dosing, and Pharmacokinetic Properties of Marker Dyes4, 5, 10,11,12,13
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 methemoglobinemia10
To determine cardiac output, liver blood flow and hepatic function, and for use in ophthalmic angiography11
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.5,10
Doses > 7 mg/kg can cause methemoglobinemia12,13
Cardiac output dilution studies: 5 mg via cardiac catheter.11
Hepatic function studies: 0.5 mg/kg intravenous. 11
Ophthalmic angiography: 40 mg intravenous. 11
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 Cystoscopy 14-23

Indigo Carmine

Methylene Blue

Indocyanine Green

There are 7 published reports of intravenous indigo carmine use to confirm ureteral patency.14-20 Dose and timing was not reported in 3 reports.14,15,16 Indigo carmine dose was 5 mL intravenous in two reports.16,18

Harris et al used indigo carmine 5 mL intravenously prior to intraoperative cystoscopy in 224 women undergoing reconstructive pelvic surgery.16

Jelovsek et al 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.18

 

Song and Kim 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.19

There are 3 published reports of intravenous methylene blue used to confirm ureteral patency.21-23 The dose of methylene blue in all three studies varied.

Joel et al 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.21

Wang 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.22

Verbeek et al 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.23

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) 24-37

Indigo Carmine

Methylene Blue

Indocyanine Green

Rauh-Hain and Laufer report one successful case of indigo carmine injected transcervically to confirm patency of fallopian tubes. Indigo carmine dose was not provided.24

 

Furuya et al 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.25

Moore et al 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.26

Hanash et al 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.27

Volkmer et al 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.28

 

Nyarangi-Dix et al 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.29

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.30-35

Lee et al 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.36

Siddighi et al 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.37

References

  1. American Regent (personal communications and website). January 10, March 8, May 22, July 25, September 19, October 28, December 9, 2013; and January 27, April 24, and May 23, 2014.
  2. Akorn (personal communications). January 19, March 11, May 22, June 15, July 25, September 19, October 28, December 9, 2013; and January 27, April 24, and May 21, 2014.
  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. Accessed May 23, 2014.
  7. Indocyanine Green Shortage. American Society of Health-System Pharmacists Drug Shortage Resource Management Center. 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. Akorn. Methylene Blue Injection [product information]. Lake Forest, IL, Akorn, 2011.
  11. Akorn. IC-Green Injection [product information]. Lake Forest, IL, Akorn, 2011.
  12. Lee M, Sharifi R. Methylene blue versus indigo carmine. Urology 1996;47(5):783-4.
  13. Gilmour D. Urinary tract injury in gynecologic surgery: evaluation and management. In: UpToDate [internet database]. Wolters Kluwer Health, 2014.
  14. Ibeanu OA, Chesson RR, Echols KT, et al. Urinary tract injury during hysterectomy based on universal cystoscopy. Obstet Gynecol 2009; 113:6-10.
  15. 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.
  16. 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.
  17. 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.
  18. 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.
  19. Song JE, Kim SK. The use of indigo carmine in ureteral operations. J Urology 1968;98:669-70.
  20. 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.
  21. Joel AB, Mueller MD, Pahira JJ, Mordkin RM. Nonvisualization of intravenous methylene blue in patients with clinically normal renal function. Urology 2001; 58: 607vii.
  22. 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.
  23. 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.
  24. Rauh-Hain JA, Laufer MR. Increased diagnostic accuracy of laparoscopy in endometriosis using indigo carmine: a new technique. Fertil Steril 2011; 95:1113-4.
  25. 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.
  26. 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.
  27. 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.
  28. Volkmer BG, Kuefer R, Nesslauer T et al. Colour Doppler ultrasound in vesicovaginal fistulas. Ultrasound Med Biol 2000; 26:771-5.
  29. 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.
  30. Campobasso P. Blue venography in adolescent varicocelectomy: a modified surgical approach. J Pediatr Surg 1997;32:1298-1301.
  31. 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.
  32. Sowande OA, Olajide TA. Using methylene blue for perioperative localization of the hydrocele sac in boys. Ann Afr Med 2011; 10:38-40.
  33. 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.
  34. 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.
  35. Rabah DM, Adwan AA, Seida MA. Lymphatic preservation using methylene blue dye during laparoscopic varicocelectomy: early results. Can J Urol 2009; 16:4826-30.
  36. 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.
  37. Siddighi S, Yune JJ, Hardesty J. Indocyanine green for intraoperative localization of ureter. Am J Obstet Gynecol 2014;211: epub.

Updated

Updated August 29, 2014 by Leslie Jensen, PharmD, Drug Information Specialist. Created May 23, 2014 by Jane Chandramouli, PharmD, Drug Information Specialist. Copyright 2014, Drug Information Service, University of Utah, Salt Lake City, UT.

Disclaimer

This information is provided through the support of Novation to ASHP solely as a service to its members, which shall not use this information for their further commercial use. The content was prepared by the Drug Information Center of University of Utah. Novation, ASHP, and the University of Utah make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, which respect to such information, and specifically disclaim all such warranties. Users of this information are advised that decisions regarding the use of drugs and drug therapies are complex medical decisions and that in using this information, each user must exercise his or her own independent professional judgment. Neither Novation, ASHP nor the University of Utah assumes any liability for persons administering or receiving drugs or other medical care in reliance upon this information, or otherwise in connection with this bulletin. Neither Novation, ASHP nor University of Utah endorses or recommends the use of any drug.

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