[Federal Register Volume 68, Number 23 (Tuesday, February 4, 2003)]
[Notices]
[Pages 5645-5648]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 03-2597]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 03D-0023]


Guidance for Industry on Prussian Blue for Treatment of Internal 
Contamination With Thallium or Radioactive Cesium; Availability

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is announcing that we 
have concluded that prussian blue, when produced under conditions 
specified in approved new drug applications (NDAs), can be found to be 
safe and effective for the treatment of internal contamination with 
radioactive thallium, nonradioactive thallium, or radioactive cesium. 
We encourage the submission of NDAs for prussian blue drug products. We 
are also announcing the availability of a guidance for industry 
entitled ``Prussian Blue Drug Products--Submitting a New Drug 
Application.'' This guidance is intended to assist manufacturers who 
plan to submit NDAs for prussian blue.

DATES: Submit written or electronic comments on agency guidances at any 
time.

ADDRESSES: Submit NDAs to the Food and Drug Administration, Center for 
Drug Evaluation and Research, Central Document Room, 12229 Wilkins 
Ave., Rockville, MD 20852. Submit requests for copies of draft labeling 
to the Division of Medical Imaging and Radiopharmaceutical Drug 
Products, (HFD-160), Center for Drug Evaluation and Research, Food and 
Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, 301-827-
7510. Copies of the reports referred to in this document will be on 
display at the Dockets Management Branch (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. 
Submit written requests for single copies of the guidance to the 
Division of Drug Information (HFD-240), Center for Drug Evaluation and 
Research, Food and Drug Administration, 5600 Fishers Lane, Rockville, 
MD 20857. Send one self-addressed adhesive label to assist that office 
in processing your requests. Submit written comments on the guidance to 
the Dockets Management Branch (address provided in third sentence of 
this paragraph). Submit electronic comments to http://www.fda.gov/dockets/ecomments. See

[[Page 5646]]

the SUPPLEMENTARY INFORMATION section for electronic access to the 
guidance document.

FOR FURTHER INFORMATION CONTACT: Kyong Kang, Center for Drug Evaluation 
and Research (HFD-160), Food and Drug Administration, 5600 Fishers 
Lane, Rockville, MD 20857, 301-827-7510.

SUPPLEMENTARY INFORMATION:

I. Background

A. Cesium

    Cesium-137, a radioactive isotope of cesium, was discovered in 1941 
by Glenn T. Seaborg and Margaret Melhase. Cesium-137 is a product of 
fusion and is found in the fallout from the detonation of nuclear 
weapons and the waste from nuclear power plants. Cesium-137 is one of 
the most common radioisotopes used in industry. It is used in various 
measuring devices, such as moisture-density gauges. Cesium-137 is also 
widely used as a source of gamma radiation for treatment of various 
forms of cancer. Cesium-137 has a half-life of 30.07 years.
    Contamination with cesium-137 can cause serious illness or death, 
depending upon the dose, and has been associated with the development 
of cancer long after exposure. In addition to concerns about exposure 
to cesium-137 in industrial and medical environments, cesium-137 
contamination is of particular concern because it has been mentioned as 
a potential component of a radiological dispersal device (RDD), 
commonly called a ``dirty bomb.'' An RDD is a conventional explosive or 
bomb containing radioactive material. The conventional bomb is used as 
a means to spread radioactive material, such as cesium-137. An RDD is 
not a nuclear bomb and does not involve a nuclear explosion.

B. Thallium

    Thallium occurs naturally in several minerals and ores. It was 
discovered independently by both William Crookes and Claude Auguste 
Lamy in the early 1860s. Thallium is very toxic, and thallium sulfate 
has been used as a rat and ant poison in the past. Other thallium 
compounds are used in the manufacture of semiconductors, photocells, 
optical glass, and other items. Thallium-201, a radioactive isotope of 
thallium, is widely used in very small doses as an approved 
radioimaging drug. Thallium-201 has a half-life of 72.912 hours.
    Acute exposure to high dose radioactive or nonradioactive thallium 
is generally characterized by severe gastrointestinal symptoms followed 
by neurological symptoms, which may lead to death. The toxicity 
resulting from chronic exposure to thallium is characterized by various 
neurological symptoms. Thallium-201 has also been mentioned as a 
potential component of a dirty bomb.
    There are no approved treatments for internal contamination with 
thallium or radioactive cesium.

C. Prussian Blue

    Prussian blue was first synthesized in 1704 by a Berlin color maker 
named Diesbach. It has been used as an industrial and artists' pigment 
ever since. The chemical name for prussian blue is ferric 
hexacyanoferrate(II).
    Since the 1960s, prussian blue has been used investigationally as 
an orally ingested drug to enhance the excretion of isotopes of cesium 
and thallium from the body by means of ion exchange. However, there is 
currently no approved NDA for prussian blue. Prussian blue has a very 
high affinity for cesium and thallium. Cesium and thallium ions are 
ordinarily excreted into the intestine, reabsorbed from there into the 
bile, and then excreted again into the gastrointestinal tract. Orally 
administered prussian blue traps thallium or cesium in the intestine, 
interrupts its reabsorption from the gastrointestinal tract, and 
thereby increases fecal excretion of thallium and cesium. Prussian blue 
itself is not absorbed across the intestinal wall in significant 
amounts.
    Prussian blue, in 500-milligram (mg) capsules, has been distributed 
by the Radiation Emergency Assistance Center/Training Site (REAC/TS) 
under investigational new drug application (IND) number 51,700. REAC/TS 
is part of the Oak Ridge Associated Universities (ORAU). ORAU operates 
the Oak Ridge Institute for Science and Education (ORISE) under a 
contract with the Department of Energy. ORISE owns the IND for prussian 
blue. The 500-mg capsules used under the IND are manufactured by HEYL 
Chemisch-pharmazeutische Fabrik GmbH & Co. KG (HEYL). HEYL uses the 
trade name Radiogardase-Cs for its 500-mg capsules of prussian blue.

II. Safety and Effectiveness of Prussian Blue Drug Products

    We have concluded that prussian blue, when produced under 
conditions specified in approved NDAs, can be found to be safe and 
effective for the treatment of internal contamination with radioactive 
thallium, nonradioactive thallium, or radioactive cesium. As described 
in the following paragraphs, our conclusion is based upon our review of 
published information.
    We encourage the submission of NDAs for prussian blue drug 
products. If you are interested in submitting an NDA for this product, 
please contact us. We also recommend that you consult the guidance 
``Prussian Blue Drug Products--Submitting a New Drug Application,'' 
which is being made available with this notice.

A. Basis for Finding of Safety and Effectiveness

    We have reviewed the published literature and have determined that 
500-mg prussian blue capsules, when produced under conditions specified 
in an approved NDA, can be found to be safe and effective for the 
treatment of patients with known or suspected internal contamination 
with radioactive thallium, nonradioactive thallium, or radioactive 
cesium. Prussian blue increases the rate of elimination of thallium or 
radioactive cesium. Administration of prussian blue decreases the risk 
of death and major morbidity after exposure to radioactive thallium, 
nonradioactive thallium, or radioactive cesium.
    In reaching our determination on the effectiveness of prussian 
blue, we evaluated published reports of a 1987 incident in 
Goi[acirc]nia, Brazil, where approximately 250 people were contaminated 
with cesium-137 that had been abandoned after use in a cancer clinic 
(see International Atomic Energy Agency, 1998). Forty-six patients with 
heavy internal contamination were treated with prussian blue. Data on 
the whole-body effective half-life of cesium-137 during treatment and 
after treatment with prussian blue was completed on 33 of the 46 
patients. The untreated mean whole-body effective half-life of cesium-
137 is 80 days in adults, 62 days in adolescents, and 42 days in 
children. Prussian blue reduced the mean whole-body effective half-life 
of cesium-137 by 69 per cent in adults, by 46 per cent in adolescents, 
and by 43 per cent in children (see International Atomic Energy Agency, 
1998). Data from additional literature articles, including a study of 7 
human volunteers contaminated with trace doses of cesium-137 and 
reports on 19 patients contaminated with cesium-137 in other incidents, 
show a similar reduction in whole-body effective half-life after 
administration of prussian blue (see Madhus, 1968 and National Council 
on Radiation Protection and Measurement, 1979).
    We also evaluated reports in the literature that describe 33 
patients who

[[Page 5647]]

were treated with prussian blue for nonradioactive thallium poisoning. 
Prussian blue treatment reduced the mean serum biologic half-life of 
thallium from 8 days to 3 days (see Barbier, 1974; De Groot, 1985; Van 
Kesteren, 1980; and Vrij, 1995).
    The primary adverse effects of prussian blue are constipation and 
nonspecific gastrointestinal distress. These side effects are more 
troublesome at high doses and respond to treatment with orally 
administered fiber (see Farina, 1991). Other rare adverse events are 
discussed in the published literature and in the draft labeling we have 
prepared.

B. Labeling for Prussian Blue

    We have prepared draft labeling for orally administered drug 
products containing 500-mg prussian blue capsules. You can submit this 
draft labeling as part of an application for 500-mg prussian blue 
capsules that relies on our findings of safety and effectiveness. The 
draft labeling reflects our conclusion on the potential safety and 
effectiveness of 500-mg prussian blue drug products for the treatment 
of internal contamination with radioactive thallium, nonradioactive 
thallium, or radioactive cesium. If you wish to change the labeling to 
include a different or broader indication, different dosage, or make 
any other significant changes to the draft labeling, you should 
provide, as part of your application, additional literature or other 
studies to support your requested changes. If you submit an application 
for a prussian blue drug product that is not based on FDA's findings of 
safety and effectiveness of prussian blue, you may not use the draft 
labeling because it is based on our review of the published literature. 
If you submit such an application, your labeling must be based on the 
safety and effectiveness data contained in your NDA.
    The draft labeling for applications based on this finding of safety 
and effectiveness is available on the Internet at http://www.fda.gov/cder/foi/label/2003/ind51700lbl.pdf. You may also contact the Center 
for Drug Evaluation and Research's Division of Medical Imaging and 
Radiopharmaceutical Drug Products for a copy of the draft labeling (see 
ADDRESSES).

III. Conclusions

    We have determined that 500-mg prussian blue capsules can be safe 
and effective for the treatment of patients with known or suspected 
internal contamination with radioactive thallium, nonradioactive 
thallium, or radioactive cesium. We encourage the submission of NDAs 
for prussian blue drug products. The requirement under 21 U.S.C. 
355(b)(1) for full reports of investigations to support these NDAs may 
be met by citing the published literature we relied on in preparing 
this notice. A list of the published literature and reprints of the 
reports will be available for public inspection in the Dockets 
Management Branch (see ADDRESSES). It is unnecessary to submit copies 
and reprints of the reports from the listed published literature. We 
invite applicants to submit any other pertinent studies and literature 
of which they are aware.

IV. Availability of a Guidance

A. Notice of Availability

    In this notice, we are also announcing the availability of a 
guidance for industry entitled, ``Prussian Blue Drug Products--
Submitting a New Drug Application.'' The guidance is intended to assist 
manufacturers who plan to submit NDAs for prussian blue.
    This guidance is being issued as a level 1 guidance consistent with 
FDA's good guidance practices regulation (21 CFR 10.115). It is being 
implemented immediately without prior public comment because the agency 
believes it is in the interest of the public health to communicate this 
information to the public as quickly as possible. However, the agency 
welcomes comments on the guidance and, if comments are submitted, the 
agency will review them and revise the guidance if appropriate. The 
guidance represents the agency's current thinking on issues associated 
with the submission of NDAs for prussian blue. It does not create or 
confer any rights for or on any person and does not operate to bind FDA 
or the public. An alternative approach may be used if such approach 
satisfies the requirements of the applicable statutes and regulations.

B. Comments

    Interested persons may, at any time, submit written or electronic 
comments on the guidance to the Dockets Management Branch (see 
ADDRESSSES). Two copies of any mailed comments are to be submitted 
except that individuals may submit one copy. Comments are to be 
identified with the docket number found in the brackets in the heading 
of this document. The document and received comments are available for 
public examination in the Dockets Management Branch between 9 a.m. and 
4 p.m., Monday through Friday.

C. Electronic Access

    Persons with access to the Internet may obtain the guidance at 
either http://www.fda.gov/cder/guidance/index.htm or http://www.fda.gov/ohrms/dockets/default.htm.

V. Published Literature on the Safety and Effectiveness of Prussion 
Blue

    The published literature we have relied on in making the 
determinations regarding prussian blue contained in this notice is 
listed in this section of this document. Copies of the published 
literature will be on display in the Dockets Management Branch (see 
ADDRESSES) and can be seen by interested persons between 9 a.m. and 4 
p.m., Monday through Friday.
    1. Atsmon, J. et al., ``Thallium Poisoning in Israel,'' American 
Journal of the Medical Sciences, 320:327-330, 2000.
    2. Barbier, F., ``Treatment of Thallium Poisoning,'' Lancet, 
7886(II):965, 1974.
    3. British Industrial Biological Research Association, ``Short-
Term Feeding Study of Sodium Ferrocyanide in Rats,'' Food and 
Cosmetics Toxicology, 7:409-410, 1969.
    4. Brandao-Mello, C. E. et al., ``Clinical Hematological Aspects 
of \137\Cs: The Goiania Radiation Accident,'' Health Physics, 60:31-
39, 1991.
    5. Buser, H. J. et al., ``The Crystal Structure of Prussian 
Blue: Fe4[Fe(CN)6]3[sbull]xH2o,'' Inorganic Chemistry, 16:2704-2709, 
1977.
    6. Dresow, B. et al., ``In Vivo Binding of Radiocesium by Two 
Forms of Prussian Blue and by Ammonium Iron Hexacyanoferrate (II),'' 
Clinical Toxicology, 31:563-569, 1993.
    7. De Groot, G. et al., ``An Evaluation of the Efficacy of 
Charcoal Haemoperfusion in the Treatment of Three Cases of Acute 
Thallium Poisoning,'' Archives of Toxicology, 57:61-66, 1985.
    8. De Groot, G., and A. N. P. Van Heijst, ``Toxicokinetic 
Aspects of Thallium Poisoning. Methods of Treatment by Toxin 
Elimination,'' The Science of the Total Environment, 71:411-418, 
1988.
    9. Farina, R., C. E. Brandao-Mello, and A. R. Oliveira, 
``Medical Aspects of 137Cs Decorporation: The Goiania Radiological 
Accident,'' Health Physics, 60:63-66, 1991.
    10. Giambarresi, L., ``Radioprotectants,'' in Military 
Radiobiology, Orlando, Academic Press, 1987.
    11. Heydlauf, H., ``Ferric-Cyanoferrate (II): An Effective 
Antidote in Thallium Poisoning,'' European Journal of Pharmacology, 
6:340-344, 1969.
    12. Hoffman, R. et al., ``Comparative Efficacy of Thallium 
Absorption by Activated Charcoal, Prussian Blue, and Sodium 
Polystyrene,'' Journal of Toxicology-Clinical Toxicology, 37:833-
837, 1999.
    13. Hoffman, R., ``The Toxic Emergency,'' Emergency Medicine, 
June:127-128, 1994.
    14. International Atomic Energy Agency, The Radiological 
Accident in Goiania, Vienna, IAEA, 1988.
    15. International Atomic Energy Agency, Dosimetric and Medical 
Aspects of the Radiological Accident in Goiania in 1987, Vienna, 
IAEA-TECDOC-1009, 1998.

[[Page 5648]]

    16. Ioannides, K. G., A. A. Mantzios, and C. P. Pappas, 
``Influence of Prussian Blue in Reducing Transfer of Radiocesium 
Into Ovine Milk,'' Health Physics, 60:261-264, 1991.
    17. Kargacin, B., and K. Kostial, ``Reduction of 85Sr, \137\Cs, 
\131\I and \141\Ce Retention in Rats by Simultaneous Oral 
Administration of Calcium Alginate, Ferrihexacyanoferrate(II) Ki and 
Zn-Dtpa,'' Health Physics, 5:859-864, 1985.
    18. Kargacin, B. et al., ``The Influence of a Composite 
Treatment for Internal Contamination by Several Radionuclides on 
Certain Health Parameters in Rats,'' Arhiv za Higijenu Rada i 
Toksikologiju, 36:165-172, 1985.
    19. Kostial, K. et al., ``Simultaneous Reduction of Radioactive 
Strontium, Caesium, and Iodine Retention by Single Treatment in 
Rats,'' The Science of the Total Environment, 22:1-10, 1981.
    20. Kostial, K. et al., ``A Method for Simultaneous Decrease of 
Strontium, Caesium, and Iodine Retention After Oral Exposure in 
Rats,'' International Journal of Radiation Biology, 37:347-350, 
1980.
    21. Kostial, K., B. Kargacin, and I. Simonovic, ``Efficacy of a 
Composite Treatment for Mixed Fission Products in Rats,'' Journal of 
Applied Toxicology, 3:291-296, 1983.
    22. Kravzov, J. et al., ``Relationship Between Physiological 
Properties of Prussian Blue and Its Efficacy as Antidote Against 
Thallium Poisoning,'' Journal of Applied Toxicology, 13:213-216, 
1993.
    23. Lehmann, P. A., and L. Favari, ``Acute Thallium 
Intoxication: Kinetic Study of the Relative Efficacy of Several 
Antidotal Treatments in Rats,'' Archives of Toxicology, 57:56-60, 
1985.
    24. Lipsztein, J. L. et al., ``Studies of Cs Retention in the 
Human Body Related to Body Parameters and Prussian Blue 
Administration,'' Health Physics, 60:57-61, 1991.
    25. Lipsztein, J. L. et al., ``Application of In-Vitro Bioassay 
for \137\Cs During the Emergency Phase of the Goiania Accident,'' 
Health Physics, 60:43-49, 1991.
    26. Madhus, K., and A. Stromme, ``Increased Excretion of Cs-137 
in Humans by Prussian Blue,'' Zeitschrift fur Naturforschung. Teil 
B: Chemie, Biochemie, Biophysik, Biologie, 23b:391-393, 1968.
    27. Melo, D. R. et al., ``\137\Cs Internal Contamination 
Involving a Brazilian Accident, and the Efficacy of Prussian Blue 
Treatment,'' Health Physics, 66:245-252, 1994.
    28. Moore, D., I. House, and A. Dixon, ``Thallium Poisoning. 
Diagnosis May Be Elusive But Alopecia Is the Clue,'' British Medical 
Journal, 306:1527-1529, 1993.
    29. Moore, Jr. W., and C. L. Comar, ``Absorption of Caesium 137 
From the Gastro-Intestinal Tract of the Rat,'' International Journal 
of Radiation Biology, 5:247-254, 1962.
    30. National Council on Radiation Protection and Measurement, 
Management of Persons Accidentally Contaminated With Radionuclides: 
Recommendations of the National Council on Radiation Protection and 
Measurement, Washington, DC, NCRPM, 1979, pp. 77-79.
    31. Nielson, P. et al., ``Intestinal Absorption of Iron from 
59Fe-Labelled Hexacyanoferrates (II) in Piglets,'' Arzneimittel 
Forschung (Aulendorf), 38:1469-1471, 1988.
    32. Nigrovic, V., ``Enhancement of the Excretion of Radiocaesium 
in Rats by Ferric Cyanoferrate (II),'' International Journal of 
Radiation Biology, 7:307-309, 1963.
    33. Nigrovic, V., ``Retention of Radiocaesium by the Rat as 
Influenced by Prussian Blue and Other Compounds,'' Physics in 
Medicine and Biology, 10:81-91, 1965.
    34. Pau, P. W. I., ``Management of Thallium Poisoning,'' Hong 
Kong Medical Journal, 6:316-318, 2000.
    35. Pearce, J., ``Studies of Any Toxicological Effects of 
Prussian Blue Compounds in Mammals-A Review,'' Food and Chemical 
Toxicology, 32:577-582, 1994.
    36. ``Prussian Blue,'' in the Extra Pharmacopeia, ed. J. E. F. 
Reynolds, 28th ed., London, Pharmaceutical Press, 1982, p. 1749.
    37. Richmond, C. R., ``Accelerating the Turnover of Internally 
Deposited Radiocesium,'' Symposium on Diagnosis and Treatment of 
Deposited Radionuclides; proceedings, pp. 315-327, 1968.
    38. Richmond, C. R., and D. E. Bunde, ``Enhancement of Cesium-
137 Excretion by Rats Maintained Chronically on Ferric 
Ferrocyanide,'' Proceedings of the Society for Experimental Biology 
and Medicine, 121:664-670, 1966.
    39. Rosoff, B., S. H. Cohn, and H. Spencer, ``Cesium-137 
Metabolism in Man,'' Radiation Research, 19:643-654, 1963.
    40. Rundo, J., and F. M. Turner, ``On the Biological Half-Life 
of Caesium in Pregnant Women and in Infants,'' Radiation Protection 
Dosimetry, 41:211-216, 1992.
    41. Stromme, A., ``Increased Excretion of 137Cs in Humans by 
Prussian Blue,'' Symposium on Diagnosis and Treatment of Deposited 
Radionuclides; proceedings, pp. 329-332, 1968.
    42. Van Kesteren, R. G. et al., ``Thallium Intoxication. An 
Evaluation of Therapy,'' Intensivmedizin, 17:293-297, 1980.
    43. Verzijl, J. M. et al., ``Hemodialysis as a Potential Method 
for the Decontamination of Persons Exposed to Radiocesium,'' Health 
Physics, 69:543-548, 1995.
    44. Verzijl, J. M. et al., ``The Influence of Extracorporeal 
Clearance Techniques on Elimination of Radiocesium After Internal 
Contamination,'' Health Physics, 69:521-529, 1995.
    45. Vrij, A., H. M. Cremers, and F. A. Lustermans, ``Successful 
Recovery of a Patient With Thallium Poisoning,'' Netherlands Journal 
of Medicine, 47:121-126, 1995.
    46. World Health Organization, Health Consequences of the 
Chernobyl Accident: Results of the IPHECA Pilot Projects and Related 
National Programmes: Summary Report, Geneva, WHO, 1995.

    Dated: January 28, 2003.
Margaret M. Dotzel,
Assistant Commissioner for Policy.
[FR Doc. 03-2597 Filed 1-31-03; 8:45 am]
BILLING CODE 4160-01-S