[Code of Federal Regulations]
[Title 21, Volume 4]
[Revised as of April 1, 2007]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR201.305]
[Page 78-79]
TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES (CONTINUED)
PART 201 LABELING--Table of Contents
Subpart G Specific Labeling Requirements for Specific Drug Products
Sec. 201.305 Isoproterenol inhalation preparations (pressurized aerosols,
nebulizers, powders) for human use; warnings.
(a) Accumulating reports have been received by the Food and Drug
Administration and have appeared in the medical literature of severe
paradoxical bronchoconstriction associated with repeated, excessive use
of isoproterenol inhalation preparations in the treatment of bronchial
asthma and other chronic bronchopulmonary disorders. The cause of this
paradoxical reaction is unknown; it has been observed, however, that
patients have not responded completely to other forms of therapy until
use of the isoproterenol inhalation preparation was discontinued. In
addition, sudden unexpected deaths have been associated with the
excessive use of isoproterenol inhalation preparations. The mechanism of
these deaths and their relationship, if any, to the cases of severe
paradoxical bronchospasm are not clear. Cardiac arrest was noted in
several of these cases of sudden death.
(b) On the basis of the above information and after discussion with
and concurrence of the Respiratory and Anesthetic Drugs Advisory
Committee for Food and Drug Administration, the Commissioner of Food and
Drugs concludes that in order for the labeling of such drugs to bear
adequate information for their safe use, as required by Sec. 201.100,
such labeling must include the following:
Warning: Occasional patients have been reported to develop severe
paradoxical airway resistance with repeated, excessive use of
isoproterenol inhalation preparations. The cause of this refractory
state is unknown. It is advisable that in such instances the use of this
preparation be discontinued immediately and alternative therapy
instituted, since in the reported cases the patients did not respond to
other forms of therapy until the drug was withdrawn.
Deaths have been reported following excessive use of isoproterenol
inhalation preparations and the exact cause is unknown. Cardiac arrest
was noted in several instances.
(c)(1) The Commissioner also concludes that in view of the manner in
which these preparations are self-administered for relief of attacks of
bronchial asthma and other chronic bronchopulmonary disorders, it is
necessary for the protection of users that warning information to
patients be included as a part of the label and as part of any
instructions to patients included in the package dispensed to the
patient as follows:
Warning: Do not exceed the dose prescribed by your physician. If
difficulty in breathing persists, contact your physician immediately.
(2) The warning on the label may be accomplished (i) by including it
on the immediate container label with a statement directed to
pharmacists not to remove the label or (ii) by including in the package
a printed warning with instructions to pharmacists to place the warning
on the container prior to dispensing.
(d) The marketing of isoproterenol inhalation preparations may be
continued if all the following conditions are met:
(1) Within 30 days following the date of publication of this section
in the Federal Register:
(i) The label and labeling of such preparations shipped within the
jurisdiction of the act are in accordance with paragraphs (b) and (c) of
this section.
(ii) The holder of an approved new-drug application for such
preparation submits a supplement to his new-drug application to provide
for appropriate labeling changes as described in paragraphs (b) and (c)
of this section.
(2) Within 90 days following the date of publication of this section
in the Federal Register, the manufacturer, packer, or distributor of any
drug containing isoproterenol intended for inhalation for which a new-
drug approval is not in effect submits a new-drug application containing
satisfactory information of the kinds required by Sec. 314.50 of this
chapter, including appropriate labeling as described in paragraphs (b)
and (c) of this section.
(3) The applicant submits additional information required for the
approval of the application as may be specified in a written
communication from the Food and Drug Administration.
[[Page 79]]
(e) After 270 days following expiration of said 90 days, regulatory
proceedings based on section 505(a) of the Federal Food, Drug, and
Cosmetic Act may be initiated with regard to any such drug shipped
within the jurisdiction of the act for which an approved new-drug
application is not in effect.
[40 FR 13998, Mar. 27, 1975, as amended at 55 FR 11576, Mar. 29, 1990]
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