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Methylene Blue (Systemic)



INN:

Methylthioninium chloride {02}

VA CLASSIFICATION
Primary: AD900
Secondary: DX900

Commonly used brand name(s): Urolene Blue.

Other commonly used names are
aniline violet {18}, methylthionine chloride {01} {18}, and tetrametylthionine chloride {05} {06} .
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antimethemoglobinemic—

diagnostic aid (tissue dye)—

Indications

Accepted

Methemoglobinemia, acquired (treatment) and
Methemoglobinemia, idiopathic (treatment)—Methylene blue is indicated in the treatment of acquired and idiopathic methemoglobinemia. {07} {09} {17} {18} {20} {24} {27} {29}

Tissue dye in diagnostic procedures—Methylene blue is used as a bacteriological stain, {07} {18} {27} as a dye in diagnostic procedures, such as fistula detection, {21} {27} and for the selective staining of certain body tissues during surgery. {07} {27} Methylene blue is also used intraamniotically to diagnose premature rupture of fetal membranes {22} {24} and to identify separate amniotic sacs in twin pregnancies. {24} {27}

Unaccepted
Methylene blue has been used to produce methemoglobinemia in the treatment of cyanide poisoning; {18} however, sodium nitrite is considered to be a safer, more effective alternative.

Methylene blue has been used as a urinary tract antibacterial agent; {01} {18} {22} however, this medication has been replaced by more effective agents. {18}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    373.90 {02} {18}


pH
    3 to 4.5 {19}

Mechanism of action/Effect:

Methemoglobinemia—Methylene blue, in low concentrations, acts as a cofactor to accelerate the conversion of methemoglobin to hemoglobin in erythrocytes. {01} {06} {07} {08} {09} {12} {13} {18} {20} {23} {29} Methylene blue combines with nicotinamide adenine dinucleotide phosphate reduced (NADPH), in the presence of NADPH-methemoglobin reductase, to produce leukomethylene blue; leukomethylene blue then reduces methemoglobin to hemoglobin. {05} {06} {11} {12} {20} {27}

Tissue dye—Methylene blue's usefulness as a diagnostic aid is based on its ability to stain tissue. {01} {07}


Other actions/effects:

In high concentrations, methylene blue oxidizes the ferrous iron of hemoglobin to the ferric state, facilitating the conversion of hemoglobin to methemoglobin. {01} {06} {07} {09} {18} {23} {24} {27} {29}

Methylene blue has mild antiseptic activity {01} {18} {22} that may inhibit bacterial proliferation.

Absorption:

Poorly absorbed from the gastrointestinal tract after oral administration. {05} {06} {20}

Biotransformation:

Rapidly reduced to leukomethylene blue. {01} {05} {06} {18}

Elimination:
    Excreted in the urine {01} {06} {17} {20} {27} and bile, {06} primarily as leukomethylene blue. Some unchanged drug is also excreted in the urine. {01} {27}


Precautions to Consider

Pregnancy/Reproduction

Pregnancy—
Studies have not been done in humans. {09}

Studies have not been done in animals. {01}

FDA Pregnancy Category C.

Breast-feeding

It is not known whether methylene blue is distributed into breast milk. {01} However, problems in humans have not been documented.

Pediatrics

Extreme caution should be exercised when administering methylene blue to infants. During the first 4 months of life, {05} {08} infants have lower concentrations of the enzymes necessary for reducing methemoglobin to hemoglobin, making these infants more susceptible to methemoglobinemia {03} {05} {06} {08} {10} {15} {27} produced by high doses of methylene blue.

Intraamniotic injection of methylene blue has resulted in hemolytic anemia, hyperbilirubinemia, methemoglobinemia, and deep blue staining of the newborn. {22} {23} {24} {25}


Geriatrics


Appropriate studies on the relationship of age to the effects of methylene blue have not been performed in the geriatric population. However, no geriatrics-specific problems have been documented to date.


Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
» Phenolsulfonphthalein (PSP) excretion test{26}    (methylene blue may cause a false positive test result)


Urinary free formaldehyde and
Urine pH    (methylene blue may interfere with analysis)


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problems exist:
» Glucose-6-phosphate dehydrogenase (G6PD) deficiency{01}{03}{04}{06}{08}{11}{12}{18}{20}{27}    (use of methylene blue may aggravate methemoglobinemia and precipitate hemolytic anemia)


» Methemoglobinemia, to treat cyanide toxicity{05}{20}    (methylene blue increases release of cyanide from methemoglobin, increasing the concentration of cyanide in the blood)


Risk-benefit should be considered when the following medical problems exist
Renal function impairment{01}{17}{27}    (elimination may be reduced; dosage reduction may be required)


Sensitivity to methylene blue{01}{20}

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Complete blood counts and
» Reticulocyte counts{20}    (recommended following methylene blue therapy to assure that hemolysis has not occurred)


» Methemoglobin concentrations{03}{04}{11}{20}    (recommended 1 to 2 hours following administration of methylene blue to assess the effectiveness of therapy)




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Greenish blue to blue discoloration of urine{01}{04}{06}{18}{26}{27} and feces{01}{18}{27}

Incidence less frequent
    
Diarrhea {01}{18}
    
nausea and vomiting {01}{18}{27}
    
painful urination or increased urinary frequency {01}{04}{06}{18}{20}{27}—with oral administration





Overdose
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
    
Abdominal pain {05}{07}{08}{18}{29}
    
anxiety {05}{06}{10}{20}
    
chest pain {03}{05}{06}{07}{08}{18}{20}
    
confusion {05}{07}{08}{18}{29}
    
electrocardiographic changes (diminished or inverted T wave amplitude; diminished R wave amplitude){05}{10}
    
hemolytic anemia (abdominal, back, or leg pain; chills){03}{11}{12}{14}{17}{27}
    
methemoglobinemia (bluish fingernails, lips, or skin; difficulty in breathing; dizziness; headache; unusual tiredness or weakness){01}{03}{05}{06}{07}{08}{10}{11}{12}{14}{18}{20}{24}{27}{29}
    
nausea and vomiting {01}{05}{07}{08}{29}
    
severe sweating {08}{18}{29}
    
tremors {03}{05}{06}{20}




Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Methylene Blue (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to methylene blue





Use in children—Cautious use in infants up to 4 months of age because they have lower concentrations of enzymes that reduce methemoglobin to hemoglobin; intraamniotic injection may cause hemolytic anemia, hyperbilirubinemia, methemoglobinemia, or deep blue staining of newborn

Other medical problems, especially glucose-6-phosphate dehydrogenase (G6PD) deficiency and methemoglobinemia to treat cyanide toxicity

Proper use of this medication
Taking tablets after meals with a full glass (240 mL) of water

» Proper dosing
Missed dose

» Proper storage

Precautions while using this medication
Possible interference with laboratory values


Side/adverse effects
Greenish blue to blue discoloration of urine and feces may be alarming to patient although medically insignificant


General Dosing Information
Treatment of acquired methemoglobinemia should be initiated with general supportive care and removal of the toxic agent, which, depending on the severity of the poisoning, may include administering 100% oxygen, {05} {12} {20} and removing the toxic agent from the body. This can be done by removing contaminated clothing and rinsing the skin with water, inducing emesis, instituting gastric lavage, administering activated charcoal and cathartic, {04} {05} {06} {10} {20} or instituting hemodialysis. {04} {06} {11} In most cases of methemoglobinemia, these treatment measures stabilize the patient. {04} {05} {12}

Specific antidotal therapy with methylene blue should be reserved for cases of methemoglobinemia in which the methemoglobin concentration is greater than 30% or in which there are clinical signs of hypoxia. {06} {08} {10} {11} {20}

If adequate methylene blue therapy fails and toxic concentrations of methemoglobin persist, the possibility of glucose-6-phosphate dehydrogenase (G6PD) deficiency, {05} {06} {08} {10} {11} {12} {13} {20} {27} nicotinamide adenine dinucleotide phosphate reduced (NADPH) methemoglobin reductase deficiency, {05} {06} {08} {10} {13} {20} {27} hemoglobin M, {08} {10} {13} or sulfhemoglobinemia {05} {06} {08} {10} {12} {20} should be considered. In these cases, exchange transfusion {03} {05} {06} {10} {13} {20} may be required. Hyperbaric oxygen {08} {10} has also been recommended, {06} {08} {10} {11} but its efficacy in this setting has been questioned and there is little experience with its use. {11}

Chronic, idiopathic methemoglobinemia usually requires treatment only for cosmetic purposes. {03} {04} Administration of ascorbic acid, orally or intravenously, 100 to 500 mg two or three times a day is a non-toxic alternative to methylene blue. Ascorbic acid usually maintains the methemoglobin concentration below the level that causes cyanosis, preventing a cyanotic appearance. {03} {06} {20} However, ascorbic acid reduces methemoglobin to hemoglobin too slowly to be of benefit in the treatment of acquired methemoglobinemia. {04} {06} {08} {11}

For oral dosage forms only
Methylene blue tablets should be taken after meals with a full glass (240 mL) of water. {01} {18}

For parenteral dosage forms only
Methylene blue should be administered by intravenous injection. Subcutaneous or intrathecal injection may result in tissue necrosis {05} {09} {27} or neural damage, {09} {27} respectively.


Oral Dosage Forms

METHYLENE BLUE TABLETS

Usual adult and adolescent dose
Methemoglobinemia, idiopathic
Oral, 100 to 300 mg per day. {03} {04} {27}


Usual adult prescribing limits
7 mg per kg of body weight. {30}

Strength(s) usually available
U.S.—


65 mg (Rx) [Urolene Blue][Generic]

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from light. {01}

Auxiliary labeling:
   • Take after meals with a full glass (240 mL) of water.
   • May discolor urine and/or stools.



Parenteral Dosage Forms

METHYLENE BLUE INJECTION USP

Usual adult and adolescent dose
Methemoglobinemia
Intravenous, 1 to 2 mg per kg of body weight {03} {04} {05} {06} {08} {09} {10} {11} {12} {13} {16} {17} {18} {20} {27} {28} {29} or 25 to 50 mg per square meter of body surface area, {20} administered over five minutes. {05} {06} {08} {10} {20} The dose may be repeated after one hour if needed. {03} {04} {05} {06} {08} {11} {12} {20} {27}

Note: For treatment of methemoglobinemia following overdose of agents in which there is prolonged or continuous methemoglobin formation (e.g., dapsone), methylene blue may be administered by continuous intravenous infusion at a rate of 0.1 to 0.15 mg per kg of body weight per hour, following an initial dose of 1 to 2 mg per kg of body weight. {13} {14}



Usual adult prescribing limits
7 mg per kg of body weight. {03} {05} {08} {11} {20}

Usual pediatric dose
See Usual adult and adolescent dose.

Strength(s) usually available
U.S.—


10 mg per mL (Rx)[Generic]

Canada—


10 mg per mL (Rx)[Generic]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), {21} {29} unless otherwise specified by manufacturer. Protect from light. {21}

Preparation of dosage form:
For continuous intravenous infusion, methylene blue should be admixed with a compatible solution, such as 0.9% sodium chloride injection, to a final concentration of 0.05%. {14}

Auxiliary labeling:
   • May discolor urine and/or stools.



Developed: 05/27/1994



References
  1. Urolene Blue package insert (Star Pharmaceuticals—US), Rev 9/92, Rec 11/9/93.
  1. Fleeger CA, editor. USAN 1994. USAN and the USP dictionary of drug names. Rockville, MD: The United States Pharmacopeial Convention, Inc., 1993: 419.
  1. Mansouri A, Lurie AA. Concise review: methemoglobinemia. Am J Hematol 1993; 42: 7-12.
  1. Mansouri A. Review: methemoglobinemia. Am J Med Sci 1985; 289: 200-9.
  1. Armstrong DJ. Methemoglobinemia. Ear Nose Throat J 1983; 62: 148-54.
  1. Curry S. Methemoglobinemia. Ann Emerg Med 1982; 11: 214-21.
  1. Devine RM, van Heerden JA, Grant CS, Muir JJ. The role of methylene blue infusion in the management of persistent or recurrent hyperparathyroidism. Surgery 1983; 94: 916-8.
  1. Caudill L, Walbridge J, Kuhn G. Methemoglobinemia as a cause of coma. Ann Emerg Med 1990; 19: 677-9.
  1. Methylene blue injection package insert (American Regent—US), Rev 5/89, Rec 1/31/94.
  1. Laney RF, Hoffman RS. Methemoglobinemia secondary to automobile exhaust fumes. Am J Emerg Med 1992; 10: 426-8.
  1. Kearney TE, Manoguerra AS, Dunford JV. Chemically induced methemoglobinemia from aniline poisoning. West J Med 1984; 140: 282-6.
  1. Erstad BL. Dapsone-induced methemoglobinemia and hemolytic anemia. Clin Pharm 1992; 11: 800-5.
  1. Dawson AH, Whyte IM. Management of dapsone poisoning complicated by methaemoglobinemia. Med Toxicol Adverse Drug Exp 1989; 4: 387-92.
  1. Berlin G, Brodin B, Hilden J-O, Martensson J. Acute dapsone intoxication: a case treated with continuous infusion of methylene blue, forced diuresis and plasma exchange. Clin Toxicol 1985; 22: 537-48.
  1. Kearns GL, Fiser DH. Metoclopramide-induced methemoglobinemia. Pediatrics 1988; 82: 364-6.
  1. Luk G, Riggs D, Luque M. Severe methemoglobinemia in a 3-week-old infant with a urinary tract infection. Crit Care Med 1991; 19: 1325-7.
  1. Sharon M, Puente G, Cohen LB. Phenazopyridine (Pyridium) poisoning: possible toxicity of methylene blue administration in renal failure. Mt Sinai J Med 1986; 53: 280-2.
  1. Gennaro AR, editor. Remington's pharmaceutical sciences. 18th ed. Easton, PA: Mack Publishing Company, 1990: 829-30.
  1. The United States pharmacopeia. The national formulary. USP 22nd revision (January 1, 1990). NF 17th ed (January 1, 1990). Rockville, MD: The United States Pharmacopeial Convention, Inc., 1990: 871.
  1. Ellenhorn MJ, Barceloux DG. Medical toxicology. Diagnosis and treatment of human poisoning. New York: Elsevier, 1988: 829-35, 844-52.
  1. Methylene blue injection product information (DBL—Canada), Rec 2/3/94.
  1. Briggs GG, Freeman RK, Yaffe SJ. A reference guide to fetal and neonatal risk. Drugs in pregnancy and lactation. 3rd ed. Baltimore: Williams & Wilkins, 1990: 422-3.
  1. McEnerney JK, McEnerney LN. Unfavorable neonatal outcome after intraamniotic injection of methylene blue. Obstet Gynecol 1983; 61 (3 Suppl): 35S-37S.
  1. Spahr RC, Salsburey DJ, Krissberg A, Prin W. Intraamniotic injection of methylene blue leading to methemoglobinemia in one of twins. Int J Gynaecol Obstet 1980; 17: 477-8.
  1. Troche BI. The methylene blue baby [letter]. N Engl J Med 1989; 320: 1756-7.
  1. Wallach J. Interpretation of diagnostic tests. A synopsis of laboratory medicine. 4th ed. Boston: Little, Brown and Company, 1986: 464, 660.
  1. Krogh CME, editor. CPS Compendium of pharmaceuticals and specialties. 28th ed. Ottawa: Canadian Pharmaceutical Association, 1993: 717.
  1. Yaffe SJ, Aranda JV. Pediatric pharmacology. Therapeutic principles in practice. 2nd ed. Philadelphia: W.B. Saunders Company, 1992: 587-8.
  1. Methylene blue injection package insert (Pasadena—US), Rev 2/94, Rec 3/1/94.
  1. Panel comment, 3/94.
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