Radiogardase (oral)

Overdose

The clinical effects of overdosing with Prussian blue insoluble are not known. Based on reported adverse events and mechanism of action, possible overdose symptoms may include obstipation, obstruction, or severe decrease in electrolytes.

Contraindications

None

Undesirable effects

Deaths or serious or severe adverse events attributed to Prussian blue insoluble have not been reported. Constipation was reported in 10/42 (24%) patients in the Goiânia accident treated with Prussian blue insoluble. Severity of constipation was mild in 7 patients and moderate in 3 patients. Constipation was successfully treated with a high fiber diet.

Undefined gastric distress was reported in 3 patients treated with 20 gram/day of Prussian blue insoluble. In these patients the dose was reduced to 10 gram/day for continued treatment.

Therapeutic indications

Prussian blue insoluble 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.

Name of the medicinal product

Qualitative and quantitative composition

Radiogardase® (insoluble prussian blue) is supplied as 0.5 gram blue powder in gelatin capsules for oral administration. The dark blue capsules are imprinted with the light blue inscription: PB. It is packaged in white plastic containers (HDPE) with a child-proof closure and tamper-evident seal. The containers contain 36 capsules each.

Open the container as shown on the picture:

Step 1: Press firmly on the closure.

Step 2: Twist the closure while pressing.

Step 3: Remove seal from plastic container before first use.

The product is manufactured by Haupt Pharma Berlin GmbH for distribution by HEYL Chemisch-pharmazeutische Fabrik GmbH & Co. KG, Berlin.

NDC 58060-002-02

Store in the dark at 25°C (77°F), excursions permitted to 15-30°C (59-86°F).

To develop long-term response data, detailed information on patient treatment should be provided to the manufacturer whenever this drug is administered. These data should include a record of the radioactive body burden and bioassay results at defined time intervals, a description of measurement methods to facilitate analysis of data, and adverse events (see attached patient data form). In cases where exposure is limited in terms of number of patients, it may be possible to collect more detailed patient information. Please see the following website, www.heyltex.com for additional suggested data collection.

Questions regarding patient treatment data collection and the use of Prussian blue insoluble for the treatment of patients exposed to radioactive cesium and/or radioactive or nonradioactive thallium may be submitted to Dr. Johann Ruprecht, Email: [email protected] Fax +49 30 8174049. HEYL Chem.-pharm. Fabrik GmbH & Co. KG. Rev. 03/2008. FDA revision date: 8/25/2008

Special warnings and precautions for use

Prussian blue insoluble is administered to decrease radiation exposure. It does not treat the complications of radiation exposure. Patients contaminated with high doses of 137Cs may develop radiation toxicity including bone marrow suppression with severe neutropenia and thrombocytopenia. Supportive treatment for radiation toxicity symptoms should be given concomitantly with Prussian blue insoluble treatment.

In radiological emergencies, the type of elemental exposure may not be known. Prussian blue insoluble may not bind to all radioactive elements and some radioactive elements may not undergo enterohepatic circulation, which is needed for Prussian blue insoluble binding and elimination. Patients contaminated with unknown or multiple radioactive elements may require treatment with other agents in addition to Prussian blue insoluble.

Prussian blue insoluble can cause constipation. Decreased gastrointestinal motility will slow the transit time of 137Cs bound to Prussian blue insoluble in the gastrointestinal tract, and may increase the radiation absorbed dose to the gastrointestinal mucosa. Constipation occurring during Prussian blue insoluble treatment may be treated with a fiber based laxative and/or a high fiber diet. Prussian blue insoluble should be used with caution in patients with disorders associated with decreased gastrointestinal motility.

Prussian blue insoluble may bind electrolytes found in the gastrointestinal tract. Asymptomatic hypokalemia, with serum potassium values of 2.5 – 2.9 (normal 3.5 – 5.0), was reported in 3/42 (7%) of patients on treatment with Prussian blue insoluble. Serum electrolytes should be closely monitored during Prussian blue insoluble treatment. Caution should be exercised when treating patients with pre-existing cardiac arrhythmias or electrolyte imbalances.

Prussian blue insoluble may bind some orally administered therapeutic drugs. As appropriate, blood levels or clinical response to oral medications should be monitored.

Studies with Prussian blue insoluble to evaluate carcinogenesis, mutagenesis and impairment of fertility have not been performed.

All males who received a whole body radiation absorbed dose greater than 1 Gy of 137Cs, 2 –8 years later had either oligospermia or azospermia.

Comprehensive animal reproductive studies have not been conducted with Prussian blue insoluble. Since Prussian blue insoluble is not absorbed from the gastrointestinal tract, effects on the fetus are not expected. In one patient that became pregnant 3 years and 8 months after being treated with Prussian blue insoluble for internal contamination with 137Cs (8 mCi), complications or birth defects were not identified in the literature report.

Cesium-137 is known to cross the human placenta. One patient, in Goiânia, was contaminated with 0.005 mCi 137Cs during her 4th month of pregnancy. She was not treated with Prussian blue insoluble. At birth the concentration of 137Cs was the same in the mother and the infant. Thallium crosses the human placenta. Reported fetal effects in the reviewed literature include fetal death, failure to thrive, alopecia, or in some instances outwardly normal development. The risk of toxicity from untreated radioactive cesium or thallium exposure is expected to be greater than the reproductive toxicity risk of Prussian blue insoluble.

Studies to determine if Prussian blue insoluble is excreted in human milk have not been conducted. Since Prussian blue insoluble is not absorbed from the gastrointestinal tract, its excretion in milk is highly unlikely. However, cesium and thallium are transmitted from mother to infant in breast milk. Women internally contaminated with cesium or thallium should not breast feed.

The safety and efficacy of Prussian blue insoluble and its dosing for the pediatric population was extrapolated from adult data and supported by pediatric patients who were internally contaminated with 137Cs and treated with Prussian blue insoluble in the Goiânia accident.

Overall, 27 pediatric patients received Prussian blue insoluble in the range of 3 – 10 grams per day in divided doses. Prussian blue insoluble treatment reduced the whole body effective halflife 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 TID and in pediatric patients treated with 1 gram TID. (See CLINICAL PHARMACOLOGY, Clinical Trials, Table 2.) By body weight, the dose ranged from 0.32 gram/kg in the 12-year old patient (10 gram Prussian blue daily dose, 31 kg weight) to 0.21 gram/kg in the 4 year old patient (3 gram Prussian blue daily dose, 14 kg weight).

Pediatric patients aged 2 up to 4 years are expected to have biliary and gastrointestinal function that is comparable to a 4-year old.

There are variations in the developmental maturity of the biliary system and gastrointestinal tract of neonates and infants (0 – 2 years). The dose-related adverse effects of Prussian blue insoluble on an immature gastrointestinal tract are not known. Dosing in infants and neonates has not been established.

Dosage (Posology) and method of administration

The recommended dose of Prussian blue insoluble is 3 grams orally three times a day.

The recommended dose of Prussian blue insoluble is 1 gram orally three times a day.

In patients who cannot tolerate swallowing large numbers of capsules, the capsules may be opened and mixed with bland food or liquids. This may result in blue discoloration of the mouth and teeth.

Prussian blue insoluble capsules may be taken with food to stimulate excretion of cesium or thallium.

Treatment with Prussian blue insoluble should be initiated as soon as possible after contamination is suspected. Contamination should be verified as soon as possible. However, even when treatment cannot be started right away, patients should be given Prussian blue insoluble as soon as it becomes available. Treatment with Prussian blue insoluble is still effective even after time has elapsed since exposure.

Treatment should continue for a minimum of 30 days and then the patient should be reassessed for the amount of residual whole body radioactivity. The duration of treatment after exposure is dictated by the level of contamination and the judgment of the attending physician. Before, during and after therapy, pertinent measurements for radioactivity should be made to help determine when to terminate treatment.

During treatment, the following information should be collected:

• the radioactivity counts in urine and fecal samples should be measured and recorded weekly to monitor 137 Cs elimination rate, and
• the occurrence of any adverse events from Prussian blue insoluble (i.e., constipation, which can be treated by increasing the amount of fiber in the diet).

When the internal radioactivity is substantially decreased, the Prussian blue insoluble dose may be decreased to 1 or 2 grams TID to improve gastrointestinal tolerance.

Treatment with Prussian blue insoluble should be initiated as soon as possible after contamination is suspected. Contamination should be verified as soon as possible. However, even when treatment cannot be started right away, treatment with Prussian blue insoluble is effective and should not be withheld.

1. Health professionals should follow appropriate radiation protective attire and procedures at all times. Protect health professionals handling patients from unnecessary radiation exposure and monitor health professionals and the area of operation 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 triage site, patient decontamination area, and a contaminated or “dirty” material dumpsite. Proper labeling, handling, and disposal of contaminated material needs to be established and followed.
2. Manage the patient to minimize further injury and to stabilize before external decontamination.
3. Establish if the patient suffers from a single or combined injury (e.g., radiation, burns, trauma, chemical, biological, etc.) and whether the contaminant may be internalized.
   The route of entry of the radiation contaminant needs to be identified and recorded. The route of entry will determine other treatment methods needed (e.g., wound debridement or stomach lavage if ingested). Patients need to be triaged based on their injuries and the level and type of contamination.
4. A quantitative baseline of the internalized contamination of 137Cs should be obtained by appropriate whole-body counting and/or by bioassay (e.g., Biodosimetry), or feces/urine sample whenever possible to obtain the following type of information to establish an elimination curve:
   • Estimated internalized radiation contamination of 137Cs, and
   • Rate of measured elimination of radiation in the feces.

General therapy guidelines for thallium contamination should follow the radioactive decontamination procedures listed above for 137 Cs, except that there is no need for radiation safety precautions when treating patients contaminated with non-radioactive thallium. For both radioactive and non-radioactive thallium contamination, a quantitative baseline of the internalized thallium contamination should be ascertained by appropriate whole body counting and/or by bioassay whenever possible.

Patients should also have weekly CBC, serum chemistry and electrolytes while under treatment. The response to other orally administered medications should be closely monitored. (See Drug-Drug Interactions.)

In cases of severe thallium intoxication, additional types of elimination 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/24h.
• 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.

In patients who have contamination with multiple or unknown radioactive isotopes, additional decontamination and treatment procedures may be needed.

Interaction with other medicinal products and other forms of interaction

In cases of severe thallium intoxication, additional types of elimination 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/24h.
• 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.

In patients who have contamination with multiple or unknown radioactive isotopes, additional decontamination and treatment procedures may be needed.

Radiogardase® (insoluble prussian blue) is supplied as 0.5 gram blue powder in gelatin capsules for oral administration. The dark blue capsules are imprinted with the light blue inscription: PB. It is packaged in white plastic containers (HDPE) with a child-proof closure and tamper-evident seal. The containers contain 36 capsules each.

Open the container as shown on the picture:

Step 1: Press firmly on the closure.

Step 2: Twist the closure while pressing.

Step 3: Remove seal from plastic container before first use.

The product is manufactured by Haupt Pharma Berlin GmbH for distribution by HEYL Chemisch-pharmazeutische Fabrik GmbH & Co. KG, Berlin.

NDC 58060-002-02

Store in the dark at 25°C (77°F), excursions permitted to 15-30°C (59-86°F).

To develop long-term response data, detailed information on patient treatment should be provided to the manufacturer whenever this drug is administered. These data should include a record of the radioactive body burden and bioassay results at defined time intervals, a description of measurement methods to facilitate analysis of data, and adverse events (see attached patient data form). In cases where exposure is limited in terms of number of patients, it may be possible to collect more detailed patient information. Please see the following website, www.heyltex.com for additional suggested data collection.

Questions regarding patient treatment data collection and the use of Prussian blue insoluble for the treatment of patients exposed to radioactive cesium and/or radioactive or nonradioactive thallium may be submitted to Dr. Johann Ruprecht, Email: [email protected] Fax +49 30 8174049. HEYL Chem.-pharm. Fabrik GmbH & Co. KG. Rev. 03/2008. FDA revision date: 8/25/2008

Deaths or serious or severe adverse events attributed to Prussian blue insoluble have not been reported. Constipation was reported in 10/42 (24%) patients in the Goiânia accident treated with Prussian blue insoluble. Severity of constipation was mild in 7 patients and moderate in 3 patients. Constipation was successfully treated with a high fiber diet.

Undefined gastric distress was reported in 3 patients treated with 20 gram/day of Prussian blue insoluble. In these patients the dose was reduced to 10 gram/day for continued treatment.

Adequate and well-controlled drug-drug interaction studies in humans were not identified in the literature. In preliminary studies, animals were contaminated with several different radioisotopes and treated with several different radioeliminators. Based on these animal data, co-administration of Prussian blue with other radioeliminators does not affect the efficacy of Prussian blue for 137Cs.

Binding to some therapeutic drugs and essential nutrients is possible. The literature contains anecdotal reports of asymptomatic hypokalemia and decreased bioavailability of oral tetracycline. The serum levels and, or clinical response to critical orally administered products should be monitored.