[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