[Code of Federal Regulations]
[Title 21, Volume 4]
[Revised as of April 1, 2003]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR201.305]

[Page 61-62]
 
                        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other forms of therapy until the drug was withdrawn.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.
    (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

[[Page 62]]

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]