Source: https://www.federalregister.gov/documents/2011/07/26/2011-18347/labeling-for-bronchodilators-to-treat-asthma-cold-cough-allergy-bronchodilator-and-antiasthmatic
Timestamp: 2017-10-22 15:48:40
Document Index: 673179036

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Federal Register :: Labeling for Bronchodilators To Treat Asthma; Cold, Cough, Allergy, Bronchodilator, and Antiasthmatic Drug Products for Over-the-Counter Human Use
44475-44489 (15 pages)
Docket No. FDA-1995-N-0031 (Formerly Docket No. 1995N-0205)
I. Changes to the Labeling of OTC Drug Products Used To Treat Asthma
Appendix B. Values and Sources Used for Estimated Benefits Calculations
https://www.federalregister.gov/d/2011-18347 https://www.federalregister.gov/d/2011-18347
The Food and Drug Administration (FDA) is amending the final monograph (FM) for over-the-counter (OTC) bronchodilator drug products to add additional warnings (e.g., an “Asthma alert”) and to revise the indications, warnings, and directions in the labeling of products containing the ingredients ephedrine, ephedrine hydrochloride, ephedrine sulfate, epinephrine, epinephrine bitartrate, racephedrine hydrochloride, and racepinephrine hydrochloride. FDA is issuing this final rule after considering data and information submitted in response to the Agency's proposed labeling revisions for these products. This final rule is part of FDA's ongoing review of OTC drug products.
Effective Date: This regulation is effective January 23, 2012.
Elaine Abraham, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 22, Rm. 5410, Silver Spring, MD 20993, 301-796-2090.
This rulemaking amends the FM for OTC bronchodilator drug products used to treat asthma. The “Indications,” “Warnings” and “Directions” portions of the Drug Facts label are being changed to help consumers better understand how to use these products and when it is appropriate to seek treatment from a doctor for their asthma. The “Indications” section now recommends use only for temporary relief of mild symptoms of intermittent asthma. Changes to both the “Warnings” and “Directions” sections emphasize that consumers should not exceed the recommended dose or duration of use with these drug products. The “Warnings” section is being changed to make it clearer that consumers whose symptoms worsen or do not improve should see a doctor. The “Indications,” “Warnings” and “Directions” portions of the Drug Facts label have also been revised to use language that is more readily understood by the average consumer.
In the Federal Register of September 9, 1976 (41 FR 38312), FDA published an advance notice of proposed rulemaking (ANPR) under 21 CFR 330.10(a)(6) to establish a monograph for OTC cold, cough, allergy, bronchodilator, and antiasthmatic drug products. The ANPR included the recommendations of the Advisory Review Panel on OTC Cold, Cough, Allergy, Bronchodilator, and Antiasthmatic Drug Products (the Panel), the advisory review panel responsible for evaluating data on the active ingredients in this drug class. The Panel recommended that ephedrine and epinephrine preparations be placed in Category I (generally recognized as safe and effective or GRASE) for OTC bronchodilator use (41 FR 38312 at 38370 through 38372).
FDA concurred with the Panel's recommendations and subsequently published the proposed rule in the Federal Register of October 26, 1982, (47 FR 47520) and the FM for OTC bronchodilator drug products in the Federal Register of October 2, 1986, (51 FR 35326). FDA included the following active ingredients in the FM:
“Ephedrine ingredients” (i.e., ephedrine, ephedrine hydrochloride, ephedrine sulfate, and racephedrine hydrochloride)
“Epinephrine ingredients” (i.e., epinephrine, epinephrine bitartrate, and racepinephrine hydrochloride)
In subsequent rulemaking documents for this category, including this final rule, the term “ephedrine ingredients” refers to the four active ephedrine ingredients, the term “epinephrine ingredients” refers to the three active epinephrine ingredients, and the term “OTC bronchodilator drug products” Start Printed Page 44476refers to products containing any of these seven active ingredients.
In the Federal Register of July 27, 1995, (60 FR 38643), FDA published a proposed rule to amend the FM to remove ephedrine ingredients and to classify them as not GRASE for OTC use. At that time, FDA had reassessed the risks and the benefits of OTC ephedrine drug products based on additional safety data and proposed their removal because of safety concerns. After reviewing the comments received in response to this proposed rule, FDA concluded that ephedrine ingredients should remain in the FM for self-treatment of mild bronchial asthma, and FDA withdrew its proposal to remove ephedrine ingredients from the OTC drug monograph in the Federal Register of July 13, 2005, (70 FR 40237).
Also, in the Federal Register of July 13, 2005, (70 FR 40237), FDA proposed to amend the FM for OTC bronchodilator drug products with revised labeling for products containing ephedrine and epinephrine ingredients. FDA proposed changes to the Indications, Warnings, and Directions sections of the labeling in 21 CFR 341.76. FDA stated that it considered the labeling revisions to be important for the safe and effective use of OTC bronchodilator drug products by providing better instructions to asthmatics about how to use the product correctly and to minimize risks. The proposed changes were:
1. Indications: Revise the indications in § 341.76(b)(1) and (b)(2) to a single indication using the OTC “Drug Facts” labeling format in § 201.66 (21 CFR 201.66). The labeling recommends use only for the “temporary relief of occasional symptoms of mild asthma.”
2. Warnings: Revise the entire warnings section into “Drug Facts” labeling as follows:
Add an “Asthma alert” section. This proposed section lists specific criteria consumers can use to identify when to seek treatment from a doctor for their asthma (e.g., failure of the product to improve symptoms, need for excessive dosing). The “Asthma alert” should appear as the first statement under the heading “Warnings” and certain parts of the “Asthma Alert” should be in bold type. This new warning replaces the warning previously found in § 341.76(c)(5)(i) for ephedrine ingredients and in § 341.76(c)(6)(ii) for epinephrine ingredients.
Advise consumers to consult a doctor before using the OTC bronchodilator drug product with other specified drugs. This information appears under the subheading “Ask a doctor or pharmacist before use if you are.” The list of other specified drugs includes prescription drugs for asthma previously stated in § 341.76(c)(3) as well as a new list of other drugs that could cause side effects when used concurrently with ephedrine or epinephrine ingredients.
List information that consumers need to know under the heading “When using this product.” This information includes the following:
a. Direct consumers' attention to information about the risks associated with increased blood pressure or heart rate by requiring that this information appear in bold type as the first bulleted statement.
b. Side effects that may occur (including side effects currently listed in § 341.76(c)(5)(ii)).
c. Information about risks associated with taking the drug more often than recommended or at higher-than-recommended doses. This information is currently in § 341.76(c)(6)(i) for products containing epinephrine ingredients. FDA proposed to include the information for all products containing either ephedrine or epinephrine ingredients.
3. Directions: Revise the directions in § 341.76(d)(1) and (d)(2) to include the statement “do not exceed dosage” [in bold type] as the first bulleted statement under the heading “Directions.”
In response to the amendment to the FM proposed in the Federal Register of July 13, 2005, FDA received comments from two consumers, one manufacturer of OTC bronchodilator drug products, and three national associations. One consumer comment discussed dextromethorphan. This comment is not addressed further in this final rule because this ingredient is a cough suppressant rather than a bronchodilator.
FDA does not plan to remove bronchodilator products from the OTC marketplace. FDA has found that the standards for safety, effectiveness, and labeling for OTC bronchodilator drug products have been met. Safety means a low incidence of adverse reactions or significant side effects under adequate directions for use and warnings against unsafe use as well as low potential for harm which may result from abuse under conditions of widespread availability (21 CFR 330.10(a)(4)(i)). Effectiveness means a reasonable expectation that, in a significant proportion of the target population, the pharmacological effect of the drug, when used under adequate directions for use and warnings against unsafe use, will provide clinically significant relief of the type claimed (21 CFR 330.10(a)(4)(ii)). OTC drug product labeling must be clear and truthful and must state the intended uses and results of the product; adequate directions for proper use; and warnings against unsafe use, side effects, and adverse reactions in such terms as to render them likely to be read and understood by the ordinary individual, including individuals of low comprehension, under customary conditions of purchase and use (21 CFR 330.10(a)(4)(v)). FDA has a reasonable expectation that these drugs provide a clinically meaningful Start Printed Page 44477benefit in the treatment of mild symptoms of intermittent asthma when they are used according to labeled instructions for the temporary relief of wheezing, tightness of chest, and shortness of breath.
In this final rule, FDA has revised the indication to provide the consumer with a better understanding of the use of these drug products. In the July 13, 2005, proposed rule (70 FR 40237), FDA proposed changes to the “Indications” section of the labeling in § 341.76(b) (21 CFR 341.76(b)). The indication proposed in that proposed rule was for the “temporary relief of occasional symptoms of mild asthma: wheezing, tightness of chest, shortness of breath” (70 FR 40237 at 40248). This indication was based on the National Asthma Education and Prevention Program (NAEPP) Guidelines of 2002, which defined mild intermittent asthma as having symptoms no more than twice a week during the day or twice a month at night. FDA determined that people with mild intermittent asthma were the only category of asthmatics who should be candidates for OTC bronchodilators and stated that asthmatics with more severe asthma disease (i.e., persistent asthma) should be under the care of a physician for consideration of additional therapy to control the disease (70 FR 40237 at 40240).
When using this product * * * increased blood pressure or heart rate can occur, which could lead to more serious problems such as heart attack, stroke, and death. Your risk can increase if you take more frequently or more than the recommended dose.
When using this product * * * increased blood pressure or heart rate may occur, which could increase your risk of more serious problems, especially if you have risk factors such as a history of high blood pressure or heart disease. Your risk may increase if you take more frequently or more than the recommended dose.
Based on these cases, we disagree with the comment that the risk of adverse reactions is limited mostly to people with risk factors such as a history of high blood pressure or heart disease. As stated in the July 13, 2005, proposed rule (70 FR 40237 at 40243), the risk of adverse events from ephedrine can occur at any dosage, even in healthy individuals who did not take excessive amounts. However, we agree with the comment that those individuals with certain risk factors are at a greater risk. As discussed in the proposed rule, cardiovascular side effects from OTC bronchodilator drug products can include an increase in blood pressure and heart rate, which could lead to more serious problems such as heart attack, stroke, and death (70 FR 40237 at 40242 to 40243). The intent of this warning is to alert all potential users of these products that there are serious risks, even potential death, associated with the use of OTC bronchodilator drug products and that these risks may increase if they take the product more frequently or take more than the recommended dose. We are revising the warning to better convey risk information in clear language to people who have a history of high blood pressure or heart disease. See the language set out in § 341.76(c)(4) in this rule.
(Comment 4) One comment noted FDA's statement in the 2005 proposed rule that, based on differences in composition between OTC ephedrine drug products and dietary supplements containing botanical sources of ephedrine alkaloids, “adverse event data for dietary supplements containing ephedrine alkaloids may not be completely applicable to ephedrine drug products” (70 FR 40237 at 40241) (Ref. 4). Emphasizing that FDA's 2004 final rule declaring dietary supplements containing ephedrine alkaloids Start Printed Page 44478adulterated (69 FR 6788) was specific to dietary supplements, the comment expressed concern that the labeling for OTC bronchodilator drug products was being revised based on data from botanically derived ephedrine alkaloids in dietary supplements, which are different from the ephedrine or epinephrine ingredients in OTC bronchodilator drugs. For example, the active ingredients in OTC bronchodilator drugs must meet United States Pharmacopeia standards of identity, strength, quality, and purity, but dietary supplements contain varying amounts and proportions of ephedrine and other ephedrine alkaloids (such as norephedrine, pseudoephedrine, and methylephedrine), depending on the plant species used (70 FR 40237 at 40241).
(Comment 6) A comment questioned the meaning of the term “temporary” in the “Indication” statement in § 341.76(b)(1) of the 1995 OTC bronchodilator FM, “for temporary relief of shortness of breath, tightness of chest, and wheezing due to bronchial asthma” (Ref. 5). The comment asked what the time period associated with “temporary” was intended to be and whether these drugs provide temporary relief for all levels of asthma severity.
(Comment 7) One comment addressed the additional “Indications” in § 341.76(b)(1)(i) and (b)(ii) of the OTC bronchodilator FM, “for the temporary relief of bronchial asthma” and “eases breathing for asthma patients by reducing spasms of bronchial muscles” (Ref. 5). The comment stated that this language does not differentiate OTC bronchodilators from other bronchodilators that “do the job better.” It was the comment's view that patients may assume that the OTC drug product works the same as prescription products.
FDA's labeling for OTC bronchodilator drug products is intended to help consumers use products safely and effectively in the OTC setting. It is not intended to compare OTC bronchodilators to prescription products. Although OTC labeling is generally not intended to compare or differentiate among various available products, the revised “Asthma alert” warning for oral ephedrine does advise the consumer that bronchodilators that have a different route of administration may be advantageous, i.e., inhaled products provide faster asthma relief than oral products (see Comment 10). The indications to which the comment objected in the FM were revised in the proposed rule to amend the FM (70 FR 40237 at 40242). FDA is finalizing the indication in § 341.76(b) to a single statement as follows: “for temporary relief of mild symptoms of intermittent asthma: [bullet] wheezing [bullet] tightness of chest [bullet] shortness of breath.” Therefore, the revised indication and “Asthma alert” should help consumers to better understand how to use these products.
(Comment 8) A comment addressed the “Warning” in § 341.76(c)(1) of the OTC bronchodilator FM, “do not use this product unless a diagnosis of asthma has been made by a doctor” (Ref. 5). The comment stated that this warning implies that a diagnosis makes the patient an expert at self-prescribing asthma treatments, but that such a diagnosis offers no information of value to the consumer when using an OTC bronchodilator drug product.
(Comment 9) A comment addressed the “Warning” in § 341.76(c)(3) of the OTC bronchodilator FM, “Do not use this product if you have ever been hospitalized for asthma or if you are taking any prescription drug for asthma unless directed by a doctor” (Ref. 5). The comment stated that a potential user does not know how hospitalization or prescription drug use will change the effectiveness of an OTC bronchodilator drug product.
FDA designed this warning to address safety concerns; a prior hospitalization or prescription drug use will not change the effectiveness of an OTC bronchodilator drug product. In addition, FDA revised the warnings from the 1995 FM for OTC bronchodilator drug products in the 2005 proposed rule (70 FR 40237 at 40248). The purpose of the warnings is to clearly convey to potential users of OTC bronchodilators that they should seek the advice of a doctor before using any bronchodilator products. The revised two part warning advises Start Printed Page 44479consumers not to use the OTC bronchodilator drug product unless directed by a doctor. Asthmatics who have previously needed hospital care, or are taking a prescription drug to treat asthma, need to consult a doctor before using an OTC bronchodilator.
The warnings in this final rule have been broadened and revised. See the language set out in § 341.76(c)(2) and § 341.76(c)(3) in this rule.
(Comment 10) The same comment also addressed the “Warning” in § 341.76(c)(5)(i) of the OTC bronchodilator FM for ephedrine products, “do not continue to use this product, but seek medical assistance immediately if symptoms are not relieved within 1 hour or become worse” (Ref. 5). The comment stated that if consumers' symptoms do not improve or become worse at any time during treatment, the labeling should advise them to seek immediate medical attention.
FDA's new “Asthma alert” for ephedrine-containing products is set out in § 341.76(c)(5) in this rule.
Similar changes were made to the “Asthma alert” for epinephrine-containing products which is revised to read as set out in § 341.76(c)(6) in this rule.
The “Asthma alert” is the type of warning identified in 21 CFR 201.66(c)(5)(ii) [the Drug Facts rule] that has an appropriate subheading that is highlighted in bold type. FDA is amending § 201.66(c)(5)(ii)(B) to cross-reference this new warning.
(Comment 11) One comment addressed the “Warning” in § 341.76(c)(6)(ii) of the OTC bronchodilator FM for epinephrine products, “do not continue to use this product, but seek medical assistance immediately if symptoms are not relieved within 20 minutes or become worse” (Ref. 5). The comment noted that while inhaled epinephrine works quickly, the duration of symptom relief is very short. The comment stated that patients are told not to use the drug more frequently than instructed, but not given a reason to comply with the instruction. The comment stated that labeling should explain that an increasing need for medication is a sign of airway swelling that must be treated by a physician. The labeling should tell users that the bronchodilator effect wears off before the next dose may be taken safely and to seek immediate treatment if symptoms are not completely relieved or if they worsen. The labeling should also warn against using inhaled epinephrine in place of, or in addition to, prescription bronchodilators.
In this rule, FDA is requiring new labeling that addresses the concerns expressed in the comment. Consumers are told not to use the drug more frequently than instructed because of an increased risk of serious adverse events. Specifically, the new required labeling will read as set out in § 341.76(c)(4) in this rule.
The labeling also warns to ask a doctor or pharmacist before using any OTC bronchodilator if taking prescription drugs for asthma. In addition, FDA's new labeling addresses the comment's concern that an increasing need for medication is a sign of airway swelling that must be treated by a physician. As discussed in comment 10, FDA's new “Asthma alert” for epinephrine-containing products will read as set out in § 341.76(c)(6) in this rule.
FDA believes that the revised Asthma alert as well as the revised warning on the potential for serious adverse events if bronchodilators are not used according to labeled instructions respond to the comment's concern regarding adequate warnings for epinephrine.
To make the bronchodilator labeling more consumer friendly and to reach a range of consumers' literacy skills, FDA has made changes to the labeling that do not affect content but make the labeling more understandable to people of all literacy levels. FDA is making these changes so as not to affect the content of the labeling as proposed in the 2005 proposed rule, but to make the labeling clear to ordinary individuals including individuals of low comprehension as stated in § 330.10(a)(4)(v). These changes are as follows:
As described in comment 10, two bulleted statements in the “Asthma alert” section were revised. These follow the statement, “Because asthma may be life threatening, see a doctor if you.” For ephedrine, the statement “[Bullet] need [insert total number of dosage units that equals 150 milligrams] in any day” was changed to “[Bullet] need more than [insert total number of dosage units that equals 150 milligrams] in 24 hours” to clarify the timeframe indicated by a “day.” Also, the statement “[Bullet] use more than [insert total number of dosage units that equals 100 milligrams] a day for more than 3 days a week” has been changed to “[Bullet] use more than [insert total number of dosage units that equals 100 milligrams] in 24 hours for 3 or more days a week.” A similar change was Start Printed Page 44480made to the epinephrine “Asthma alert.”
The phrase, “avoid caffeine-containing foods and beverages” under the heading “When using this product” has been changed to “avoid foods or beverages that contain caffeine.”
FDA has added a “Stop use and ask a doctor if” section by moving warning statements proposed in 2005 under, “when using this product” to this new section. The section will read as set out in § 341.76(c)(7) in this rule.
The statement “your asthma is getting worse (see Asthma alert)” is taken from the “Asthma alert” warning and has been moved to this new section to clarify what the consumer should do if the product is not providing the necessary relief for them. The other three bulleted statements were previously in the labeling section under the heading “When using this product.” Moving these statements under this heading does not affect content and may clarify for consumers how they should handle any of these side effects by emphasizing that they should see a doctor.
Under “Directions” for ephedrine and epinephrine, the first bulleted statement, “do not exceed dosage” has been changed to “do not take more than directed” or “do not use more than directed,” respectively.
The second bulleted statement under Directions for epinephrine states the dose as 1 to 3 inhalations not more often than every 3 hours. This has been revised by adding, “do not use more than 12 inhalations in 24 hours” to be consistent with information provided in the “Asthma alert.” The bulleted statement now reads as follows: “[Bullet] adults and children 4 years of age and over: 1 to 3 inhalations not more often than every 3 hours. Do not use more than 12 inhalations in 24 hours. The use of this product by children should be supervised by an adult.”
FDA has determined in order to provide for safe and effective use of OTC bronchodilator drug products at the earliest possible time because of the safety issues involved with the use of these products that this final rule be implemented within 180 days after its publication. Therefore, on or after 180 days after the date of publication of this final rule in the Federal Register, any OTC bronchodilator drug product that is subject to the final rule and that contains nonmonograph labeling or packaging may not be initially introduced or initially delivered for introduction into interstate commerce unless it is the subject of an approved application. Any OTC bronchodilator drug product that is initially introduced or initially delivered for introduction into interstate commerce after the effective date of this final rule, and is not in compliance with the regulations, is subject to regulatory action. Further, any OTC drug product that was previously initially introduced or initially delivered for introduction into interstate commerce may not be repackaged or relabeled with the prior monograph labeling for these products after the effective date of this final rule. Manufacturers are encouraged to comply voluntarily as soon as possible.
Mandating warnings in an OTC drug monograph does not require a finding that any or all of the OTC drug products covered by the regulation actually caused an adverse event, and FDA does not so find. Nor does FDA's requirement of warnings repudiate the prior OTC drug monographs and regulations under which the affected drug products have been lawfully marketed. Rather, as a consumer protection agency, FDA has determined that warnings are necessary to ensure that these OTC drug products continue to be safe and effective for their labeled indications under ordinary conditions of use as those terms are defined in the Federal Food, Drug, and Cosmetic Act. This judgment balances the benefits of these drug products against their potential risks (see 21 CFR 330.10(a)).
FDA's decision to act in this instance need not meet the standard of proof required to prevail in a private tort action (Glastetter v. Novartis Pharmaceuticals, Corp., 252 F.3d 986, 991 (8th Cir. 2001)). To mandate warnings, or take similar regulatory action, FDA need not show, nor do we allege, actual causation. For an expanded discussion of case law supporting FDA's authority to require such warnings, see the December 6, 2002, (67 FR 72555), final rule entitled “Labeling of Diphenhydramine-Containing Drug Products for Over-the-Counter Human Use.”
FDA has examined the impacts of the final rule under Executive Order 12866, Executive Order 13563, the Regulatory Flexibility Act (5 U.S.C. 601-612), and the Unfunded Mandates Reform Act of 1995 (Pub. L. 104-4). Executive Orders 12866 and 13563 direct 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 not a significant regulatory action as defined by the Executive order.
Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires that agencies prepare a written statement, which includes an assessment of anticipated costs and benefits, before proposing “any rule that includes any Federal mandate that may result in the expenditure by State, local, and Tribal governments, in the aggregate, or by the private sector, of $100,000,000 or more (adjusted annually for inflation) in any one year.” The current threshold after adjustment for inflation is $136 million, using the most current (2010) Implicit Price Deflator for the Gross Domestic Product. FDA does not expect this final rule to result in any 1-year expenditure that would meet or exceed this amount.Start Printed Page 44481
The purpose of this final rule is to revise the labeling of the “Indications,” “Warnings,” and “Directions” sections for over-the-counter (OTC) single-ingredient ephedrine and epinephrine bronchodilators. The required revised labeling would indicate the condition (mild symptoms of intermittent asthma) for which the product is intended and would warn consumers about when to seek medical assistance. The final rule would also use language that is more readily understood by the average consumer. The revised labeling may lead consumers to seek medical care and to improved asthma management. Thus, the estimated benefits of the final rule may come from reduced medical costs associated with adverse events arising from the misuse or abuse of the product. The estimated annual benefits range from $14.0 million to $69.3 million. One-time labeling costs from personnel, reallocation time, materials, and inventory disposal range from $0.7 million to $4.1 million. In addition, costs may arise from increased physician and medication expenses paid by consumers who may switch to managed care. The estimated annual costs from additional medical care range from $1.3 million to $2.5 million. Annualized over 20 years, the estimated total costs range from $1.3 million to $2.8 million with a 3-percent discount rate, and from $1.3 million to $2.9 million with a 7-percent discount rate. Annualized over 20 years, the estimated net benefits (estimated benefits minus estimated costs) from the regulation range from $11.2 million to $68.0 million with a 3-percent discount rate and from $11.1 million to $68.0 million with a 7-percent discount rate.
The Centers for Disease Control and Prevention (CDC) reported that in 2009, 7.7 percent (or 17.5 million) of non-institutionalized adults and 9.6 percent (7.1 million) of children suffer from asthma in the United States. Within population subgroups, asthma prevalence is higher among females, children of non-Hispanic Black and Puerto Rican race or ethnicity, and persons with family income below the poverty level (Ref. 7). In 2006, asthma was listed as one of the top five most costly conditions in the United States (Ref. 8). Asthma leads to direct health care costs and indirect costs such as mortality and lost productivity that pose a high burden on society. For example, in 2007, there were 1.75 million asthma-related emergency department visits and 456,000 asthma hospitalizations (Ref. 7), and in 2009, there were 3,447 persons who died of asthma (Ref. 9).
Executive Order 12866 directs agencies to assess the need for any regulatory action and to provide an explanation of how the regulation will meet that need. FDA is responsible for protecting the public health and for helping the public get the accurate, science-based information they need to use medicines to maintain and improve their health. FDA concludes that current labeling of single ingredient ephedrine and epinephrine products available over-the-counter provide inadequate information. The revised labeling would provide consumers access to information that may enable them to better assess the risk of taking OTC bronchodilators and to possibly improve the management of asthma.
The estimated benefits of the final rule would derive from a reduction in the number of adverse events, namely hospitalizations, emergency department (ED) visits, physician visits, and mortality, associated with self-medication or mismanagement of asthma medication that may be prevented with revised information or with the help of professional guidance.
FDA estimates the number of preventable events based on the range of individuals with asthma that use OTC bronchodilators as monotherapy, which is between 5 percent (Low) and 10 percent (High) (Ref. 10). Table 1 of this document presents the number of preventable events by category. The analysis assumes that the percent of ambulatory or ED visits related to medication adverse effects approximates the percent of events that may be preventable due to mismanagement or misuse of the medication, and that adults and children face the same incidence rates or likelihood of experiencing each of these events. (See Appendix A for a description on how these are estimated.)Start Printed Page 44482
Description a
Ambulatory Visits 0.8 hr 282 564
Emergency Department (ED) Visits 3.0 hrs 67 134
Inpatient 3.4 days 4 7
Emergency Department (ED).b 4.0 days 13 27
Statistical Lives Saved 2 9
Notes:a See Appendix A for calculations.
b ED hospital length of stay includes 4.93 hours of estimated ED wait time. Sources: Refs. 10-12, 15, 18-25.
Estimated benefit a
Ambulatory Visits $155/visit 282 564 43.71 87.43
Emergency Department (ED) Visits $569/visit 67 134 38.04 76.09
Inpatient 3.4 days $1,400/day 4 7 21.04 42.08
ED 4.0 days $1,400/day 13 27 75.19 150.38
Loss of Work Time:
Ambulatory Visits 0.8 hr $20.73/hrb 282 564 4.58 9.16
ED Visits 3.0 hrs $20.73/hrb 67 134 3.19 6.38
Inpatient 27.2 hrsc $20.73/hrb 4 7 2.11 4.22
ED 32.1 hrsc $20.73/hrb 13 27 8.91 17.82
Statistical Lives Saved $7.9 Mil/life 2 9 $13,788 $68,941
Total Estimated Benefits $13,985 $69,334
Notes:a Statistical Lives Saved are valued in millions of dollars.
b Median hourly wage of $15.95 plus benefits.
c Time estimates for loss of work related to hospital stays assume 8-hour work days.
The estimated costs come from labeling costs and additional costs borne by those consumers who switch to prescription medication or other OTC products within the same therapeutic class.
Based on Universal Product Code (UPC) counts of the number of OTC products listed in the Red Book and where ephedrine or epinephrine is the single-active ingredient, the number of OTC bronchodilators has decreased from 19 UPCs in 2000 to 13 in 2010. While inhalers are the most prevalent form, OTC bronchodilators are also available in capsules and tablets. FDA estimates that approximately seven manufacturers and distributors market five different brands that are sold in 13 product-form variations or UPCs (see table 3 of this document).
No. of Brands a 5 5 5
Form: Aerosol 3 3 3
Form: Capsule 1 1 1
Form: Tablet 1 1 1
No. of UPCs 19 15 13
Form: Aerosol 11 8 7
Form: Capsule 5 4 4
Form: Tablet 3 3 2
No. of Manufacturers and Distributors a 8 6 7
Note:a A brand, manufacturer or distributor is counted only once.
Source: Calculations based on the Red Book, Refs. 31-33.
Midpoint ($000)
Labor 206 729 1,354
Materials 45 112 230
Inventory 486 1,015 2,481
Recordkeeping 9 18 22
Total Labeling Cost 746 1,873 4,087
Since the revised labeling requirement advises consumers that moderate and severe cases of asthma and all cases of persistent asthma should be under the supervision of a physician and that inhalers provide faster relief, this may have two possible effects on users of OTC ephedrine products with mild-to-severe asthma. Some individuals may respond to this new advice and seek medical help that gets them under a managed care plan. While some of these individuals may seek a physician and switch to prescription medicine as a result, others may substitute other OTC products within the same therapeutic class. FDA does not estimate the number of switchers within the same class and assumes that all switchers will seek a physician and switch to prescription medicine. This estimate may be considered an upper bound of the costs as nonprescription medicine is, on average, lower than prescription medicine.
The additional annual estimated costs of switching to prescription care is calculated using the difference in total medical expenditures of current asthma users without preventive prescription care ($4,721, Ref. 36) and with preventive prescription care ($7,586, Ref. 36), and the estimated number of switchers. The total estimated cost of switching is calculated by multiplying the additional estimated cost from switching to preventive prescription care ($2,865) times the estimated number of individuals switching to preventive care. The total estimated cost from switching ranges from $1,278,000 to $2,555,000.
The estimated total costs include one-time labeling costs plus annual switching costs. Annualized over 20 Start Printed Page 44484years, total estimated costs range from $1.3 million to $2.8 million with a 3-percent discount rate and from $1.3 million to $2.9 million with a 7-percent discount rate (see table 5 of this document).
Switching Cost 1,278.00 2,555.00
Labeling Cost 745.57 4,086.83
3 Percent 1,326.65 2,821.70
7 Percent 1,343.77 2,915.53
The net benefits are determined based on the various combinations (Low and High) of costs and benefits and annualizing over 20 years assuming a 3 and 7 percent discount rate, separately. Annualized over 20 years, the minimum and maximum estimated net benefits range from $11.2 million to $68.0 million with a 3 percent discount rate, and from $11.1 million to $68.0 million with a 7 percent discount rate (see table 6 of this document).
Annualized at 3% over 20 years
$13,985 $1,327 $2,822 $12,658 $11,163
69,334 1,327 2,822 68,008 58,171
Annualized at 7% over 20 years
13,985 1,344 2,916 12,641 11,069
69,334 1,344 2,916 67,991 58,265
Notes: Estimates are in $000s. Net Benefits are benefits minus costs.
Several factors such as growing asthma prevalence and educational programs geared to improving asthma management and care may impact the market for OTC epinephrine and ephedrine bronchodilators. Current asthma treatment and management guidelines (Ref. 3) do not recommend OTC ephedrine and epinephrine as the standard of care and this may impact the demand for epinephrine and ephedrine bronchodilators and their substitutes, e.g., other OTC bronchodilators or prescription medication within the same therapeutic class. Moreover, the expected withdrawal of chlorofluorocarbon (CFC) inhalers may affect the sale of OTC epinephrine and ephedrine bronchodilators. FDA is uncertain on the impact of these effects on the overall market for OTC bronchodilators in the coming years, but at best, the benefits from preventable adverse events or improved asthma management due to the revised labeling may offset the additional cost of switching to prescription medication and managed care.
The final rule seeks to change the labeling to make it more understandable to the average reader and to warn users when to seek medical assistance. Changes would also include information that alternative medication may provide faster relief. The final rule establishes an implementation period of 180 days from publication.
The following alternatives were identified: (1) Extend the compliance period, and (2) require more labeling. The compliance periods were 12 and 18 months. Another alternative would be to require additional labeling changes that would be considered “Major.” This type of labeling change would involve multiple color changes that would require a label redesign such as substantial changes or elimination of a claim, caution statement or disclaimer. Table 7 of this document presents the relabeling costs associated with these alternatives. Extending the implementation period would lower the costs under both minor and major labeling changes. Extending the period, however, would also postpone the period in which benefits may be observed.Start Printed Page 44485
Compliance period (months)
6 746 1,873 4,087 1,200 2,813 5,851
12 429 1,063 1,840 870 1,974 3,550
18 244 656 1,164 540 1,267 2,308
FDA has examined the economic implications of the final rule as required by the Regulatory Flexibility Act. If a rule will have a significant economic impact on a substantial number of small entities, the Regulatory Flexibility Act requires agencies to analyze regulatory options that would lessen the economic effect of the rule on small entities. This analysis serves as the Initial Regulatory Flexibility Analysis as required under the Regulatory Flexibility Act.
The Small Business Administration (SBA) uses different definitions of what a small entity is for different industries. Using 2009 SBA size standard definitions, a firm categorized in NAICS code 315412 (Pharmaceutical Preparations) is considered small if it employs fewer than 750 persons (Ref. 37). Using the most currently available data on the number of establishments by employee size from the 2007 Economic Census (Ref. 38) shows that the majority of the establishments have employee sizes by which they would be considered small (see table 7). Using data at the establishment level implicitly assumes that the typical manufacturing establishment is roughly equivalent to the typical small manufacturing firm.
FDA uses data on the total value of shipments by employment size from the 2007 Economic Census (Ref. 38) to determine the unit labeling cost as a percent of the total value of shipments for a typical manufacturer. The average value of shipments is presented for all establishments in NAICS code 325412 and for establishments employing 1-10, 11-499 and over 500 employees, separately. The average value of shipments for entities that employ up to 10 workers is $1,433,000 while for entities with more than 500 employees it is over $1,160 million. It is estimated that the average one-time labeling cost per UPC as a percent of average value of shipments for small entities may be between 0 and 22 percent (see table 8 of this document). The Agency tentatively concludes that this rule would have a significant impact on a substantial number of small entities, but the impact is uncertain.
Establishments (NAICS 325412)
Value of shipments ($000)
Percent cost per UPC of average value of shipment
0-10 408 41 $584,656 1,433 4.00 10.05 21.94
11-499 508 51 55,256,380 108,772 0.05 0.13 0.29
500+ 75 8 87,035,221 1,160,470 0.00 0.01 0.03
Source: Pharmaceutical Preparations (NAICS 325412), 2007 Economic Census (Ref. 38).
In this section, we discuss alternatives that would present reductions in costs which would be channeled through small entities.
Average Value of shipments ($000)
Percent cost of average value of shipment
6 0-10 $1,433 4.0 10.1 21.9
12 0-10 1,433 2.3 5.7 9.9
18 0-10 1,433 1.3 3.5 6.2
FDA has analyzed this final rule in accordance with the principles set forth in Executive Order 13132. Section 4(a) of the Executive order requires agencies to “construe * * * a Federal statute to preempt State law only where the statute contains an express preemption provision or there is some other clear evidence that the Congress intended preemption of State law, or where the exercise of State authority conflicts with the exercise of Federal authority under the Federal statute.” The sole statutory provision giving preemptive effect to the final rule is section 751 of the act (21 U.S.C. 379r). We believe that we have complied with all of the applicable requirements under the Executive order and have determined that the preemptive effects of this rule are consistent with Executive Order 13132.
The following references are on display in the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852, under Docket No. FDA-1995-N-0031 (formerly Docket No. 1995N-0205), and may be seen by interested persons between 9 a.m. and 4 p.m., Monday through Friday. (FDA has verified the Web site addresses, but FDA is not responsible for any subsequent changes to the Web sites after this document publishes in the Federal Register.)
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(B) Allergic reaction and asthma alert warnings. Allergic reaction warnings set forth in any applicable OTC drug monograph or approved drug application for any product that requires a separate allergy warning. This warning shall follow the subheading “Allergy alert:” The asthma alert warning set forth in §§ 341.76(c)(5) and 341.76(c)(6) of this chapter. This warning shall follow the subheading “Asthma alert:”
(b) Indication. The labeling of the product states the following under the heading “Use”: “for temporary relief of mild symptoms of intermittent asthma: [bullet] [1] wheezing [bullet] tightness of chest [bullet] shortness of breath”. Other truthful and nonmisleading statements, describing only the indication for use that has been established and listed in this paragraph (b) may also be used, as provided in § 330.1(c)(2) of this chapter, subject to the provisions of section 502 of the Federal Food, Drug, and Cosmetic Act relating to misbranding and the prohibition in section 301(d) of the Federal Food, Drug, and Cosmetic Act against the introduction or delivery for introduction into interstate commerce of unapproved new drugs in violation of section 505(a) of the Federal Food, Drug, and Cosmetic Act.
(iii) “[Bullet] avoid foods or beverages that contain caffeine”.Start Printed Page 44488
(5) For products containing ephedrine, ephedrine hydrochloride, ephedrine sulfate, or racephedrine hydrochloride identified in § 341.16(a), (b), (c), and (f).—(i) The following information shall appear after the subheading “Asthma alert: Because asthma may be life threatening, see a doctor if you” [in bold type]:
(6) For products containing epinephrine, epinephrine bitartrate, or racepinephrine hydrochloride identified in § 341.16(d), (e), and (g).—(i) The following information shall appear after the subheading “Asthma alert: Because asthma may be life threatening, see a doctor if you” [in bold type]:
(1) For products containing ephedrine, ephedrine hydrochloride, ephedrine sulfate, or racephedrine hydrochloride identified in § 341.16(a), (b), (c), and (f): (i) “[Bullet] do not take more than directed” [sentence appears as first bulleted statement under “Directions” and in bold type]
(2) For products containing epinephrine, epinephrine bitartrate, and racepinephrine hydrochloride identified in § 341.16(d), (e), and (g) for use in a hand-held rubber bulb nebulizer. The ingredient is used in an aqueous solution at a concentration equivalent to 1-percent epinephrine:
Population at Risk: Population with asthma x percent of individuals with asthma using OTC bronchodilators as monotherapy x percent of individuals with mild-to-moderate asthma using OTC epinephrine inhalers
Note: See Appendix B for values and sources.
Individuals with Asthma that use OTC Bronchodilators as Monotherapy 5-10% Ref. 10
Individuals with Mild-to-moderate Asthma Using OTC Epinephrine Inhalers 20% Ref. 12
Individuals with Acute Asthma Visiting the ED and Requiring Admission 20-30% Ref. 21
Fatal Asthma Cases and Use of OTC Epinephrine 5% Ref. 15
Population with Asthma (Adults and Children) 24,587,000 Refs. 22, 23
Total Ambulatory Visits 994,321,000 Ref. 24
Total Ambulatory Visits, Asthma 13,872,000 Ref. 24
Total Visits, Injury-related 106,451,000 Ref. 24
Total Visits, Injury-related due to Medication Adverse Effects 8,752,000 Ref. 24
Total ED Visits 116,802,000 Ref. 25
Total ED Visits, Asthma 1,750,000 Ref. 25
Total ED Visits, Injury-related 39,395,000 Ref. 25
Total ED Visits, Injury-related due to Medication Adverse Effects 716,000 Ref. 25
Total ED Visits, Admitted 14,641,000 Ref. 25
Total ED Visits, Admitted with Asthma 158,000 Ref. 25
Total Hospital Discharges 34,369,000 Ref. 18
Total Hospital Discharges, Asthma 456,000 Ref. 18
Mortality, Asthma 3,447 Ref. 11
[FR Doc. 2011-18347 Filed 7-25-11; 8:45 am]