Advertisement

Methylene Blue Injection

[29 July 2014]

Products Affected - Description

Methylene Blue 10 mg/mL, American Regent
1 mL vial (NDC 00517-0301-10)
10 mL vial (NDC 00517-0310-10)
1 mL ampule (NDC 00517-0372-71)
10 mL ampule (NDC 00517-0373-70)

Reason for the Shortage

  • Akorn had methylene blue on back order due to increased demand for the product.1
  • American Regent has methylene blue on back order due to manufacturing delays.2

Available Products

Methylene Blue 10 mg/mL, Akorn
1 mL vial (NDC 17478-0504-01)
10 mL vial (NDC 17478-0504-10)

Estimated Resupply Dates

American Regent has all methylene blue presentations on back order and the company cannot estimate a release date.2

Implications for Patient Care

Methylene blue is a dye used in a variety of procedures such as lymph node biopsy, endoscopic evaluation of lesions, and urologic evaluations and pulmonary nodule evaluations.3 Methylene blue is an unapproved drug without FDA approved labeling, however the package insert for methylene blue notes it is indicated for drug induced methemoglobinemia.4 Methylene blue has also been used to treat methemoglobinemia due to toxic chemicals or substance abuse.3

Safety

Ensure appropriate dosing and indications when alternative dyes are used.

Alternative Agents & Management

  • Consider reserving a supply of methylene blue for the treatment of methemoglobinemia. A recommended stocking level is five 10 mL vials to treat 1 patient.5
  • There is no single dye that can replace methylene blue. Table 1 summarizes potential alternatives to methylene blue for selected clinical scenarios.
  • Table 2 compares indigo carmine, methylene blue, and indocyanine green with regard to indication for use, dosing, metabolism and drug interactions. Table 3 summarizes the published primary literature for intravenous use of marker dyes to evaluate ureter patency during intraoperative cystoscopy. Table 4 summarizes the use of these products given by direct instillation for urologic or gynecologic procedures.
Table 1. Potential Alternatives to Methylene Blue for Selected Clinical Situations3, 6, 7-9  

Use
Treatment Regimen
Comments
Methemoglobinemia
Supportive care
Methylene blue is the drug of choice to treat drug induced methemoglobinemia dosed at 1 mg/kg intravenously and repeated if needed.3
Lymph node and vessels delineation
Isosulfan blue: usual dose is 0.5 mL subcutaneously into 3 interdigital spaces of each extremity per study (maximum 3 mL).
Sentinel lymph node biopsy for patients with neoplasms such as breast cancer or other delineation of lymphatic vessels such as patients with lymphedema or chyluria.6
Endoscopy procedures
Indigo carmine
Methylene blue is used for endoscopic evaluation in patients with Barrett’s esophagus or gastroesophageal reflux disease.3,7
Urology
Indigo carmine
Methylene blue is used for endoscopic evaluations of ureteral or pelvic injuries.3
Indigo carmine is used during cystoscopy and ureteral catheterization as a marker dye.8,9

 

Table 2. Comparative Summary of Indications for Use, Dosing, and Pharmacokinetic Properties of Marker Dyes4,9, 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 catheterization9

Drug-Induced methemoglobinemia4

To determine cardiac output, liver blood flow and hepatic function, and for use in ophthalmic angiography11

Common doses

Localizing ureteral orifices: 5 mL intravenous9

Usual dose when used as marker dye: 40 mg or 5 to 10 mL of 0.8% solution.10

Drug induced methemoglobinemia: 1 to 2 mg/kg intravenous slowly over several minutes.4,10

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.10

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.10

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)9

5 to 6.5 hours

3.2 to 3.5 minutes


 

Table 3. 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 4. 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. Akorn (personal communications). March 5, April 29, June 27, August 26 and 30, September 16 and 25, October 28, December 10, 2013; and January 27, April 24, and July 14, 2014.
  2. American Regent (personal communications and website). March 5, April 29, June 27, August 26 and 30, September 16 and 26, October 28, December 9, 2013; and January 27 April 24, and July 14, 2014.
  3. American Regent,(personal communications and website). March 5, April 29, June 27, August 26 and 30, September 16 and 26, and October 28, 2013. 
  4. Methylene Blue. In McEvoy, GK, Snow EK, et al., Eds. AHFS Drug Information Online. Accessed September 17, 2013.
  5. Akorn. Methylene blue injection [product information]. Lake Forest, IL, Akorn, 2011.
  6. The University of Utah Poison Control Center. Antidotes for Poisoned Patients.
  7. Mylan Institutional LLC. Isosulfan blue 1% injection [product information]. Rockford, IL, Mylan Institutional LLC, 2013.
  8. Kiesslich R, Neurath MF, Galle PR. Chromoendoscopy and magnifying endoscopy in patients with gastroesophageal reflux disease. Useful or negligible? Dig Dis.2004;22(2):142-7.
  9. Indigotindisulfonate sodium. In McEvoy, GK, Snow EK, et al., Eds. AHFS Drug Information Online. Accessed September 17, 2013.
  10. Anon, editor. Drugdex System. Micromedex 2.0 [internet database]. Greenwood Village, CO: Truven Health Analytics; 2014.
  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 July 29, 2014 by Jane Chandramouli, PharmD, Drug Information Specialist. Created September 17, 2013 by Erin Fox, PharmD, FASHP, Director, Drug Information Service, and Michelle Wheeler, 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.

« Back to Drug Shortage Product Bulletins

Advocacy Activity
Get the latest updates on ASHP's advocacy activity on drug shortages.
Advertisement