Radiogardase

To make sure Prussian blue is safe for you, tell your doctor if you have:

• a digestive disorder;

• chronic constipation;

• a blockage in your stomach or intestines;

• a heart rhythm disorder; or

• an electrolyte imbalance (such as low levels of potassium in your blood).

FDA pregnancy category C. It is not known whether Prussian blue will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medicine.

It is not known whether Prussian blue passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine.

Exposure to radiation could cause a man to have low sperm counts up to several years later. Talk with your doctor if you have concerns about how radiation may affect your fertility.

A crystal lattice of ferric hexacyanoferrate (II); an ion-exchange medium with high affinity for cesium and thallium, including radioactive isotopes of these metals.1 3

• Importance of taking prussian blue with food; importance of taking appropriate measures (i.e., oral fiber-based laxatives and/or a high-fiber diet) to promote regular fecal elimination.1

• Importance of instructing patients on safety measures that should be used to minimize radiation exposure to others, including appropriate disposal of urine and feces.1 Clothing contaminated with blood or urine should be washed separately.1

• Advise patients of possible bluish appearance of their stools.1

• Advise patients who are unable to swallow capsules that their mouth and teeth might be colored blue if prussian blue capsules are opened and the contents mixed with food or liquid.1

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.1

• Importance of informing patients of other important precautionary information.1 (See Cautions.)

• Tell all of your health care providers that you take Radiogardase. This includes your doctors, nurses, pharmacists, and dentists.
• Have blood work checked as you have been told by the doctor. Talk with the doctor.
• Urine and stools may need to be checked. Talk with the doctor.
• If you have hard stools (constipation), talk with your doctor. There may be ways to lower this side effect.
• Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using this medicine while you are pregnant.

To avoid exposing or re-exposing others:

• Use the toilet instead of a urinal.
• Flush the toilet a few times after using.
• Clean up any spilled urine, feces, or blood right away. Avoid touching.
• Wash your hands after using the toilet.
• Wash exposed clothing, bedding, and bath towels alone.
• Avoid children's urine or feces.

Use Radiogardase as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• Take this medicine with food.
• Capsules may be opened and contents mixed with food or liquid.

What do I do if I miss a dose?

• Take a missed dose as soon as you think about it.
• If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
• Do not take 2 doses at the same time or extra doses.

2.1 Important Administration Instructions

• Obtain quantitative baseline of the internalized contamination by radioactive cesium (137Cs) and/or thallium by appropriate whole-body counting and/or by bioassay (e.g., biodosimetry), or feces/urine samples, whenever possible prior to Radiogardase treatment.
• Initiate treatment with Radiogardase as soon as possible after contamination is suspected. Even when delayed, treatment with Radiogardase is effective and should not be withheld.
• Take Radiogardase capsules with food to stimulate excretion of cesium or thallium.
• In patients who cannot tolerate swallowing large numbers of capsules, open the capsules and mix with bland food or liquids.

Decontamination Procedures for Radioactive Cesium or Thallium Contamination

Prior to initiating treatment with Radiogardase, follow radioactive decontamination safety procedures including:

• Use appropriate radiation protective attire and closely monitor personnel and treatment area for radiation levels using radiation detection, indication, and computation devices (RADIAC) or thermal luminescent devices (TLD).
• Control spread of radiation contamination through the establishment of a patient decontamination area and a contaminated material disposal site (with proper labeling, handling, and disposal of contaminated material).

Recommended Dosage

• Adults and Adolescents: 3 grams (6 capsules) taken orally three times a day (a total daily dose of 9 grams)
• Pediatric Patients (2 – 12 years): 1 gram (2 capsules) taken orally three times a day (a total daily dose of 3 grams)

Treatment of Radioactive Cesium Contamination

• Anticipate that treatment with Radiogardase may last 30 days or longer.
• Base duration of Radiogardase treatment on weekly measurements of radioactivity in urine and fecal samples to monitor cesium elimination rate.
• Obtain weekly laboratory evaluations (complete blood count, serum chemistry and electrolytes).

Treatment of Radioactive and Non-radioactive Thallium Contamination

• Anticipate that treatment with Radiogardase may last 30 days or longer.
• For radioactive thallium:
  • Base duration of Radiogardase treatment on weekly measurements of radioactivity inurine and fecal samples to monitor thallium elimination rate.
  • Continue Radiogardase treatment until a 24-hour urine thallium test is normal (less than 5 micrograms per liter) and radiation level is acceptable.
• For non-radioactive thallium: Continue Radiogardase treatment until a 24-hour urine thallium test is normal (less than 5 micrograms per liter).
• Obtain weekly laboratory evaluations (complete blood count, serum chemistry and electrolytes).
• In cases of severe thallium intoxication, additional types of treatment may be necessary, such as:
  • Induced emesis, followed by gastric intubation and lavage
  • Forced diuresis until urinary thallium excretion is less than 1 mg/24 hours
  • Charcoal hemoperfusion may be useful during the first 48 hours after thallium ingestion (biodistribution phase).
  • Hemodialysis has also been reported to be effective in thallium intoxication.

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 [see Warnings and Precautions (5.2)].

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.

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.

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.

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.

Applies to prussian blue: oral capsule

General

The most common adverse event was constipation.[Ref]

Gastrointestinal

Very common (10% or more): Constipation (24%)
Frequency not reported: Gastrointestinal motility decreased, stools blue color, oral mucosa and dentition colored blue[Ref]

Metabolic

Common (1% to 10%): Hypokalemia[Ref]

Some side effects of Radiogardase may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.