Prussian blue
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alara Ece Dagsali, M.D.[2]
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Overview
Prussian blue is {{{aOrAn}}} RADIOGARDASE that is FDA approved for the treatment of Radiogardase is indicated for treatment of patients with known or suspected internal contamination with radioactive cesium and/or radioactive or non-radioactive thallium to increase their rates of elimination. Common adverse reactions include Most common adverse reaction (incidence >24%) was constipation Constipation was reported in 10 (24%) of 42 patients treated with Radiogardase. Severity of constipation was mild in 7 patients and moderate in 3 patients.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
Radiogardase is indicated for treatment of patients with known or suspected internal contamination with radioactive cesium and/or radioactive or non-radioactive thallium to increase their rates of elimination.
Capsules: 0.5 grams Adults and Adolescents: 3 grams orally three times a day
Off-Label Use and Dosage (Adult)
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
Radiogardase is indicated for treatment of patients with known or suspected internal contamination with radioactive cesium and/or radioactive or non-radioactive thallium to increase their rates of elimination.
Pediatrics (2 – 12 years): 1 gram orally three times a day
Off-Label Use and Dosage (Pediatric)
Contraindications
None
Warnings
Increased radiation absorbed dose to gastrointestinal mucosa: Monitor for decreased gastrointestinal motility Constipation: Monitor and treat Electrolyte abnormalities: Monitor serum electrolytes during treatment Blue discoloration of stool, oral mucosa and dentition
Adverse Reactions
Clinical Trials Experience
There is limited information regarding Prussian blue Clinical Trials Experience in the drug label.
Postmarketing Experience
There is limited information regarding Prussian blue Postmarketing Experience in the drug label.
Drug Interactions
Based on animal data, co-administration of Radiogardase with other decorporation agents does not affect the efficacy of Radiogardase for treatment of internal contamination with radioactive cesium and/or radioactive or non-radioactive thallium.
Use in Specific Populations
Pregnancy
Pregnancy Category (FDA): C It is not known whether Radiogardase can cause fetal harm when administered to a pregnant woman or if it can affect reproduction capacity. Animal reproduction studies have not been conducted with prussian blue insoluble. However, since Radiogardase is not absorbed from the gastrointestinal tract, effects on the fetus are not expected.
Radioactive cesium ( 137Cs) crosses the human placenta. One patient, contaminated with 0.005 mCi 137Cs during her 4 th month of pregnancy, was not treated with Radiogardase. At birth, the concentration of 137Cs was the same in the mother and the infant.
Thallium crosses the human placenta. Reported fetal effects include failure to thrive and death. The toxicity from untreated radioactive cesium or thallium exposure is greater than the potential reproductive toxicity of Radiogardase.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Prussian blue in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Prussian blue during labor and delivery.
Nursing Mothers
Studies to determine if Radiogardase is excreted in human milk have not been conducted. Since Radiogardase is not absorbed from the gastrointestinal tract, its excretion in milk is unlikely. However, cesium and thallium are transmitted from mother to infant in breast milk. Women internally contaminated with cesium or thallium should not breastfeed.
Pediatric Use
Radioactive Cesium Contamination The safety and efficacy of Radiogardase in the treatment of 137Cs in pediatric patients ages, 2 to 18 years old, was established from data from Radiogardase-treated pediatric patients exposed to 137Cs in the Goiânia, Brazil, contamination incident and from Radiogardase-treated adults exposed to 137Cs [see CLINICAL STUDIES (14.1)].
Overall, 27 pediatric patients received Radiogardase in the range of 3 to 10 grams per day in divided doses (the maximum recommended adolescent dosage is 9 grams per day). Radiogardase treatment reduced the whole body effective half-life of 137Cs by 46% in adolescents and by 43% in children aged 4 to 12 years of age. In 12 patients for whom the rate of radiation elimination data are available, the rate was similar to that in adults treated with 3 grams three times daily and in pediatric patients treated with 1 gram three times daily. By body weight, the dose ranged from
0.32 gram/kg in the 12-year old patient (10 gram Radiogardase daily dose, 31 kg weight) to
0.21 gram/kg in the 4 year old patient (3 gram Radiogardase daily dose, 14 kg weight) [see CLINICAL STUDIES (14.1)] .
Pediatric patients aged 2 up to 4 years are expected to have biliary and gastrointestinal function that is comparable to that of a 4-year old.
The safety and efficacy of Radiogardase has not been established in the treatment of 137Cs contamination in pediatric patients 0 to 2 years old. There are differences in the developmental maturity of the biliary system and gastrointestinal tract of neonates and infants (0 – 2 years). The dosage-related adverse reactions of Radiogardase on an immature gastrointestinal tract are not known.
Radioactive and Non-Radioactive Thallium Contamination The safety and efficacy of Radiogardase for the treatment of radioactive and non-radioactive thallium contamination in pediatric patients has not been established.
Geriatic Use
The safety and efficacy of Radiogardase in patients aged 65 and over have not been evaluated, to determine whether they respond differently from younger subjects.. In general, elderly patients should be monitored closely, reflecting the greater frequency of decreased cardiac function and of concomitant disease or other drug therapy.
Gender
There is no FDA guidance on the use of Prussian blue with respect to specific gender populations.
Race
There is no FDA guidance on the use of Prussian blue with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of Prussian blue in patients with renal impairment.
Hepatic Impairment
Radiogardase is not systemically bioavailable and does not rely on hepatic metabolism for activation or inactivation. However, Radiogardase may be less effective in patients with hepatic impairment, due to decreased excretion of cesium and thallium in the bile.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Prussian blue in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Prussian blue in patients who are immunocompromised.
Administration and Monitoring
Administration
Adults and Adolescents: 3 grams orally three times a day ( 2.3) Pediatrics (2 – 12 years): 1 gram orally three times a day ( 2.3) Administer as soon as possible after internal contamination with cesium or thallium is suspected ( 2.1)
Monitoring
ncreased radiation absorbed dose to gastrointestinal mucosa: Monitor for decreased gastrointestinal motility Constipation: Monitor and treat Electrolyte abnormalities: Monitor serum electrolytes during treatment Blue discoloration of stool, oral mucosa and dentition
IV Compatibility
There is limited information regarding the compatibility of Prussian blue and IV administrations.
Overdosage
Based on reported adverse reactions and mechanism of action, possible overdosage symptoms may include constipation, obstruction, or severe decrease in electrolytes. Gastric distress was reported in 3 patients treated with 20 gram/day of Radiogardase (approximately 2.2 times the maximum recommended dosage). In these patients, the dose was reduced to 10 gram/day for continued treatment.
Pharmacology
There is limited information regarding Prussian blue Pharmacology in the drug label.
Mechanism of Action
Prussian blue insoluble, ferric hexacyanoferrate(II), acts by ion-exchange, adsorption, and mechanical trapping within the crystal structure, and has a high affinity for radioactive and non-radioactive cesium and thallium.
Prussian blue insoluble binds cesium and thallium isotopes in the gastrointestinal tract after these isotopes are ingested or excreted in the bile by the liver, thereby reducing gastrointestinal reabsorption (enterohepatic circulation). The rate of cesium and thallium elimination is proportional to the duration and dose of prussian blue insoluble.
Structure
There is limited information regarding Prussian blue Structure in the drug label.
Pharmacodynamics
Cesium-137 ( 137Cs) 137Cs has a physical half-life of 30 years, with a beta energy peak at 174.0 keV. Following entry into the blood, it is distributed uniformly through all body tissues. Approximately 10% of 137Cs is eliminated rapidly with a biological half-life of 2 days; 90% is eliminated more slowly, with a biological half-life of 110 days; and less than 1% of the 137Cs is retained with a biological half-life of about 500 days. 137Cs follows the movement of potassium and is excreted into the intestine, reabsorbed from the gastrointestinal (GI) tract into the blood, then to the bile, where it is excreted again into the GI tract by bile via enterohepatic circulation. Without Radiogardase treatment, about 80% of 137Cs is excreted through the kidneys and about 20% in the feces.
Thallium-201 ( 201Tl) Radioactive thallium ( 201Tl) has a physical half-life of 3 days with electron and photon emissions with a gamma energy peak at 167.4 keV. Non-radioactive thallium has a biological half-life of
8 – 10 days.The physiologic transport of thallium follows the same route as potasium and is excreted by bile in enterohepatic circulation. Without Radiogardase treatment, the fecal to urine excretion ratio of thallium is approximately 2:1.
The results of fecal analysis from patients contaminated with 137Cs and treated with Radiogardase showed higher activities of 137Cs in feces, and the associated whole body radioactivity counts showed a more rapid rate of elimination from the body. The effectiveness of Radiogardase for one patient is shown in Figure 1. The whole body content of radioactive material of 137Cs in kilo-Bequerels (kBq) is shown on the y-axis. Time in days is on the x-axis. Line “A” represents the whole body activity of 137Cs during prussian blue insoluble treatment at 10 g/day. The dotted line represents extrapolation of the whole body activity if treatment was continued. Line “B” represents the whole body activity of 137Cs, after prussian blue insoluble was stopped.
Pharmacokinetics
Absorption/Elimination: Prussian blue insoluble is not absorbed through the intact gastrointestinal wall. Its clearance from the body depends on the gastrointestinal tract transit time.
Food Effects: Food effect studies have not been conducted. In animal studies, Prussian blue insoluble was not significantly absorbed. Food may increase the effectiveness of prussian blue insoluble by stimulating bile secretion.
Nonclinical Toxicology
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Animal studies have not been performed to evaluate the carcinogenic or mutagenic potential of prussian blue insoluble. No study on impairment of male or female fertility and reproductive performance has been conducted in animals.
13.2 Animal Toxicology and/or Pharmacology Absorption/Elimination In an animal study (pigs, n =38), after a single dose of 40 mg of labeled prussian blue insoluble, 99% of the administered prussian blue dose was excreted unchanged in feces. Absorption from multiple doses has not been studied.
In a study using rats (n = 40, mean body weight range of 188 – 219 grams) injected with 137Cs, a dose response relationship was demonstrated for the amount of radiation elimination with prussian blue insoluble at doses of 1 to 50 mg/day (Table 1). There is little difference in radiation elimination rate between prussian blue insoluble at doses of 50 to 100 mg/day. In Table 1, the % of Injected Radiation Dose Remaining is defined as the percentage of the total injected dose of 137Cs remaining in the body at 96 hours post administration.
In studies of rats, pigs, and dogs that were internally contaminated with cesium and thallium, the presence of the insoluble complexes in the gastrointestinal lumen changed the primary elimination route from the kidney to the feces and increased the rate of elimination of these two contaminants.
Clinical Studies
14.1 Cesium-137 Contamination In literature reports, 72 people received Radiogardase after exposure to radioactive cesium ( 137Cs):
46 patients with 137Cs contamination 19 patients 137Cs contamination in other incidents 7 healthy human subjects who voluntarily ingested trace doses of 137Cs In a 1987 incident in Goiânia, Brazil, 46 patients with heavy internal contamination with 137Cs were treated with Radiogardase (Table 2). Data on the whole body effective half-life of 137Cs, during and after Radiogardase treatment, was completed on 33 of these 46 patients (see Table 2). Radiogardase reduced the mean whole-body effective half-life of 137Cs by 69%, 46%, and 43% in adults, adolescents, and younger children, respectively.
Table 2 shows the decrease in whole body effective half-life of 137Cs in patients during Radiogardase treatment compared to the half-life of 137Cs after Radiogardase discontinuation (after treatment). Data from additional literature articles including 19 patients contaminated with 137Cs in other incidents and a study of 7 human subjects who voluntarily ingested trace doses of 137Cs showed a similar reduction in whole body effective half-life with Radiogardase treatment.
14.2 Thallium Contamination Thirty-four patients treated with Radiogardase for non-radioactive thallium poisoning have been reported in the literature. Radiogardase treatment reduced the mean serum biologic half-life of thallium from 8 days to 3 days.
How Supplied
Radiogardase is supplied as gelatin capsules containing 0.5 grams of prussian blue insoluble for oral administration. The dark blue capsule is imprinted with the light blue inscription: Heyl imprint imagePB. It is packaged in white plastic containers with a child-resistant tamper-evident closure. Each container contains 36 capsules.
Storage
Store at 20 °C to 25 °C (68 °F to 77 °F), excursions permitted between 15 °C and 30°C (between 59 °F and 86 °F). Brief exposure to temperatures up to 40 °C (104 °F) may be tolerated, provided the mean kinetic temperature does not exceed 25 °C (77 °F); however, minimize such exposure.
Images
Drug Images
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Patient Counseling Information
Decreased Gastrointestinal Motility
Inform patients that Radiogardase can decrease gastrointestinal motility. This can slow the transit time of cesium or thallium bound to Radiogardase and increase the radiation absorbed dose to the gastrointestinal mucosa. Alert patients to monitor for signs and symptoms of constipation and advise patients to seek medical management if symptoms develop.
Precautions to Mitigate Radiation Exposure
Inform patients of safety measures to be taken to minimize radiation exposure to others or re-exposure to self. This includes instruction on appropriate use of the toilet, hand washing, and handling of items such as clothing that might get contaminated with body fluids.
Discoloration of Stool, Oral Mucosa and Dentition
Inform patients taking Radiogardase that their stools might be blue-colored. Also inform patients that if the Radiogardase capsules are opened and the contents are mixed with food and eaten, the mouth and teeth may be colored blue.
Precautions with Alcohol
Alcohol-Prussian blue interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
Brand Names
RADIOGARDASE
Look-Alike Drug Names
There is limited information regarding Prussian blue Look-Alike Drug Names in the drug label.
Drug Shortage Status
Price
References
The contents of this FDA label are provided by the National Library of Medicine.