(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 § 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instituted, since in the reported cases the patients did not respond to other forms of therapy until the drug was withdrawn.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
(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
(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 such drug shipped within the jurisdiction of the act for which an approved new-drug application is not in effect.