Radiogardase (cellulose, microcrystalline 38 mg gelatin 83.12 mg water 14.21 mg indigotindisulfonate sodium 0.67 mg sodium lauryl sulfate 0.15 mg ferric ferrocyanide 500 mg) Dailymed

10 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.

11 Description

Radiogardase (prussian blue insoluble) is a decorporation agent for oral use. Radiogardase capsules contain insoluble ferric hexacyanoferrate(II), with an empirical formula of Fe ₄[Fe(CN) ₆] ₃ and a molecular weight of 859.3 Daltons. It is supplied as 0.5 gram of blue powder in gelatin capsules with 0 – 38 mg of microcrystalline cellulose. The dark blue capsule is imprinted with the light blue inscription: <sub>PB. The powder may vary from uniformly fine, dark granules to coarse light and dark-colored granules. The structural formula for prussian blue insoluble is shown below.

The crystal structure of prussian blue insoluble is a cubic lattice with the Fe ^II and Fe ^III atoms occupying the corners of the cube and the cyanide groups positioned on the sides.</sub>

12 Clinical Pharmacology

12.1 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.

12.2 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.

12.3 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.

13 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.

Table 1: Dose Response Relationship in Rats at 96 Hours
Prussian blue insoluble dose (mg/day)	% Injected 137Cs dose remaining (Range)
Untreated	58.1 (63.3 – 53.4)
1	9.42 (13.2 – 6.72)
10	1.17 (1.64 – 0.84)
50	0.57 (0.80 – 0.41)
100	0.52 (0.73 – 0.37)

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.

14 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).

Table 2: Cesium-137 Effective Half-life During and After Treatment with Radiogardase
Group	Age (years)	Radiogardase Dosage	137Cs Effective Half Life
			During Radiogardase Treatment	After Radiogardase Treatment
Adults (n=5)	> 18	10 grams/day	26 ± 6 days	80 ± 15 days (all 21 adult patients)
Adults (n=10)		6 grams/day	25 ± 15 days
Adults (n=6)		3 grams/day	25 ± 9 days
Adolescents (n=5)	12 -14	< 10 grams/day	30 ± 12 days	62 ± 14 days
Children (n=7)	4 – 9	< 3 grams/day	24 ± 3 days	42 ± 4 days

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.

16 How Supplied/storage And Handling

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: PB. It is packaged in white plastic containers with a child-resistant tamper-evident closure. Each container contains 36 capsules.

• NDC: 58060-002-02

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. [see USP Controlled Room Temperature]

17 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 lis 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.

Manufactured by: Haupt Pharma Wülfing GmbH

Distribution by: HEYL Chemisch-pharmazeutische Fabrik GmbH & Co. KG, Berlin

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