Radiogardase (Page 2 of 3)

8.5 Geriatric 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.

8.6 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.

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: Heyl imprint image 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.

Structural formula for Prussian blue insoluble
(click image for full-size original)

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.

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 ( 137 Cs)
137 Cs 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 137 Cs 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 137 Cs is retained with a biological half-life of about 500 days. 137 Cs 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 137 Cs is excreted through the kidneys and about 20% in the feces.

Thallium-201 ( 201 Tl)
Radioactive thallium ( 201 Tl) 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 137 Cs and treated with Radiogardase showed higher activities of 137 Cs 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 137 Cs 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 137 Cs 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 137 Cs, after prussian blue insoluble was stopped.

Figure 1 : Comparisons of 137Cs whole body activity during and after Radiogardase treatment.
(click image for full-size original)

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 137 Cs, 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 137 Cs 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 137 Cs 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.

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