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[Federal Register: November 2, 2001 (Volume 66, Number 213)]
[Notices]
[Page 55679-55682]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr02no01-85]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. 01N-0494]
Prescription Drug Products; Doxycycline and Penicillin G Procaine
Administration for Inhalational Anthrax (Post-Exposure)
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
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SUMMARY: The Food and Drug Administration (FDA) is clarifying that the
currently approved indications for doxycycline and penicillin G
procaine drug products include use in cases of inhalational exposure to
Bacillus anthracis (the bacterium that causes anthrax). We also are
providing dosing regimens that we have determined are appropriate for
these products for this use. We encourage the submission of
supplemental new drug applications (labeling supplements) to add the
dosage information to the labeling of currently marketed drug products.
ADDRESSES: Submit labeling supplements to the Center for Drug
Evaluation and Research, Food and Drug Administration, Central Document
Room, 12229 Wilkins Ave., Rockville, MD 20852.
FOR FURTHER INFORMATION CONTACT: Dianne Murphy, Center for Drug
Evaluation and Research (HFD-950),
[[Page 55680]]
Food and DrugAdministration, 5600 Fishers Lane, Rockville, MD 20857,
301-827-2350.
SUPPLEMENTARY INFORMATION:
I. Anthrax
Anthrax is caused by the spore-forming bacterium Bacillus
anthracis. There are three types of anthrax infection in humans:
Cutaneous, gastrointestinal, and inhalational.
Until recently, most human experience with anthrax was associated
with exposure to infected animals or animal products. Anthrax is
reported annually among livestock. In areas where these animal cases
occur, most human cases are the cutaneous form. Such cases occur among
workers who have handled infected hoofed animals or products from these
animals. Gastrointestinal anthrax has been reported following the
ingestion of undercooked or raw meat from infected animals.
Inhalational anthrax, resulting from inhalation of aerosolized spores,
was associated with industrial processing of infected wool, hair, or
hides in the United States in the past. Before October 2001, no case of
inhalational anthrax had been reported in the United States since 1978.
In 1979, at least 64 people died in Sverdlovsk (currently
Ekaterinburg), Russia, of inhalational anthrax after Bacillus anthracis
spores were accidentally released from a Soviet military laboratory.
Administration of certain anti-microbial agents may prevent or
reduce the incidence of disease following inhalational exposure to
Bacillus anthracis.
II. Approved Drug Products
Drug products containing doxycycline, doxycycline calcium,
doxycycline hyclate,\1\ and penicillin G procaine are currently
approved with indications foranthrax.\2\ The approved labeling for the
doxycycline products states that the drugs are indicated in infections
caused by Bacillus anthracis. The approved labeling for penicillin G
procaine drug products states that the drugs are indicated for anthrax.
Presently, the labeling for these drug products does not specify a
dosing regimen for inhalational exposure to Bacillus anthracis. The
indication sections of approved labeling for these drug products does
not specify cutaneous, gastrointestinal, or inhalational anthrax. We
have determined that the language in the labeling of drug products
containing doxycycline, doxycycline calcium, doxycycline hyclate, and
penicillin G procaine is intended to, and does, cover all forms of
anthrax, including inhalational anthrax (post-exposure): To reduce the
incidence or progression of disease following exposure to aerosolized
Bacillus anthracis.
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\1\ Doxycycline hyclate tablets, equivalent to 20 milligrams
(mg) base, and doxycycline hyclate 10 percent for controlled release
in subgingival application are not subjects of this notice because
they have periodontal indications and do not have indications for
anthrax or infections caused by Bacillus anthracis.
\2\ Other drug products are currently approved with indications
for anthrax or infections caused by Bacillus anthracis, i.e.,
minocycline, tetracycline, oxytetracycline, demeclocycline, and
penicillin G potassium. We have not completed a review on these
other drugs. We will not discuss these other drugs further in this
notice.
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On August 30, 2000, we approved supplements to provide an
indication for inhalational anthrax (post-exposure) for ciprofloxacin
hydrochloride tablets and ciprofloxacin intravenous (IV) solution, IV
in 5 percent dextrose, IV in 0.9 percent saline, and oral suspension.
The approved labeling for these ciprofloxacin products provides for a
60-day dosing regimen. Because ciprofloxacin drug products are already
specifically indicated for inhalational anthrax (post-exposure) and
their approved labeling provides a regimen for inhalational anthrax
(post-exposure), we do not discuss ciprofloxacin any further in this
notice. It is relevant, however, that the rhesus monkey study
supporting the approval of ciprofloxacin for inhalational anthrax also
included separate doxycycline and penicillin G procaine treatment arms.
Each of these arms showed a survival advantage over placebo.\3\ No
other antimicrobial drugs were tested in this study.
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\3\ Friedlander, A. M. et al., ``Postexposure Prophylaxis
Against Experimental Inhalation Anthrax,'' Journal of Infectious
Diseases, 167:1239-1243, 1993.
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III. Doxycycline Drug Products
We have determined that 100 mg of doxycycline, taken orally twice
daily for 60 days, is an appropriate dosing regimen for administration
to adults who have inhalational exposure toBacillus anthracis. The
corresponding oral dosing regimen for children under 100 pounds (lb) is
1 mg per (/) lb of body weight (2.2 mg/kilogram (kg)), given twice
daily for 60 days.
We have determined that IV doxycycline can be administered to
adults in a 100 mg dose twice daily for inhalational anthrax (post-
exposure). The corresponding IV dosing regimen for children under 100
lb is 1 mg /lb of body weight (2.2 mg/kg), twice daily. Intravenous
therapy is indicated only when oral therapy is not indicated.
Intravenous therapy should not be given over a prolonged period of
time. Patients should be switched to oral doxycycline, or another
antimicrobial drug product, as soon as possible, to complete a 60-day
course of therapy.
A. Safety
Doxycycline drug products have been used for over 30 years, and the
literature on the products is voluminous. We have reviewed the
literature dealing with the long-term administration of doxycycline for
treatment of diseases other than anthrax. Several articles report the
results of studies involving the administration of doxycycline in
amounts comparable to the doses recommended in this notice. They also
involve administration of doxycycline for 60 days and periods
approaching and exceeding 60 days. We have also reviewed data from our
Adverse Event Reporting System (AERS). Analysis of these articles and
data indicates no pattern of unlabeled adverse events has been
associated with the long-term use of doxycycline.
Doxycycline and other members of the tetracycline class of
antibiotics are not generally indicated for the treatment of any
patients under the age of 8 years. Tetracyclines are known to be
associated with teeth discoloration and enamel hypoplasia in children
and delays in bone development in premature infants after prolonged
use. We have balanced the nature of the effect on teeth and the fact
that this delay in bone development is apparently reversible against
the lethality of inhalational anthrax, and concluded that doxycycline
drug products can be labeled with a pediatric dosing regimen for
inhalational anthrax (post-exposure).
We are not recommending that IV doxycycline be administered for
prolonged periods because of the possibility of thrombophlebitis and
other complications of IV therapy. Thrombophlebitis as a possible
adverse reaction is already described in the approved labeling for IV
doxycycline drug products. Patients administered IV doxycycline for
inhalational anthrax (post-exposure) should be switched to oral
doxycycline or another antimicrobial drug product as soon as possible
to complete a 60-day course of therapy.
B. Effectiveness
We have reviewed minimal inhibitory concentration (MIC) data for
the tetracycline class and Bacillus anthracis, pharmacokinetic data,
data from the Sverdlovsk incident, and the outcome data from a study of
[[Page 55681]]
inhalational exposure to Bacillus anthracis in rhesus monkeys.\4\ We
have concluded that 100 mg of doxycycline, administered twice a day for
60 days, is an effective dosing regimen for adults who have
inhalational exposure to Bacillus anthracis. The corresponding dosing
regimen for children under 100 lb of 1mg/lb of body weight (2.2 mg/kg),
given twice daily for 60 days, is also effective.
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\4\ Friedlander.
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C. Labeling for Oral Doxycyline
We encourage the submission of labeling supplements for orally
administered doxycycline, doxycycline calcium, and doxycycline hyclate
drug products. The revised labeling should contain a specific
indication for inhalational anthrax (post-exposure), the recommended
dosing regimen, safety information relevant to use in children, and
other information described below. The following specific changes to
the current approved labeling are recommended:
Indications and Usage. The indication for anthrax should
be revised from ``Anthrax due to Bacillus anthracis'' to ``Anthrax due
to Bacillus anthracis, including inhalational anthrax (post-exposure):
to reduce the incidence or progression of disease following exposure to
aerosolized Bacillus anthracis.'' This indication should be removed
from the paragraph of the ``Indications and Usage'' section that begins
``When penicillin is contraindicated, doxycycline is an alternative
drug in the treatment of the following infections:'' and inserted at
the end of the preceding paragraph that begins ``Doxycycline is
indicated for the treatment of infections caused by the following gram-
positive microorganisms when bacteriologic testing indicates
appropriate susceptibility to the drug:.''
Warnings. The last sentence in the first paragraph of the
``Warnings'' section should be revised to read as follows:
``TETRACYCLINE DRUGS, THEREFORE, SHOULD NOT BE USED IN THIS AGE GROUP,
EXCEPT FOR ANTHRAX, INCLUDING INHALATIONAL ANTHRAX (POST-EXPOSURE),
UNLESS OTHER DRUGS ARE NOT LIKELY TO BE EFFECTIVE OR ARE
CONTRAINDICATED.''
Dosage and Administration. The following text should be
inserted as the last item of the ``Dosage and Administration'' section:
``Inhalational anthrax (post-exposure):
ADULTS: 100 mg of doxycycline, by mouth, twice a day for 60
days.
CHILDREN: weighing less than 100 lb (45 kg); 1 mg/lb (2.2 mg/kg)
of body weight, by mouth, twice a day for 60 days. Children weighing
100 lb or more should receive the adult dose.''
D. Labeling for IV Doxycycline
We encourage the submission of labeling supplements for doxycycline
hyclate injectable drug products. The revised labeling should contain a
specific indication for inhalational anthrax (post-exposure), the
recommended dosing regimen, safety information relevant to use in
children and prolonged use, and other information described below. We
recommend that labeling supplements for doxycycline hyclate injectable
drug products include the following specific changes:
Indications. The indication for anthrax should be revised
from``Bacillus anthracis'' to ``Anthrax due to Bacillus anthracis,
including inhalational anthrax (post-exposure): to reduce the incidence
or progression of disease following exposure to aerosolized Bacillus
anthracis.'' This indication should be removed from the paragraph of
the ``Indications'' section that begins ``When penicillin is
contraindicated, doxycycline is an alternative drug in the treatment of
infections due to:'' and inserted at the end of the preceding paragraph
that begins ``Doxycycline is indicated for the treatment of infections
caused by the following gram-positive microorganisms when bacteriologic
testing indicates appropriate susceptibility to the drug:.''
Warnings. The last sentence in the first paragraph of the
``Warnings'' section should be revised to read as follows:
``TETRACYCLINE DRUGS, THEREFORE, SHOULD NOT BE USED IN THIS AGE GROUP,
EXCEPT FOR ANTHRAX, INCLUDING INHALATIONAL ANTHRAX (POST-EXPOSURE),
UNLESS OTHER DRUGS ARE NOT LIKELY TO BE EFFECTIVE OR ARE
CONTRAINDICATED.''
Dosage and Administration. The following paragraph should
be inserted in the ``Dosage and Administration'' section after the
paragraph describing the treatment for syphilis:
``In the treatment of inhalational anthrax (post-exposure) the
recommended dose is 100 mg of doxycycline, twice a day. Parenteral
therapy is only indicated when oral therapy is not indicated and
should not be continued over a prolonged period of time. Oral
therapy should be instituted as soon as possible. Therapy must
continue for a total of 60 days.''
The following paragraph should be inserted in the ``Dosage and
Administration'' section after the paragraph describing the dosages for
children above 8 years of age:
``In the treatment of inhalational anthrax (post-exposure) the
recommended dose is 1 mg/lb (2.2 mg/kg) of body weight, twice a day
in children weighing less than 100 lb (45 kg). Parenteral therapy is
only indicated when oral therapy is not indicated and should not be
continued over a prolonged period of time. Oral therapy should be
instituted as soon as possible. Therapy must continue for a total of
60 days.''
IV. Penicillin G Procaine Drug Products
We have determined that 1,200,000 units of penicillin G procaine,
administered every 12 hours, is an appropriate dosing regimen for
adults who have inhalational exposure to Bacillus anthracis. The
corresponding dosing regimen for children is 25,000 units/kg of body
weight (maximum 1,200,000 units) every 12 hours.
A. Safety
Penicillin drug products have been used for over 50 years. The
amount of literature on penicillin is correspondingly large. We have
reviewed published literature on the safety of penicillin G procaine.
We have also reviewed data from AERS. Analysis of these articles and
data indicates that no pattern of unexpected adverse events is
associated with the use of penicillin G procaine as described in the
recommended dosing regimen. All adverse events that we have identified
are described in the approved labeling. We note that there may be an
increased risk of neutropenia and an increased incidence of serum
sickness-like reactions associated with use of penicillin for more than
2 weeks. Because prescribing health care professionals should take
those factors into consideration when continuing administration of
penicillin G procaine for longer than 2 weeks for inhalational anthrax
(post-exposure), we are suggesting that the labeling for the drug
products reflect these concerns about neutropenia and serum sickness-
like reactions.
B. Effectiveness
We have reviewed MIC data for penicillin G and Bacillus anthracis,
pharmacokinetic data, data from the Sverdlovsk incident, clinical data
regarding the use of penicillins in treatment of primarily cutaneous
anthrax, and the outcome data from a study of inhalational exposure to
Bacillus anthracis in rhesus monkeys.\5\ We have concluded that the
recommended dosing regimens are effective for adults and children who
[[Page 55682]]
have inhalational exposure to Bacillus anthracis.
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\5\ Friedlander.
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C. Labeling
We encourage the submission of labeling supplements for penicillin
G procaine injectable drug products. The revised labeling should
contain a specific indication for inhalational anthrax (post-exposure),
the recommended dosing regimen, safety information relevant to
prolonged use and use in children, and other information described
below. The following specific changes to the current approved labeling
are recommended:
Indications. In the ``Indications'' section, the
indication for anthrax should be revised from ``Anthrax'' to ``Anthrax
due to Bacillus anthracis, including inhalational anthrax (post-
exposure): to reduce the incidence or progression of the disease
following exposure to aerosolized Bacillus anthracis.''
Precautions. In the ``Precautions'' section, at the end
of the paragraph that begins ``In prolonged therapy with penicillin,
and particularly with high-dosage schedules, periodic evaluation of the
renal and hematopoietic systems is recommended,'' the following text
should be added: ``In such situations, use of penicillin for more than
2 weeks may be associated with an increased risk of neutropenia and an
increased incidence of serum sickness-like reactions.''
Dosage and Administration. In the ``Dosage and
Administration'' section, immediately following ``Anthrax--cutaneous:
600,000 to 1,000,000 units/day.'' the following text should be
inserted:
``Anthrax--inhalational (post-exposure): 1,200,000 units every
12 hours in adults, 25,000 units per kilogram of body weight
(maximum 1,200,000 unit) every 12 hours in children. The available
safety data for penicillin G procaine at this dose would best
support a duration of therapy of 2 weeks or less. Treatment for
inhalational anthrax (post-exposure) must be continued for a total
of 60 days. Physicians must consider the risks and benefits of
continuing administration of penicillin G procaine for more than 2
weeks or switching to an effective alternative treatment.''
V. Conclusions
Drug products containing the following active ingredients are
currently approved for administration in cases of inhalational anthrax:
Doxycycline
Doxycycline calcium
Doxycycline hyclate
Penicillin G procaine
We encourage the submission of labeling supplements for these drug
products. The revised labeling should specifically mention inhalational
anthrax (post-exposure), the recommended dosing regimen, safety
information relevant to prolonged exposure (60 days or longer), and
other information described in this notice. The requirement for data to
support these labeling changes may be met by citing the published
literature we relied on in publishing this notice. A list of the
published literature and reprints of the reports will be available
forpublic inspection in the Dockets Management Branch (HFA-305), Food
and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD
20852. 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.
VI. Published Literature
The published literature we have relied on in making our
recommendations will be placed on display in the Dockets Management
Branch (address above) and may be seen by interested persons between 9
a.m. and 4 p.m., Monday through Friday. A list of this published
literature will be on display in the Dockets Management Branch and on
the Internet at http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/cder/drug/infopage/penG_doxy/bibliolist.htm.
Dated: October 26, 2001.
Bernard A. Schwetz,
Acting Principal Deputy Commissioner.
[FR Doc. 01-27493 Filed 10-29-01; 4:35 pm]
BILLING CODE 4160-01-S