[Federal Register Volume 66, Number 213 (Friday, November 2, 2001)]
[Notices]
[Pages 55679-55682]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 01-27493]


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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 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