[Federal Register Volume 60, Number 144 (Thursday, July 27, 1995)]
[Rules and Regulations]
[Pages 38636-38642]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-18449]




[[Page 38635]]

_______________________________________________________________________

Part IV





Department of Health and Human Services





_______________________________________________________________________



Food and Drug Administration



_______________________________________________________________________



21 CFR Parts 310 and 341



Cold, Cough, Allergy, Bronchodilator, and Antiasthmatic Drug Products 
for Over-the-Counter Human Use, Combination Bronchodilator Drug 
Products Containing Theophylline and Proposed Amendment of Monograph 
for OTC Bronchodilator Drug Products; Final Rule and Proposed Rule

  Federal Register / Vol. 60, No. 144 / Thursday, July 27, 1995 / Rules 
and Regulations  

[[Page 38636]]


DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 310

[Docket No. 76N-052G]
RIN 0905-AA06


Cold, Cough, Allergy, Bronchodilator, and Antiasthmatic Drug 
Products for Over-the-Counter Human Use; Combination Bronchodilator 
Drug Products Containing Theophylline

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA) is issuing a final rule 
establishing that cough-cold combination drug products containing 
theophylline are not generally recognized as safe and effective and are 
misbranded for over-the-counter (OTC) use. FDA is issuing this final 
rule after considering public comments on the agency's proposed 
regulation, which was issued in the form of a tentative final 
monograph, and all new data and information on OTC cough-cold 
combination drug products containing theophylline that have come to the 
agency's attention. Also, this final rule lists in a regulation all OTC 
bronchodilator ingredients that have been found to be not generally 
recognized as safe and effective and are misbranded. This final rule is 
part of the ongoing review of OTC drug products conducted by FDA.

EFFECTIVE DATE: January 29, 1996.

FOR FURTHER INFORMATION CONTACT: William E. Gilbertson, Center for Drug 
Evaluation and Research (HFD-810), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-594-5000.

SUPPLEMENTARY INFORMATION:

I. Background

    In the Federal Register of September 9, 1976 (41 FR 38312), FDA 
published, under Sec. 330.10(a)(6) (21 CFR 330.10(a)(6)), an advance 
notice of proposed rulemaking to establish a monograph for OTC cold, 
cough, allergy, bronchodilator, and antiasthmatic drug products, 
together with the recommendations of the Advisory Review Panel on OTC 
Cold, Cough, Allergy, Bronchodilator, and Antiasthmatic Drug Products 
(the Panel), which was the advisory review panel responsible for 
evaluating data on the active ingredients in these drug classes. The 
Panel recommended that theophylline as a single ingredient be Category 
I (generally recognized as safe and effective) (41 FR 38312 at 38373 
and 38374). The Panel also recommended that combinations containing an 
oral sympathomimetic bronchodilator (e.g., ephedrine hydrochloride) and 
an oral bronchodilator (theophylline) be Category I (41 FR 38312 at 
38326). Interested persons were invited to submit comments by December 
8, 1976. Reply comments in response to comments filed in the initial 
comment period could be submitted by January 7, 1977.
    In accordance with Sec. 330.10(a)(10), the data and information 
considered by the Panel, after deletion of a small amount of trade 
secret information, were placed on public display in the Dockets 
Management Branch (HFA-305), Food and Drug Administration, rm. 1-23, 
12420 Parklawn Dr., Rockville, MD 20857.
    In the Federal Register of December 10, 1976 (41 FR 54032 at 
54033), the agency announced that it did not agree with the Panel's 
recommendation that theophylline be classified in Category I and be 
made available for OTC use as a single ingredient because additional 
information, not available during the Panel's deliberations, indicated 
that the Panel's recommended therapeutic dose for theophylline may be 
toxic to some individuals. The new information suggested that the safe 
and effective use of theophylline requires careful dosage titration 
based on theophylline serum concentrations. The agency reaffirmed its 
decision to restrict single-ingredient theophylline preparations to 
prescription use only in the tentative final monograph for OTC 
bronchodilator drug products (47 FR 47520 at 47521, October 26, 1982). 
In the final monograph for OTC bronchodilator drug products (51 FR 
35326 at 35331, October 2, 1986), the agency stated that it would 
address theophylline combinations in the tentative final monograph for 
OTC cough-cold combination drug products, in a future issue of the 
Federal Register.
    In the tentative final monograph for OTC cough-cold combination 
drug products (53 FR 30522 at 30544 to 30546, August 12, 1988), 
combination drug products containing theophylline and ephedrine were 
reclassified from Category I to Category II (not generally recognized 
as safe and/or effective). Additionally, the agency classified in 
Category II any OTC combination drug product that contains 
theophylline. Interested persons were invited to submit written 
comments, objections, or requests for oral hearing on the proposed 
regulation before the Commissioner of Food and Drugs (the Commissioner) 
and on the agency's economic impact determination for the proposal by 
December 12, 1988. New data could have been submitted by August 14, 
1989, and comments on the new data by October 12, 1989.
    In response to the OTC cough-cold combination drug products 
tentative final monograph, two manufacturers submitted comments and 
data on theophylline combination drug products, and two physicians 
submitted a case study related to a theophylline- ephedrine-
phenobarbital combination product. Another comment reported injuries it 
considered to be caused by theophylline toxicity. Although that comment 
was submitted after the administrative record had closed, the agency 
considered it important and has addressed it in this final rule. Copies 
of the comments are on public display in the Dockets Management Branch 
(address above).
    In this final rule, the agency is declaring OTC cough-cold 
combination drug products containing theophylline to be new drugs under 
section 201(p) of the Federal Food, Drug, and Cosmetic Act (the act) 
(21 U.S.C. 321(p)), for which an application or abbreviated application 
(hereinafter called application) approved under section 505 of the act 
(21 U.S.C. 355) and 21 CFR part 314 is required for marketing. In the 
absence of an approved application, products containing drugs for this 
use also would be misbranded under section 502 of the act (21 U.S.C. 
352). In this final rule, the agency is amending part 310 (21 CFR part 
310) (nonmonograph conditions) by adding to Sec. 310.545(a)(6) new 
paragraph (iv) to include any cough-cold combination drug products 
containing theophylline.
    In the advance notice of proposed rulemaking for OTC cold, cough, 
allergy, bronchodilator, and antiasthmatic drug products (41 FR 38312), 
the agency stated that the conditions for products excluded from the 
monograph (Category II) should be eliminated from OTC drug products 
effective 6 months after the date of publication of the final monograph 
in the Federal Register, regardless of whether further testing is 
undertaken to justify their future use. The agency also stated that 
conditions included in the monograph (Category I) should be effective 
30 days after the date of publication of the final monograph in the 
Federal Register. In the tentative final monograph for OTC cough-cold 
combination drug products, the agency extended this 30-day period to 12 
months in order to provide a reasonable 

[[Page 38637]]
period of time for relabeling and reformulation of products covered by 
the monograph (53 FR 30522 at 30523).
    In the case of OTC combination bronchodilator drug products 
containing theophylline, the agency has determined that no combination 
is generally recognized as safe and effective for this use. 
Accordingly, the agency is not establishing any monograph conditions 
for these combination drug products. Thus, there is no need for a 12-
month period for relabeling and reformulation of these products. As 
stated in the advance notice of proposed rulemaking, these conditions 
should be eliminated from OTC drug products effective 6 months after 
the date of publication of this final rule. Therefore, on or after 
January 29, 1996, no OTC cough-cold combination drug products 
containing theophylline may be initially introduced or initially 
delivered for introduction into interstate commerce unless they are the 
subject of an approved application. Any such OTC drug product in 
interstate commerce after the effective date of this final rule that is 
not in compliance with the regulation is subject to regulatory action. 
Manufacturers are urged to comply voluntarily with this final rule at 
the earliest possible date.
    In the final rule for OTC bronchodilator drug products (51 FR 35326 
at 35338), the agency listed a number of nonmonograph bronchodilator 
ingredients. At that time, Sec. 310.545 had not been established. Thus, 
none of these nonmonograph bronchodilator ingredients are listed in 
that regulation.
    Accordingly, at this time, the agency is also listing in 
Sec. 310.545(a)(6)(iv) all of the nonmonograph bronchodilator active 
ingredients discussed in that final rule. The effective date of 
nonmonograph status for these ingredients, which did not apply to 
combinations containing theophylline, was October 2, 1987. The date of 
nonmonograph status of combinations containing theophylline will be 
January 29, 1996.

II. The Agency's Conclusions on the Comments

    1. One comment requested that the agency ban theophylline in OTC 
drug products. The comment mentioned the growing body of medical 
literature highly critical of theophylline's safety record. The comment 
contended that theophylline can be a dangerous drug and its use should 
be tailored (by a physician) to the individual patient. The comment 
mentioned 26 incidents of theophylline-caused injuries, most of which 
involved young asthma patients who sustained brain damage from seizures 
or died as a result of using theophylline. The comment emphasized the 
need for greater understanding of the use of theophylline, especially 
when used by children or anyone suffering from fever or a viral 
infection, such as the flu.
    Another comment reported a case involving a 6-year-old child who 
had been admitted to the hospital with a diagnosis of complex febrile 
seizures (Ref. 1). Because such febrile seizures often do not reoccur, 
the child was not placed on anticonvulsant medication, but was observed 
over time. Several months later, when the child was readmitted with 
gastroenteritis presumably of viral etiology, the physician discovered 
that the child had been taking an OTC drug product containing 130 
milligrams (mg) theophylline, 24 mg ephedrine, and 8 mg phenobarbital 
twice daily for asthma prophylaxis. The comment indicated that the 
presence of phenobarbital in this product could have affected the 
patient's clinical course and/or recognition of reoccurring seizures. 
The comment urged the agency to remove this type of combination product 
from the OTC marketplace.
    The agency agrees with the comments that theophylline-containing 
combination drug products should no longer be available OTC. In the OTC 
cough-cold combination tentative final monograph (53 FR 30522 at 30544 
to 30546), the agency stated its awareness of the increase in adverse 
effects associated with the use of theophylline and ephedrine 
combination drug products. Moreover, the agency concluded that whether 
theophylline is administered as a single ingredient or in combination 
with other drugs, it is essential that a physician titrate theophylline 
dosage based on individual patient measurements of theophylline serum 
levels. Thus, the agency classified any OTC combination drug product 
containing theophylline as Category II (not generally recognized as 
safe and/or effective) and reaffirmed its position that theophylline 
should be administered under professional supervision.
    More recent data also support the conclusion that theophylline is 
not safe for OTC use. These include:
    (1) Twenty-six incidents of theophylline-caused injury between 1980 
and 1991 (involving mostly young asthma patients), including 6 deaths 
(likely causally related), 15 cases of brain damage (not otherwise 
defined), 4 seizures and/or coma, and 1 rapid heartbeat (Ref. 2); (2) 
FDA adverse reaction reports for the years 1969 to March, 1994 (Ref. 
3); and (3) the American Association of Poison Control Centers National 
Data Collection System (Refs. 4 through 7).
    The agency's adverse reaction reporting system (Ref. 3) includes 
116 adverse reactions associated with theophylline-containing 
combination drug products. Twenty-two of these reactions were serious: 
4 resulted in death; 15 resulted in hospitalization; and 3 were 
disabling. These reports include both prescription and OTC use of 
theophylline combination drug products. Adverse reaction reports 
involving single ingredient theophylline drug products include 2,175 
cases. Of these, 782 were serious, 111 resulted in death, 5 others were 
considered life-threatening, 4 required medical intervention to prevent 
impairment, 698 resulted in hospitalization, and 27 were disabling 
(Ref. 3).
    The annual reports of the American Association of Poison Control 
Centers for the years 1990 to 1993 (Refs. 4 through 7) concerning 
theophylline exposures state the following: (1) In 1990, there were 
6,527 theophylline exposures resulting in 36 deaths, 93 major (severe) 
outcomes, 622 moderate outcomes, and 2,039 minor outcomes; (2) in 1991, 
there were 6,744 theophylline exposures resulting in 38 deaths, 138 
major outcomes, 619 moderate outcomes, and 2,101 minor outcomes; (3) in 
1992, there were 5,735 theophylline exposures resulting in 35 deaths, 
113 major outcomes, 596 moderate outcomes, and 1,343 minor outcomes; 
and (4) in 1993, there were 4,473 theophylline exposures resulting in 
27 deaths, 120 major outcomes, 782 moderate outcomes, and 1,026 minor 
outcomes. The agency notes that these reports do not differentiate 
theophylline exposure as resulting from prescription or OTC drug 
products; nor do the reports differentiate exposure as resulting from 
drug products containing theophylline as a single ingredient or in 
combination with another active ingredient.
    Tsiu et al. (Ref. 8) reported 1,570 published cases of 
theophylline-induced toxicities from 1973 through 1988, which included 
198 seizures, 525 cardiovascular complications, and 63 deaths. The 
study indicates that many patients suffered serious and frequently 
fatal side effects, despite receiving ``standard'' prescription doses 
of theophylline. This type of reporting emphasizes the narrow 
therapeutic index of theophylline and the need to determine individual 
dose titration levels.
    Sessler (Ref. 9) examined the clinical and pharmacokinetic 
characteristics of 

[[Page 38638]]
5,557 theophylline-related toxicity reports from two hospitals over a 
2-year period. Ten percent of the reported cases had serum theophylline 
concentrations above the therapeutic range, while 2 percent of these 
cases reported serum theophylline concentrations greater than 30 
micrograms per milliliter (g/mL). Of the 116 cases having 
serum theophylline concentrations greater than 30 g/mL, 12 
percent were due to acute overdose and 88 percent due to chronic 
overmedication. Sessler stated that cases of theophylline-induced 
toxicity are relatively common in hospital emergency departments, 
result primarily from patient and physician dosing errors, and cause a 
broad range of toxic manifestations of varying severity. Sessler 
indicated that the most common single cause of toxicity is 
inappropriate drug administration by the patient, i.e., additional 
doses administered for the relief of bronchospasm and/or dyspnea 
(difficulty in breathing).
    In a recent prospective study (Ref. 10), Shannon evaluated major 
theophylline toxicity of 249 subjects with acute theophylline 
intoxication: 119 subjects with acute intoxication who were not 
receiving theophylline therapy, 92 subjects with chronic intoxication 
due to overmedication, and 38 subjects who ere acutely intoxicated 
while on theophylline therapy. The study pointed out that chronic 
overmedication is responsible for the high rate of morbidity and 
mortality in elderly subjects with theophylline intoxication. Shannon 
concluded that the data support the admonition that theophylline should 
be used cautiously, if at all, in elderly patients, and that close 
patient monitoring is necessary.
    The data discussed above demonstrate an incidence of theophylline-
related, life-threatening events and deaths, and a narrow therapeutic 
window for the safe use of theophylline. Accordingly, the agency 
concludes that theophylline should be administered under professional 
supervision and not be available OTC. Therefore, all OTC cough-cold 
combination drug products containing theophylline are considered 
nonmonograph.

References

    (1) Comment No. C211, Docket No. 76N-052G, Dockets Management 
Branch.
    (2) Letter from M. Maher, Association of Trial Lawyers of 
America, to J. S. Benson, FDA, dated October 25, 1990, in OTC Vol. 
04THFM, Docket No. 76N-052G, Dockets Management Branch.
    (3) Department of Health and Human Services, Food and Drug 
Administration, ``Spontaneous Reporting System, Line Listing of 
Adverse Reports: Theophylline Adverse Drug Event Profile,'' January 
1969 to March 1994, in OTC Vol. 04THFM, Docket No. 76N-052G, Dockets 
Management Branch.
    (4) Litovitz, T.L. et al., ``1990 Annual Report of the American 
Association of Poison Control Centers National Data Collection 
System,'' The American Journal of Emergency Medicine, 9:488, 1991.
    (5) Litovitz, T.L. et al., ``1991 Annual Report of the American 
Association of Poison Control Centers National Data Collection 
System,'' The American Journal of Emergency Medicine, 10:480, 1992.
    (6) Litovitz, T.L. et al., ``1992 Annual Report of the American 
Association of Poison Control Centers Toxic Exposure Surveillance 
System,'' The American Journal of Emergency Medicine, 11:530, 1993.
    (7) Litovitz, T.L. et al., ``1993 Annual Report of the American 
Association of Poison Control Centers Toxic Exposure Surveillance 
System,'' The American Journal of Emergency Medicine, 12:580, 1994.
    (8) Tsiu, S.J. et al., ``Theophylline Toxicity: Update,'' Annals 
of Allergy, 64:241-257, 1990.
    (9) Sessler, C.N., ``Theophylline Toxicity: Clinical Features of 
116 Consecutive Cases,'' The American Journal of Medicine, 88:567-
576, 1990.
    (10) Shannon, M., ``Predictors of Major Toxicity after 
Theophylline Overdose,'' Annals of Internal Medicine, 119:1161-1167, 
1993.

    2. Two comments disagreed with the agency's Category II 
classification of any OTC cough-cold combination drug product 
containing theophylline (53 FR 30544 at 30546). One comment stated that 
OTC combination bronchodilator drug products containing theophylline 
and ephedrine provide the same benefit to asthmatics as either single 
active ingredient when used for temporary relief of symptoms associated 
with episodic asthma. The comment asserted that low dose theophylline 
and ephedrine combinations have an extensive marketing history and a 
record of safe and effective use. The comment submitted two clinical 
studies (Refs. 1 and 2) in support of the therapeutic benefit of both 
theophylline and ephedrine and the additive effect(s) when both 
ingredients are taken in combination in fixed dosage. The comment 
contended that the two clinical studies confirm the following: (1) Low 
dose theophylline in combination products is therapeutically effective; 
(2) addition of low dose theophylline enhances the effectiveness of 
ephedrine; and (3) significant clinical benefit is achieved from using 
the combination product. The comment concluded that these studies 
provide substantial evidence to adequately support a final 
determination by the agency that low dose theophylline in combination 
with ephedrine is generally recognized as safe and effective as an OTC 
combination bronchodilator drug product.
    The second comment stated that adequate and well-controlled 
clinical studies and 50 years of successful OTC use in the management 
of reversible bronchospastic disorder have demonstrated the safety and 
effectiveness of its OTC combination bronchodilator drug product 
containing 130 mg theophylline, 24 mg ephedrine, and 8 mg 
phenobarbital. In support of the additive effects and benefits from 
combining theophylline with ephedrine, the comment submitted data, 
literature reviews, and affidavits from several health care providers 
(Refs. 3 through 50). The comment stated that the data presented show 
that the combination drug product containing theophylline and ephedrine 
is a rational drug combination by virtue of the synergistic effects of 
the two bronchodilators, and that the reduction in the dosage of each 
component reduces the risk of toxicity from either ingredient. The 
comment added that such combination drug products provide mild to 
moderate chronic and stable asthmatic individuals with safe and 
effective medication that is convenient and cost- effective.
    The agency has reviewed the submitted data and information, 
considered other pertinent information, and determined that the 
existing data do not support the safety and effectiveness of OTC 
combination drug products containing theophylline and ephedrine. The 
agency notes that on July 20 and 21, 1981, the FDA Pulmonary-Allergy 
Drugs Advisory Committee (the Committee) met and concluded that there 
was insufficient evidence to demonstrate the additive effect for 
combination drug products containing theophylline and ephedrine (Ref. 
51). The Committee met again on November 4, 1982, and stated that it 
did not favor the continued OTC or prescription marketing of 
theophylline and ephedrine fixed combination drug products (Ref. 52). 
In the tentative final monograph for OTC cough-cold combination drug 
products (53 FR 30522 at 30545 to 30546), the agency agreed with the 
Committee that: (1) Insufficient evidence exists to support the use of 
theophylline and ephedrine in combination; (2) ephedrine adds little 
benefit to the theophylline and ephedrine combination when theophylline 
is given in a dosage titrated for the individual patient; (3) 
individual dosage titration for theophylline is needed; and (4) an 
increase in adverse effects has been associated with the use of 
theophylline and ephedrine combination drug products. 

[[Page 38639]]

    The additional data submitted by the comments do not change the 
agency's position. One unpublished study (WM-339) (Ref. 1) addressed 
the therapeutic benefit of a combination containing 130 mg theophylline 
and 24 mg ephedrine. This randomized, double-blind, placebo-controlled, 
four-way crossover study compared the bronchodilator effects of single 
doses of theophylline, ephedrine, theophylline with ephedrine, and 
placebo in 30 subjects with reversible bronchospasm. According to the 
comment, the study demonstrates that ephedrine is an effective single 
ingredient bronchodilator and that combination drug treatment with 
theophylline plus ephedrine is significantly more effective than 
treatment with either single ingredient in providing relief from 
reversible airway obstruction attributable to bronchial asthma.
    The agency finds that study WM-339 (Ref. 1) does not provide 
substantial evidence that both ingredients in the combination drug 
product make a contribution to the claimed effects. According to the 
authors, effectiveness of the two single ingredient products (130 mg 
theophylline and 24 mg ephedrine), the combination product (both 
theophylline and ephedrine), and placebo (inert tablet) was compared 
using the following endpoints: (1) Results of spirometric measurements 
of forced expiratory volume in 1 second (FEV 1) and the peak 
expiratory flow rate, (2) subjective evaluations of test subjects, and 
(3) incidence of therapeutic failure. The authors concluded that the 
combination therapy was superior to both placebo and to the single 
ingredients for spirometric measurements at several time points and for 
subjective patient global responses. Although significantly fewer 
failure rates were reported for the combination treatment group than 
for the placebo group, there was no significant difference in treatment 
failures between either individual ingredient and the combination 
product.
    Flaws in the design and analysis of this study preclude 
substantiation of the authors' conclusions. First, the agency does not 
consider a single-dose, crossover study sufficient to establish 
effectiveness of both components of this fixed combination that would 
be used for multiple doses in a dynamic illness. Treatment-by-sequence 
effects, possible carryover effects, and dynamic changes in the 
subject's baseline disease over time could not be assessed because 
individual subject information was not provided.
    Second, the agency considers inappropriate the method utilized to 
specify and analyze all effectiveness data recorded for treatment 
failures. Treatment failures were defined by inability to record at 
least one FEV 1 measurement with a minimum 15 percent improvement 
during the first 2 hours, and dropouts after the first 2 hours of 
observation. The planned analysis specified proper handling of 
treatment failure dropouts. However, 88 percent (15 of 17) of the 
subjects with at least a single treatment failure at the 2-hour 
observation point were allowed to finish the same 6-hour study period 
and were included in the evaluation of effectiveness. Some of these 
subjects may have received the allowed 2-hour rescue medication 
generating ``improved'' data for observation points between 2 and 6 
hours, which cannot be attributed to the assigned study drug.
    Finally, beta-agonist aerosol rescue medication was allowed by the 
study protocol at the single 2-hour observation point. This caused 
effectiveness results to be compromised by inclusion of further data in 
the analysis of effectiveness whether or not use of the rescue 
medication was considered a treatment failure.
    The agency discussed the Sims et al. study (Ref. 2), submitted by 
one comment, in the tentative final monograph for OTC cough-cold 
combination drug products (53 FR 30522 at 30544). During two phases in 
that study, several combination products, including one containing 130 
mg theophylline and 25 mg ephedrine, were compared to single doses of 
theophylline and ephedrine in 10 adults with mild but continuously 
symptomatic asthma and in 10 nonsmoking healthy adults. Reported 
results were that: (1) A single dose of 130 mg theophylline combined 
with 25 mg ephedrine produced a bronchodilator effect in subjects with 
mild to moderate asthma; (2) the theophylline and ephedrine combination 
caused more side effects (i.e., tremor, nervousness, nausea) than 
either ingredient alone; and (3) one theopylline and ephedrine 
combination was more effective than either drug alone, but there was no 
improvement in bronchodilator effectiveness for another combination 
despite higher theophylline blood levels achieved after 2 weeks of 
multiple dosing with a combination product containing theophylline, 
ephedrine, and phenobarbital. To explain the observed lack of improved 
lung function after multiple dosing with higher theophylline blood 
levels, the authors suggested the development of tolerance to 
theophylline, ephedrine, or both. The agency considers this two-phase 
study insufficient to support the claim that the combination of 
theophylline and ephedrine is more effective than either single active 
ingredient alone for the treatment of mild, continuously symptomatic 
asthma. The agency concludes that this study does not provide 
sufficient data to support the use of OTC combination drug products 
containing theophylline and ephedrine.
    The agency has also reviewed the other studies (Refs. 3 through 50) 
and determined that the data do not substantiate the safe and effective 
use of OTC combination drug products containing theophylline. 
References 3 through 6 were previously addressed in the tentative final 
monograph for OTC cough-cold combination drug products (53 FR 30522 at 
30544). Reference 7 reported superior effects of a combination of two 
drugs (theophylline and ephedrine) over single ingredient products 
(theophylline or ephedrine) in ameliorating exercise-induced 
bronchospasm. However, a three ingredient combination drug product 
(theophylline, ephedrine, and hydroxyzine hydrochloride) was used in 
these studies. Further, the side effects (drowsiness, tremors, nausea, 
insomnia, and palpitations) made the theophylline-ephedrine combination 
product unacceptable to almost one-half of the subjects in the study.
    References 8 and 9 suggested that combinations are more effective 
than their individual components in controlling induced bronchospasm 
and modifying both early asthmatic response and late asthmatic 
response. However, two other reports (Refs. 49 and 50) indicated that 
oral theophylline has no effect on airway hyperresponsiveness even at 
dose levels greater than the fixed dose (780 mg per day) currently 
available OTC.
    Reference 10 noted that in some studies additive effects of the 
combination drug product containing theophylline are recorded and in 
other studies they are not. Reference 11 was a double-blind, placebo-
controlled, randomized cross-over study of a combination of three 
ingredients (theophylline, ephedrine, and hydroxyzine), another 
combination of three ingredients (theophylline, ephedrine, and 
phenobarbital), and a single ingredient product containing ephedrine. 
The authors reported that both combinations were more effective than 
ephedrine alone, but the study did not include a single ingredient 
product containing theophylline. Therefore, the study was unable to 
evaluate the contribution of ephedrine.
    References 12 and 13 indicated that the prescription drugs 
metaproterenol 

[[Page 38640]]
(Ref. 12) and terbutaline (Ref. 13) produced additive effects when 
given with theophylline. However, these data concerning additive 
effects of prescription drugs are irrelevant to OTC use of ephedrine. 
Reference 14 involved a comparison of a three ingredient combination 
drug product containing 130 mg theophylline, 24 mg ephedrine, and 8 mg 
phenobarbital to a single ingredient product containing 300 mg 
theophylline, given four times a day. The investigators recorded 
similar pulmonary function responses for the two products. However, it 
is difficult to assess these results because the two products contained 
different amounts of theophylline. The appropriate study to establish 
effectiveness would have been to compare the combination product to a 
single ingredient product containing the same amount of theophylline.
    None of the other reports (Refs. 15 through 48) contains 
information to demonstrate safety and effectiveness. References 15 
through 26 provided general information only. References 27 through 31 
do not contain any clinical trials, and references 32 through 48 
involved the comment's sustained action formulation. Some of these 
studies employed either a placebo control (Ref. 33) or a beta-agonist 
control other than ephedrine (Refs. 35 through 38). Two other studies 
(Refs. 32 and 34) compare the safety and effectiveness of a 
theophylline-containing sustained action dosage form and a 
theophylline-containing immediate release dosage form. References 39 
through 48 lack study controls and are some of the early 1976 trials in 
Europe that dealt with a variety of disease entities.
    The affidavits contained statements from several health care 
providers that the combination therapy of 130 mg theophylline and 24 mg 
ephedrine in fixed doses provides safe and effective therapy for the 
treatment of mild asthma. However, none of the affidavits included any 
new scientific data to support the safety and effectiveness of any OTC 
combination drug product containing theophylline and ephedrine.
    The agency concludes that the submitted data do not support any 
combination bronchodilator drug products containing theophylline as 
safe and effective for OTC use, particularly with regard to 
effectiveness at steady state. Substantial evidence has not been 
provided to demonstrate that each ingredient in the combination of 
theophylline and ephedrine makes a contribution to the claimed effects 
as noted in Sec. 330.10(a)(4)(iv) (21 CFR 300.10(a)(4)(iv)). 
Accordingly, in this final rule, combination bronchodilator drug 
products containing theophylline are not generally recognized as safe 
and effective and are considered misbranded for OTC use.

References

    (1) Unpublished Clinical Study No. WM-339, ``Clinical-
Biostatistical Report,'' Comment No. C193, Docket No. 76N-052G, 
Dockets Management Branch.
    (2) Sims, J.A. et al., ``Bronchodilating Effect of Oral 
Theophylline-Ephedrine Combination,'' Journal of Allergy and 
Clinical Immunology, 62:15-21, 1978.
    (3) Plummer, A.L., ``Choosing a Drug Regimen for Obstructive 
Pulmonary Disease,'' Postgraduate Medicine, 63:36-47, 1978.
    (4) Piafsky, K.M., and R.I. Ogilvie, ``Dosage of Theophylline in 
Bronchial Asthma,'' New England Journal of Medicine, 292:1218-1222, 
1975.
    (5) Tinkelman, D.G., and S. Avner, ``Ephedrine Therapy in 
Asthmatic Children,'' Journal of the American Medical Association, 
237:553-557, 1977.
    (6) Plummer, A.L., and B.A. Cassidy, ``A Comparison of the 
Bronchodilator Effects of Terbutaline, Tedral, and the Simultaneous 
Use of Both Agents,'' Annals of Allergy, 42:218-223, 1979.
    (7) Bierman, C.W. et al., ``Exercise-Induced Asthma,'' Journal 
of the American Medical Association, 234:295-298, 1975.
    (8) Falliers, C.J., and C.P. Katsampes, ``Pharmacologic 
Modification of Induced Asthma,'' Annals of Allergy, 36:99-103, 
1976.
    (9) Falliers, C.J., and M.A. Redding, ``Combined vs. Single-
Entity Inhibition of Induced Asthma,'' Annals of Allergy, 44:335-
340, 1980.
    (10) Paterson, J.W., and G.M. Shenfield, ``Bronchodilators,'' 
The British Thoracic and Tuberculosis Association Review, 4:61-74, 
1974.
    (11) Whitcomb, N.J., and E. Rubinstein, ``Clinical Effectiveness 
of Commonly Used Oral Bronchodilators in Asthmatic Children,'' 
Annals of Allergy, 31:603-606, 1973.
    (12) Chodosh, S., and W. Baigelman, ``Bronchodilator Effects of 
Metaproterenol and Oxtriphylline in Asthma,'' Chest, 73:1014-1015, 
1978.
    (13) Shapiro, G.G. et al., ``Effectiveness of Terbutaline and 
Theophylline Alone and in Combination in Exercise-Induced 
Bronchospasm,'' Pediatrics, 67:508-513, 1981.
    (14) Steen, S.N. et al., ``Clinical Efficacy of Theophylline 
Combination Therapy for Chronic Obstructive Airways Disease,'' 
Current Therapeutic Research, 27:608-619, 1980.
    (15) Knott, R.P., ``Drug Therapy of Bronchial Asthma,'' 
Pharmindex, 24:7-18, 1982.
    (16) Baigelman, W., ``Here Come the Anticholinergics,'' Chest, 
85:297, 1975.
    (17) Tong, T.G., ``Aminophylline--Review of Clinical Use,'' Drug 
Intelligence and Clinical Pharmacy, 7:156-167, 1973.
    (18) Klein, J.J. et al., ``Relationship Between Serum 
Theophylline Levels and Pulmonary Function Before and After Inhaled 
Beta Agonist in `Stable' Asthmatics,'' American Review of 
Respiratory Disease, 127:413-416, 1983.
    (19) Caplin, I., and J.T. Haynes, ``A Reevaluation of Ephedrine/
Theophylline Combinations in the Treatment of Asthma,'' Journal of 
the Indiana State Medical Association, 71:492-495, 1978.
    (20) Mountain, R.D., and T.A. Neff, ``Oral Theophylline 
Intoxication,'' Archives of Internal Medicine, 144:724-727, 1984.
    (21) Culpit, G.C., ``Pharmacologic Management of Asthma in 
Children,'' Hospital Pharmacy, 9:490-499, 1974.
    (22) Lyons, H.A. et al., ``Theophylline and Ephedrine in 
Asthma,'' Current Therapeutic Research, 18:573-577, 1975.
    (23) Wolfe, J.D. et al., ``Bronchodilator Effects of Terbutaline 
and Aminophylline Alone and in Combination in Asthmatic Patients,'' 
New England Journal of Medicine, 298:363-367, 1978.
    (24) Brooks, S.M. et al., ``The Effects of Ephedrine and 
Theophylline on Dexamethasone Metabolism in Bronchial Asthma,'' 
Journal of Clinical Pharmacology, 17:308-318, 1977.
    (25) Cohen, B.M., ``Sympathomimetic/Xanthine Broncholysis in 
Obstructive Ventilatory Disorder,'' International Journal of 
Clinical Pharmacology, 9:6-15, 1974.
    (26) Jenne, J.W., ``Beta Adrenergic Drugs--How Much Is Enough?'' 
Journal of Allergy and Clinical Immunology, 63:74-78, 1979.
    (27) Wray, B.F., ``Pharmacologic Management of Asthma in 
Childhood,'' Southern Medical Journal, 71:1387-1392 and 1396, 1978.
    (28) Richards, W., ``Differential Diagnosis of Childhood 
Asthma,'' Current Problems in Pediatrics, 4:1-36, 1974.
    (29) Freedman, S.O., ``Drug Treatment of the Out-Patient 
Asthmatic (Chronic Asthmatic),'' Applied Therapy, 11:81-84, 1969.
    (30) AMA Drug Evaluations, 3rd ed., American Medical 
Association, Publishing Sciences Group, Inc., Littleton, MA, pp. 
627-643, 1977.
    (31) Berman, B.A., ``Bronchial Asthma,'' in Current Pediatric 
Therapy, 7th ed., edited by S.S. Gellis, and B.M. Kagan, W.B. 
Saunders Co., Philadelphia, pp. 650-658, 1976.
    (32) Heimlich, E.M. et al., ``Clinical and Laboratory Evaluation 
of an Antiasthmatic Preparation with Prolonged Action,'' Journal of 
Allergy, 35:27-37, 1964.
    (33) Cohen, B., ``Double-Blind Crossover Comparative Study of 
the Effect of Tedral SA vs. Placebo on Airway Resistance,'' 
Clinical- Biostatistical Report No. 932-0387, Comment No. C193, 
Docket No. 76N-052G, Dockets Management Branch.
    (34) Bellis, T.G.L. et al., ``General Practitioner Clinical 
Trial: A Long- and Short-Acting Antiasthmatic Drug,'' Practitioner, 
191:218-220, 1963.
    (35) Cohen, B.M., ``The Cardiorespiratory Effects of Oral 
Terbutaline and an Ephedrine- Theophylline-Phenobarbital 
Combination; Comparison in Patients with Chronic Obstruction 
Ventilatory Disorders,'' Annals of Allergy, 40:233-239, 1978.
    (36) Bush, R.K. et al., ``A Comparison of a Theophylline-
Ephedrine Combination with Terbutaline,'' Annals of Allergy, 41:13-
17, 1978.

[[Page 38641]]

    (37) Prime, F.G., ``A Comparison of Efficacy Between Tedral SA 
and Salbutamol Tablets on Pulmonary Function,'' Research Report No. 
950-0137, Comment No. C192, Docket No. 76N-052G, Dockets Management 
Branch.
    (38) Lal, S. et al., ``Slow Release Salbutamol and Tedral in the 
Treatment of Reversible Airways Obstruction,'' Postgraduate Medical 
Journal, 47:89-92, 1971.
    (39) Geisler, L., ``Pulmonary Function Analytic Investigation of 
the Duration of Action of a Combination Preparation in Obstructive 
Pulmonary Disorders,'' Medizinische Klinik, 62:1200-1202, 1967.
    (40) Osten, H., ``Measurable Results in the Treatment of Spastic 
Bronchitis with a Combination of Theophylline, Ephedrine, and 
Phenylethylbarbituric Acid,'' Arzneimittel Forschung, 21:876-880, 
1971.
    (41) Worth, G., ``Discussion by Invitation,'' in Bronchitis: 
Second International Symposium, edited by N.G.M. Orie and H.J. 
Sluiter, Assen, The Netherlands, pp. 289-290, 1964.
    (42) Kries, P., ``Permanent Dyspnea in Chronic Bronchopathy; 
Effect of a Long-Acting Bronchodilator,'' Gazette Medicale de 
France, 80:6072-6074, 1973.
    (43) Siehoff, F. et al., ``The Effects of a New Combination 
Preparation on Distribution- Disturbances and on the Partial 
Pressures of Alveolar Oxygen and Carbon Dioxide,'' Arzeimittel 
Forschung, 16:11 55-1157, 1965.
    (44) Neurang, O., ``Spasmolytic Therapy of Chronic Bronchitis, 
Particularly in Silicosis and Silicotuberculosis,'' Medizinische 
Welt, 39:2317-2319, 1967.
    (45) Miller, J., ``Sustained-Action Medication in Perennial 
Bronchial Asthma,'' Medical Times, 90:347-351, 1962.
    (46) Schiller, I.W., ``A Brief Review of Drug Therapy in 
Bronchial Asthma,'' West Virginia Medical Journal, 58:263-267, 1962.
    (47) Naik, B.K. et al., ``Allergic Airway Disease-Management 
with a New Sustained Release Bronchodilator,'' Indian Practitioner, 
21:579-582, 1969.
    (48) Hyde, J.S. et al., ``Therapeutic Strategy for Children with 
Chronic Asthma,'' Annals of Allergy, 27:552-564, 1969.
    (49) Cockcroft, D.W. et al., ``Theophylline Does Not Inhibit 
Allergy-Induced Increase in Airway Responsiveness to Methacholine,'' 
Journal of Allergy and Clinical Immunology, 83:913-920, 1989.
    (50) Dutoit, J.I. et al., ``Inhaled Corticosteroids Reduce the 
Severity of Bronchial Hyperresponsiveness in Asthma but Oral 
Theophylline Does Not,'' American Review of Respiratory Disease, 
136:1174, 1987.
    (51) Minutes of the FDA Pulmonary-Allergy Advisory Committee 
Meeting, July 20 and 21, 1981, in OTC Vol. 04GTFM, Docket No. 76N-
052G, Dockets Management Branch.
    (52) Minutes of the FDA Pulmonary- Allergy Advisory Committee 
Meeting, November 4, 1982, in OTC Vol. 04GTFM, Docket No. 76N-052G, 
Dockets Management Branch.

III. Analysis of Impacts

    An analysis of the cost and benefits of this regulation, conducted 
under Executive Order 12291, was discussed in the tentative final 
monograph of August 12, 1988 (53 FR 30522). No comments were received 
in response to the agency's request for specific comment on the 
economic impact of this rulemaking (53 FR 30522 at 30560), and the 
substance of that analysis has not changed. Executive Order 12291 has 
been superseded by Executive Order 12866.
    FDA has examined the impacts of the final rule under Executive 
Order 12866 and the Regulatory Flexibility Act (Pub. L. 96-354). 
Executive Order 12866 directs agencies to assess all costs and benefits 
of available regulatory alternatives and, when regulation is necessary, 
to select regulatory approaches that maximize net benefits (including 
potential economic, environmental, public health and safety, and other 
advantages; distributive impacts; and equity). The agency believes that 
this final rule is consistent with the regulatory philosophy and 
principles identified in the Executive Order. In addition, the final 
rule is not a significant regulatory action as defined by the Executive 
Order and, thus, is not subject to review under the Executive Order.
    The Regulatory Flexibility Act requires agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. The agency concludes that there is no basis for the 
continued marketing of any OTC combination cough-cold drug products 
containing theophylline with claims or directions for use as a 
bronchodilator and/or antiasthmatic drug product. In the interim, 
manufacturers may be able to reformulate to single ingredient ephedrine 
drug products. However, elsewhere in this issue of the Federal 
Register, the agency is proposing to remove the ingredients ephedrine, 
ephedrine hydrochloride, ephedrine sulfate, and racephedrine 
hydrochloride from the bronchodilator final monograph and to require 
premarket approval for any OTC drug product containing these 
ingredients. If that proposal is finalized, manufacturers will not be 
able to market any OTC bronchodilator drug products containing 
theophylline or ephedrine without obtaining an approved application.
    Early finalization of the nonmonograph status of OTC cough- cold 
combination drug products containing theophylline will benefit 
consumers by early removal from the marketplace of drug products for 
which safety and effectiveness have not been established. This will 
result in a direct economic savings to consumers. Bronchodilator drug 
products containing epinephrine will continue to be available for 
consumers to use on an OTC basis to treat bronchial asthma. Based on 
the information above, the agency certifies that this final rule will 
not have a significant economic impact on a substantial number of small 
entities. Therefore, under the Regulatory Flexibility Act, no further 
analysis is required.
    The agency has determined under 21 CFR 25.24(c)(6) that this action 
is of a type that does not individually or cumulatively have a 
significant effect on the human environment. Therefore, neither an 
environmental assessment nor an environmental impact statement is 
required.
    At the time that the final monograph for OTC bronchodilator drug 
products was published in the Federal Register of October 2, 1986 (51 
FR 35326), the agency had not established Sec. 310.545, which lists 
certain active ingredients that are not generally recognized as safe 
and effective for certain OTC drug uses. Therefore, bronchodilator 
ingredients that were found to be nonmonograph in 1986 are not 
currently included in Sec. 310.545. In this final rule, the agency is 
listing in new Sec. 310.545(a)(6)(iv) all nonmonograph bronchodilator 
ingredients. New Sec. 310.545(a)(6)(iv)(A) includes the following 
ingredients: Aminophylline, belladonna alkaloids, euphorbia pilulifera, 
metaproterenol sulfate, methoxyphenamine hydrochloride, pseudoephedrine 
hydrochloride, pseudoephedrine sulfate, and theophylline preparations 
(theophylline, anhydrous; theophylline calcium salicylate; theophylline 
sodium glycinate). New Sec. 310.545(a)(6)(iv)(B) includes any 
combination drug product containing theophylline (e.g., theophylline 
and ephedrine, or theophylline and ephedrine and phenobarbital). The 
agency is also amending Sec. 310.545(d) to add new paragraphs (d)(19) 
and (d)(20) to list the effective dates for the ingredients in new 
Sec. 310.545(a)(6)(iv)(A) and (a)(6)(iv)(B), respectively.

List of Subjects in 21 CFR Part 310

    Administrative practice and procedure, Drugs, Labeling, Medical 
devices, Reporting and recordkeeping requirements.
    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, 21 CFR part 
310 is amended as follows:

[[Page 38642]]


PART 310--NEW DRUGS

    1. The authority citation for 21 CFR part 310 continues to read as 
follows:

    Authority: Secs. 201, 301, 501, 502, 503, 505, 506, 507, 512-
516, 520, 601(a), 701, 704, 705, 721 of the Federal Food, Drug, and 
Cosmetic Act (21 U.S.C. 321, 331, 351, 352, 353, 355, 356, 357, 
360b-360f, 360j, 361(a), 371, 374, 375, 379e); secs. 215, 301, 
302(a), 351, 354-360F of the Public Health Service Act (42 U.S.C. 
216, 241, 242(a), 262, 263b-263n).

    2. Section 310.545 is amended by adding new paragraphs (a)(6)(iv), 
(d)(19), and (d)(20) to read as follows:


Sec. 310.545  Drug products containing certain active ingredients 
offered over-the-counter (OTC) for certain uses.

    (a) * * *
    (6) * * *
    (iv) Bronchodilator drug products--(A) Approved as of October 2, 
1987.

Aminophylline
Belladonna alkaloids
Euphorbia pilulifera
Metaproterenol sulfate
Methoxyphenamine hydrochloride
Pseudoephedrine hydrochloride
Pseudoephedrine sulfate
Theophylline, anhydrous
Theophylline calcium salicylate
Theophylline sodium glycinate

    (B) Approved as of January 29, 1996. Any combination drug product 
containing theophylline (e.g., theophylline and ephedrine, or 
theophylline and ephedrine and phenobarbital).
* * * * *
    (d) * * *
    (19) October 2, 1987, for products subject to paragraph 
(a)(6)(iv)(A) of this section.
    (20) January 29, 1996, for products subject to paragraph 
(a)(6)(iv)(B) of this section.
* * * * *
    Dated: July 5, 1995.
William K. Hubbard,
Acting Deputy Commissioner for Policy.
[FR Doc. 95-18449 Filed 7-26-95; 8:45 am]
BILLING CODE 4160-01-P