Inspections, Compliance, Enforcement, and Criminal Investigations
Bayer HealthCare LLC 27-Oct-08
Department of Health and Human Services
Public Health Service
Rockville MD 20857
October 27, 2008
Mr. Gary S. Balkema
Bayer HealthCare L.L.C.
36 Columbia Road
Morristown, New Jersey 07962
Dear Mr. Balkema:
This letter concerns "BAYER WOMEN'S Low Dose Aspirin + CALCIUM" (BAYER Women's), which is marketed by your firm as a combination over-the-counter (OTC) drug-dietary supplement product. According to the package labeling, each caplet (tablet) contains, among other ingredients, 81 mg of aspirin and an undisclosed amount of calcium carbonate that includes 300 mg of elemental calcium. The product is prominently labeled as a "PAIN RELIEVER/CALCIUM SUPPLEMENT" and for "ASPIRIN REGIMEN" use. The package labeling bears a "Drug Facts" panel that lists the product's uses as "• for the temporary relief of minor aches and pains or as recommended by your doctor" and "• ask your doctor about other uses for Bayer Women's 81 mg aspirin," and a "Supplement Facts" panel that is preceded by directions for use with respect to the calcium ("Directions: For calcium, adults and children 12 years and over, take up to 4 caplets per day").
Regarding the daily use of BAYER Women's as a source of dietary calcium, the package labeling prominently features the statement "• Provides 300mg of Calcium Which Helps Strengthen Bones To Help Fight Osteoporosis." The package labeling also bears a health claim about calcium and reduced risk of osteoporosis (see 21 C.F.R. § 101.72): "Menopausal women and women with a family history of the disease are groups at risk for developing osteoporosis. Adequate calcium intake throughout life, along with a healthy diet and regular exercise, builds and maintains good bone health and may reduce the risk of osteoporosis. While adequate calcium intake is important, daily intakes above 2,000 mg may not provide additional benefits." The package labeling also prominently features a glass of milk pictured in close proximity to these statements and to the name, "BAYER Women's Low Dose Aspirin + CALCIUM." This further represents that, like milk, BAYER Women's is a source of dietary calcium.
Regarding the use of BAYER Women's as a source of aspirin, the package labeling states that the analgesic is intended to treat pain. However, other statements and representations on the package suggest that the product is also offered for long-term daily use in preventing or treating cardiovascular diseases. For example, the package labeling bears the statement "• Aspirin Protects Your Heart by Keeping Your Blood Flowing Freely" along with the statements "For more information on how to fight heart disease and stroke, visit the American Heart Association website at www.americanheart.org" and "Aspirin is not appropriate for everyone, so be sure to talk to your doctor before you begin an aspirin regimen." In addition, statements on the labeling enclosed within the carton include: "Cardiovascular disease is the #1 health threat in the United States"; "• 40% of deaths in the United States are due to cardiovascular disease. • 1 in 5 adults has some form of cardiovascular disease"; "BAYER Aspirin can help prevent recurrent heart attacks and ischemic strokes"; "It has been proven that regular aspirin use can prevent 1 out of 4 heart attacks among patients with a previous event"; 'BAYER Aspirin can reduce the risk of recurrent ischemic stroke by up to 22%"; "BAYER Aspirin can help prevent blood clots from forming, which helps ensure that blood keeps flowing to your heart and your brain"; and "If I am taking BAYER Aspirin to prevent recurrent heart attacks and strokes, can I also take it for occasional relief of pain?" Moreover, the labeled directions for adult analgesic use specify a daily dosage of "4 caplets, not to exceed 4 caplets in 24 hours," which falls within the range of the dosages listed in the professional labeling for aspirin for cardiovascular-related indications (see 21 C.F.R. § 343.80), but is well below the dosages that are listed in the tentative final monograph1 for internal analgesics for adults and children 12 and over (325 mg to 650 mg every four hours or 325 to 500 milligrams every 3 hours or 650 to 1,000 milligrams every 6 hours, not to exceed 4000 mg in 24 hours, or as directed by a doctor). See 53 FR 46204 at 46257.
As stated above, the American Heart Association's website is referenced on the package labeling: "For more information on how to fight heart disease and stroke, visit the American Heart Association website at: www.americanheart.org." That website includes recommendations for the use of aspirin in the treatment of cardiovascular-related diseases.
As labeled, BAYER Women's is a "drug" under section 201(g)(1)(B) of the Federal Food, Drug, and Cosmetic Act (the Act) (21 U.S.C. § 321(g)(1)(B)), because it is intended to be used as an internal analgesic and to mitigate, treat, or prevent disease (specifically, heart disease and osteoporosis), and under section 201(g)(1)(C) of the Act (21 U.S.C. § 321(g)(1)(C)) because it is intended to affect the structure or function of the body.
Notwithstanding your attempt to market this product as a combination drug-dietary supplement, the presence of aspirin in this product, with its intended uses as an analgesic and to mitigate, treat, and prevent cardiovascular diseases, renders the entire product a drug. The calcium carbonate in this product could be marketed separately as a dietary supplement if the claims about fighting osteoporosis were removed and no osteoporosis-related claims other than the authorized health claim for calcium and reduced risk of osteoporosis (see 21 C.F.R. § 101.72) were made in the product's labeling. Alternatively, the calcium carbonate could be combined as a buffering agent with aspirin as long as no osteoporosis-related claims were made for the product. However, when, as here, a drug and a dietary ingredient are combined into a single dosage form, the combination becomes a "drug" under section 201(g) of the Act (21 U.S.C. § 321(g)).
Although the package labeling for Bayer Women's bears a health claim for calcium and reduced risk of osteoporosis, as described under 21 C.F.R. § 101.72, the presence of this claim does not exempt the product from regulation as a drug if it meets the definition of a drug in section 201(g)(1) of the Act (21 U.S.C. § 321(g)(1)) for other reasons. Moreover, the claim on the package labeling that calcium "helps strengthen bones to fight osteoporosis" is not a health claim under 21 C.F.R. § 101.72, but rather a claim to treat, mitigate, or prevent osteoporosis under section 201(g)(1)(B) of the Act (21 U.S.C. § 321(g)(1)(B)).
There is no provision in the Act, as amended by the Nutrition Labeling and Education Act of 1990 (NLEA) or by the Dietary Supplement Health and Education Act of 1994 (DSHEA), that exempts any part of your product from the scope of section 201(g) of the Act (21 U.S.C. § 321(g)).2 Under section 201(g)(1)(D) of the Act (21 U.S.C. § 321(g)(1)(D)), the calcium carbonate used in combination with the aspirin in BAYER Women's is also a drug, even in the absence of any claims to treat, mitigate, or prevent osteoporosis, because the calcium carbonate is a component of the finished drug product. See 21 C.F.R. § 210.3(b)(3). And, based on the labeling claims attributed specifically to calcium (e.g., "Calcium . . . Helps Strengthen Bones To Help Fight Osteoporosis . . . Adequate calcium intake throughout life . . . builds and maintains good bone health and may reduce the risk of osteoporosis . . ."), the calcium carbonate in this product is an "active" drug ingredient within the meaning of 21 C.F.R. § 201.66(b)(2).3
Moreover, based on the combination of active drug ingredients (i.e., aspirin and calcium carbonate) and their combined labeled uses in mitigating, treating, or preventing cardiovascular-related diseases and osteoporosis, as described above, BAYER Women's is a new drug within the meaning of section 201(p) of the Act (21 U.S.C. § 321(p)) and 21 C.F.R. § 310.3(h), because it is not generally recognized as safe and effective for its labeled uses. BAYER Women's is not subject to the Food and Drug Administration's (FDA's) OTC Drug Review, because no product formulated with these active ingredients and labeled for use by consumers for these intended uses has previously been commercially marketed, and the Agency has never proposed that such a product be included in that Review.4 Thus, the current marketing of BAYER Women's violates section 505(a) of the Act (21 U.S.C. § 355(a)) because it is a new drug and it is not the subject of an approved new drug application.
In addition, BAYER Women's is misbranded under section 502(f)(1) of the Act (21 U.S.C. § 352(f)(1)) because it does not bear adequate directions for its intended uses, i.e., for treating osteoporosis, for preventing heart attacks, and for preventing/treating heart disease in general. "Adequate directions for use" is defined in 21 C.F.R. § 201.5 as "directions under which the layman can use a drug safely for the purposes for which it is intended." Thus, if an indication requires the supervision of a practitioner licensed to prescribe drugs, adequate directions for use cannot be written for an OTC product for that indication. See U.S. v. Articles of Drug, 625 F.2d 665, 672-673 (5th Cir. 1980). The osteoporosis treatment and cardiovascular-related indications claimed in the labeling of your product require the supervision of a practitioner licensed to prescribe drugs. Indeed, with regard to aspirin, when the Agency finalized the regulations for the professional labeling for aspirin (21 C.F.R. § 343.80) (63 FR 56802, 56809) (Oct. 21, 1998), it explicitly rejected a comment recommending that FDA allow consumer-directed OTC labeling for aspirin for various cardiovascular indications, stating:
"The Agency considers the conditions and uses of aspirin that are the subject of this final rule to require the supervision of a physician (or other practitioner licensed to prescribe drugs) to ensure safe use . . . It is not possible, in OTC drug product labeling, to provide adequate directions and warnings to enable the layperson to make a reasonable self assessment of these factors [relating to the need for drug therapy and its safety for these purposes]."
As described in 21 C.F.R. § 343.80, cardiovascular indications are permissible only in the professional labeling for aspirin. Under that regulation, manufacturers are not permitted to disseminate labeling for their OTC aspirin products to lay consumers for cardiovascular-related indications.
BAYER Women's is also misbranded under sections 502(f)(2) and 502(a) of the Act (21 U.S.C. §§ 352(f)(2) and (a)) because its labeling does not bear adequate warnings and is misleading. Warnings that appear within the "Drug Facts" panel are both inconsistent and incompatible with the directions elsewhere on the labeling that recommend the daily consumption of BAYER Women's as a source of dietary calcium (i.e., "Directions: For calcium, adults and children 12 years and over, take up to 4 caplets per day . . ."). Furthermore, the placement of warnings within the perimeter for the "Drug Facts" panel, and the separate "Supplement Facts" panel and directions for use that do not include those warnings, suggests that the information in the "Drug Facts" panel pertains only to the uses of the product listed in that panel, and that such warnings are not relevant when using the product for the calcium component. Thus, these labeled warnings are not adequate because they are undermined by the inconsistent and incompatible language pertaining specifically to the calcium component. The Agency is concerned that persons using your product to supplement their diet may overlook or disregard the importance of these warnings, or may be unsure as to their relevance when there are no such warnings associated with the supplement portion of the labeling, and that adverse events may occur as a result. Specific examples of this include:
(1) Your product labeling specifies a ten-day use limit under the "Warnings" heading in the "Drug Facts" panel (i.e., "Stop use and ask a doctor if . . . • pain gets worse or lasts more than 10 days"), but this warning appears only within the "Drug Facts" panel of the retail package. Its placement within the perimeter of the "Drug Facts" panel suggests that it applies exclusively to the analgesic use discussed in that panel. It is contradicted by the statement elsewhere on the labeling: "For calcium, adults and children 12 years and over, take up to 4 caplets per day . . . ... without any limitation on duration indicated.
(2) Your product labeling warns against use by children and teens, to prevent Reye's Syndrome (i.e., "Warning[ ] . . . Reye's syndrome: Children and teenagers should not use this medicine for chicken pox or flu symptoms before a doctor is consulted about Reye's syndrome, a rare but serious illness reported to be associated with aspirin.") but this warning appears only within the "Drug Facts" panel of the retail package. Its placement within the perimeter of the "Drug Facts" panel suggests that it applies exclusively to the analgesic use discussed in that panel. It is contradicted by the statement elsewhere on the labeling: "For calcium, adults and children 12 years and over, take up to 4 caplets per day . . .", without any warning that there are circumstances where it is not appropriate for children and teenagers to take the product.
The concerns with the two warnings listed above also apply to the following warnings within the perimeter of the "Drug Facts" panel:
(1) the warning against use by those who are allergic to aspirin;
(2) the warning regarding use by those who consume alcohol;
(3) the warning regarding use by those who may have stomach problems, bleeding problems, ulcers, or asthma;
(4) the warning regarding use by those who may be taking prescription drugs for anticoagulation, gout, diabetes, or arthritis;
(5) the warning to stop use if an allergic reaction occurs, redness or swelling is present, or ringing in the ears or loss of hearing occurs; and
(6) the warning against use when pregnant or breast-feeding.
Moreover, BAYER Women's is misbranded under section 502(a) of the Act (21 U.S.C. § 352(a)) in that the directions for daily supplement use (i.e., "Directions: For calcium, adults and children 12 years and over, take up to 4 caplets per day . . .") are misleading when juxtaposed with the ten-day use limitation under the "Warnings" heading in the "Drug Facts" panel, as described above. Thus, these statements on the labeling send consumers a mixed message about the purpose of the product and the duration for which it can be safely used. Because these two different directions for use are inconsistent and contradictory, BAYER Women's fails to bear adequate directions for use in this regard and, therefore, is also misbranded under section 502(f)(1) of the Act (21 U.S.C. § 352(f)(1)).
The violations cited in this letter are not intended to be an all-inclusive list of deficiencies regarding your products, nor are the arguments raised here regarding them exhaustive. You are responsible for investigating and determining the causes of these violations and for preventing their recurrence and the occurrence of other violations. It is your responsibility to assure that your firm complies with all requirements of federal law and FDA regulations.
You should take prompt action to correct the violations cited in this letter. Failure to promptly correct these violations may result in legal action without further notice, including, without limitation, seizure and injunction. Other federal agencies may take this Warning Letter into account when considering the award of contracts.
Within fifteen working days of receipt of this letter, please notify this office in writing of the specific steps that you have taken to correct the referenced violations. Include an explanation of each step being taken to prevent the recurrence of violations, as well as copies of related documentation. If you cannot complete corrective action within fifteen working days, state the reason for the delay and the time within which you will complete the correction. Your reply should be directed to Kevin M. Budich, Compliance Officer, at the following address:
Food and Drug Administration
CDER/Office of Compliance
Division of New Drugs & Labeling Compliance
OTC Drugs Team
10903 New Hampshire Ave.
Silver Spring, MD 20993
If you have any questions about the content of this letter, you may contact Mr. Budich at 301-796-3304 or email@example.com.
Deborah M. Autor, Esq.
Office of Compliance
Center for Drug Evaluation and Research
1 Although a final OTC drug monograph for internal analgesics has not yet issued, 324 mg of aspirin (4 tablets, 81 mg each) is such a low daily dosage that it has never been considered as part of the agency's OTC Drug Review for adult pain relief. See 42 FR 35346 (July 8, 1977) and 53 FR 46204 (November 16, 1988).
2 In addition, the presence of aspirin in BAYER Women's excludes this product from the definition of a "dietary supplement" under section 201(ff)(3)(B) of the Act (21 U.S.C. § 321(ff)(3)(B)), because a new drug application for aspirin was approved under section 505(a) of the Act (21 U.S.C. § 355(a)) before any marketing of aspirin as a dietary supplement or as a food. FDA approved a new drug application for aspirin, marketed under the name "Measurin," on June 25, 1965. To the best of FDA's knowledge, aspirin has not been marketed as a dietary supplement or other food to date.
3 Furthermore, even if the calcium were included in the product as a buffering agent, and no osteoporosis claims were made for it, the calcium would nevertheless meet the definition of "active" drug ingredient under 21 C.F.R. § 201.66(b)(2).
4 FDA issued a Tentative Final Monograph (TFM) for OTC internal analgesics in the Federal Register on November 16, 1988 (53 FR 46204). However, that TFM does not describe the combination of calcium carbonate with aspirin labeled for use by consumers for the mitigation, treatment, or prevention of either cardiovascular disease or osteoporosis.