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Prussian Blue (Oral-Local)


VA CLASSIFICATION
Primary: AD300

Commonly used brand name(s): Antidotum Thallii-Heyl; Radiogardase-Cs.

Other commonly used names are:
Berlin blue {01} {04} {16}, ferric ferrocyanide {01} {16}, ferric (III) hexacyanoferrate (II) {01} {02}, and iron blue {04} .

Note: In the literature, the form of prussian blue used is often imprecisely defined. {02} {04} {14} The insoluble form, and the soluble or colloidal form, also known as potassium ferric (III) hexacyanoferrate (II), have been confused. The following information applies only to the insoluble form of prussian blue. {02}

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

*Not commercially available in the U.S.

Not commercially available in Canada.



Category:


Chelating agent—

Indications

Note: Because prussian blue is not commercially available in the U.S. or Canada, the bracketed information and the use of the superscript 1 in this monograph reflect the lack of labeled (approved) indications for this medication in these countries.


Accepted

[Toxicity, thallium (treatment)]1—Prussian blue may be used for the treatment of acute and chronic thallium poisoning. {01} {02} {11} {13}
—Administration of systemic chelating agents is not recommended in thallium poisoning because these agents may cause an increase in the uptake of thallium into the brain. {15} {18}

[Toxicity, radiocesium (treatment)]1—Prussian blue may be used for the treatment of radiocesium contamination. {01} {02} {04} {10} {11} {14}
—Radiocesium's biological half-life may be as long as 150 days in humans. {02} {21} Administration of prussian blue has been shown to reduce the half-life of radiocesium by one-third in some patients. {02} {16} {21}

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    859.3 {02}

Mechanism of action/Effect:

Chelating agent—Prussian blue has a strong affinity for thallium and cesium {02} and binds with them in the intestine {02} {04} {08} {09} {11} {16} {18} {24} to form a complex, {01} {02} {05} {09} which is eliminated via the feces. {02} {03} {04} {05} {09}

Absorption:

Poorly absorbed from the gastrointestinal tract following oral administration. {02} {03} {05} {08} {11} {16}

Biotransformation:

Approximately 7% of prussian blue is metabolized to cyanoferrate, which may also bind thallium. {05}

Elimination:
    Prussian blue—Predominantly fecal. {01} {02} {03} {05} {10} {11}
    Cyanoferrate—Renal. {05}


Precautions to Consider

Carcinogenicity/Mutagenicity

No evidence of carcinogenicity or mutagenicity was observed in rats administered prussian blue orally for up to 17 weeks. {02}

Pregnancy/Reproduction

Problems in humans have not been documented.

Breast-feeding

It is not known whether prussian blue is distributed into breast milk. However, thallium is distributed into breast milk. {05}

Pediatrics

Appropriate studies on the relationship of age to the effects of prussian blue have not been performed in the pediatric population. However, pediatrics-specific problems that would limit the usefulness of this medication in children are not expected.


Geriatrics


Appropriate studies on the relationship of age to the effects of prussian blue have not been performed in the geriatric population. However, geriatrics-specific problems that would limit the usefulness of this medication in the elderly are not expected.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Tetracyclines, oral{02}    (prussian blue may impair absorption of tetracyclines)


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:
» Constipation{06}{09}{10} and
» Paralytic ileus{06}    (intestinal motility is required for efficacy {02} {06} {09})


Risk-benefit should be considered when the following medical problem exists
Sensitivity to prussian blue

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):

» Thallium, serum or urine{05}{17}    (concentrations recommended to assess the extent of thallium exposure and to guide treatment)




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
Incidence more frequent
    
Constipation {02}{03}{16}



Those not indicating need for medical attention
Incidence more frequent
    
Unusually dark feces {02}





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

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

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





Breast-feeding—Thallium distributed into breast milk
Other medical problems, especially constipation and paralytic ileus

Proper use of this medication
» Compliance with full course of therapy

For patients who cannot swallow capsules: Adding contents of capsule to warm water

Taking with laxative, if advised by physician

» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next dose; not doubling doses

» Proper storage


Side/adverse effects
Signs of potential side effects especially, constipation

Unusually dark stools may be alarming to patient, although medically insignificant


General Dosing Information
For more information on the management of thallium or radiocesium overdose, contact a poison control center. {22}

Immediately following an acute exposure to thallium or radiocesium, the gastrointestinal tract should be decontaminated via gastric lavage {01} {02} {03} {05} {10} {12} {19} {20} or whole bowel irrigation. {23} Symptomatic and supportive treatment should also be started, with special attention given to the patient's respiratory and circulatory status. {05}

Hemodialysis {01} {02} {05} {07} {12} {13} {18} {19} {20} {24} and charcoal hemoperfusion {02} {06} {12} {20} are effective in enhancing the elimination of thallium if initiated within the first 48 hours after intoxication. {01} {02} {12} Once thallium has been sequestered intracellularly, hemodialysis is of little benefit in enhancing its elimination; {05} however, hemodialysis is still recommended if renal failure is present. {05} {06} {07}

Forced diuresis has not been shown to increase the urinary excretion of radiocesium. {16} However, it has been shown to enhance the elimination of thallium and may be useful in acute intoxications. {05} {09} {12} {13} {18} {19} Forced diuresis should be continued until the 24-hour urinary thallium excretion is less than 1 mg. {01} {02} {12}

Forced diuresis may be combined with an intravenous infusion of potassium chloride to further enhance the urinary excretion of thallium. {03} {05} {06} {07} However, potassium chloride must be used with extreme caution. It may increase the concentration of thallium in the blood by displacing thallium from tissue stores, {03} {05} {06} {12} thereby increasing the amount of thallium available for elimination. {05} {12} This may cause a redistribution of thallium into the central nervous system {05} {09} and an initial worsening of symptoms. {06} If potassium chloride is given, the patient must be carefully monitored for exacerbation of neurologic and cardiovascular symptoms. {05}

The daily dosage of prussian blue should be spread evenly over a 24-hour period. {02}

Prussian blue may be mixed with a cathartic, such as 15% mannitol solution {05} {07} {08} {10} {12} {19} {24} or sorbitol, {03} to prevent or lessen constipation. {05} {12} {19}

Activated charcoal is not as effective but may be used if prussian blue is unavailable to treat thallium toxicity. The recommended dose is 500 mg per kg of body weight two times a day. {05} {10} Activated charcoal is not effective in the treatment of radiocesium toxicity. {14}


Oral Dosage Forms

Note: Because prussian blue is not available in the U.S. or Canada, the bracketed uses and the use of the superscript 1 in the Dosage Forms section reflect the lack of labeled (approved) indications for this product in these countries.


PRUSSIAN BLUE CAPSULES

Usual adult dose
[Toxicity, thallium (acute)]1
Oral, 3 grams administered immediately, followed by either 3 to 20 grams a day in evenly divided doses {02} or 250 mg per kg of body weight a day in four divided doses. {03} {05} {08} {10} The dosage may be given for two to three weeks {06} or until the twenty-four-hour urinary thallium excretion is less than 0.5 mg. {05} {11} {12} {24}

[Toxicity, thallium (chronic)]1
Oral, 3 to 20 grams a day in evenly divided doses {02} or 250 mg per kg of body weight a day in four divided doses. {03} {05} {08} {10} The dosage may be given for two to three weeks {06} or until the twenty-four-hour urinary thallium excretion is less than 0.5 mg. {05} {11} {12} {24}

[Toxicity, radiocesium]1
Oral, 500 mg six times a day at two-hour intervals {02} for several days to three weeks. {16}


Usual adult prescribing limits
20 grams within 24 hours. {02}

Usual pediatric dose
See Usual adult dose.{02}

Usual geriatric dose
See Usual adult dose.

Strength(s) usually available
U.S.—
Not commercially available.

Canada—
Not commercially available.

Germany—


500 mg (Rx) [Antidotum Thallii-Heyl] [Radiogardase-Cs]

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

Preparation of dosage form:
For patients who cannot take oral solids—Contents of capsules may be added to warm water and the resulting suspension taken orally. {02} Contents of capsules may also be added to 15% mannitol solution (1 gram prussian blue per 10 mL of 15% mannitol solution) {01} and administered via duodenal {02} {06} {15} {24} or nasogastric {03} tube.



Revised: 04/19/1995



References
  1. Reynolds JEF, editor. Martindale, the extra pharmacopeia. 30th ed. London: The Pharmaceutical Press, 1993: 693.
  1. Antidotum Thallii-Heyl, Radiogardase-Cs package insert (Heyl—Germany), Rec 12/12/94.
  1. Ellenhorn MJ, Barceloux DG. Medical toxicology. Diagnosis and treatment of human poisoning. New York: Elsevier, 1988: 83, 1060-2.
  1. Pearce J. Studies of any toxicological effects of prussian blue compounds in mammals—a review. Food Chem Toxicol 1994; 32: 577-82.
  1. Mulkey JP, Oehme FW. A review of thallium toxicity. Vet Hum Toxicol 1993; 35: 445-53.
  1. Saddique A, Peterson CD. Thallium poisoning: a review. Vet Hum Toxicol 1983; 25: 16-22.
  1. Wainwright AP, Kox WJ, House IM, et al. Clinical features and therapy of acute thallium poisoning. Q J Med 1988; 69: 939-44.
  1. Ghezzi R, Bozza Marrubini M. Prussian blue in the treatment of thallium intoxication. Vet Hum Toxicol 1979; 21 Suppl: 64-6.
  1. Pai V. Acute thallium poisoning. Prussian blue therapy in 9 cases. West Indian Med J 1987; 36: 256-8.
  1. Stevens W, van Peteghem C, Heyndrickx A, et al. Eleven cases of thallium intoxication treated with prussian blue. Int J Clin Pharmacol 1974; 10: 1-22.
  1. Kamerbeek HH, Rauws AG, ten Ham M, et al. Prussian blue in therapy of thallotoxicosis. An experimental and clinical investigation. Acta Med Scand 1971; 189: 321-4.
  1. de Groot G, van Heijst ANP. Toxicokinetic aspects of thallium poisoning. Methods of treatment by toxin elimination. Sci Total Environ 1988; 71: 411-8.
  1. Pederson RS, Olesen AS, Freund LG, et al. Thallium intoxication treated with long-term hemodialysis, forced diuresis and prussian blue. Acta Med Scand 1978; 204: 429-32.
  1. Verzijl JM, Joore JCA, van Dijk A, et al. In vitro binding characteristics for cesium of two qualities of prussian blue, activated charcoal and resonium-A. J Toxicol Clin Toxicol 1992; 30: 215-22.
  1. de Groot G, Savelkoul TJF, Remmert HP, et al. No evidence for general thallium poisoning in Guyana [letter]. Lancet 1987; 1: 1084.
  1. Farina R, Brandão-Mello CE. Medical aspects of 13 7Cs decorporation: the Goiânia radiological accident. Health Phys 1991; 60: 63-6.
  1. Jacobs DS, Kasten BL Jr., Demott WR, Wolfson WL. Laboratory test handbook. 2nd ed. Hudson (Cleveland): Lexi-Comp Inc., 1990: 818.
  1. Gilman AG, Rall TW, Nies AS, Taylor P, editors. Goodman and Gilman's the pharmacological basis of therapeutics. 8th ed. New York: Pergamon Press, 1990: 1633.
  1. de Groot G, van Heijst ANP, van Kesteren RG, et al. An evaluation of the efficacy of charcoal haemoperfusion in the treatment of three cases of acute thallium poisoning. Arch Toxicol 1985; 57: 61-6.
  1. de Backer W, Zachee P, Verpooten GA, et al. Thallium intoxication treated with combined hemoperfusion-hemodialysis. J Toxicol Clin Toxicol 1982; 19: 259-64.
  1. Lipsztein JL, Bertelli L, Oliveira AN, et al. Studies of Cs retention in the human body related to body parameters and prussian blue administration. Health Phys 1991; 60: 57-61.
  1. Panel comment, 2/95.
  1. Panel comment, 2/95.
  1. Haddad LM, Winchester JF. Clinical management of poisoning and drug overdose. 2nd ed. Philadelphia: W.B. Saunders Company, 1990: 1032.
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