Inspections, Compliance, Enforcement, and Criminal Investigations
University Pharmacy 04-Dec-06
Department of Health and Human Services
Public Health Service
Denver District Office
December 4, 2006
VIA FEDERAL EXPRESS
Mr. Richard E. Rasmuson, Owner
1320 East 200 South
Salt Lake City, UT 84102
Dear Mr. Rasmuson:
On March 21, 2005, investigators from the U.S. Food and Drug Administration (FDA) and Utah Division of Occupational and Professional Licensing inspected University Pharmacy, 1320 East 200 South, Salt Lake City, UT 84102. This inspection revealed that your firm compounds a drug product called Photocaine gel that contains [redacted] lidocaine and [redacted] tetracaine. This product is associated with the death of a 25 year old female on November 1, 2004. The inspection also revealed that your firm compounds different strengths of progesterone cream.
FDA's position is that the Federal Food, Drug, and Cosmetic Act (FDCA) establishes agency jurisdiction over "new drugs," including compounded drugs. FDA's view that compounded drugs are "new drugs" within the meaning of 21 U.S.C. § 321(p), because they are not "generally recognized, among experts . . . as safe and effective," is supported by substantial judicial authority. See Weinberger v. Hynson, Westcott & Dunning, 412 U.S. 609, 619, 629-30 (1973) (explaining the definition of "new drug"); Prof'ls & Patients for Customized Care v. Shalala, 56 F.3d 592, 593 n.3 (5th Cir. 1995) (the FDCA does not expressly exempt pharmacies or compounded drugs from its new drug provisions) ; In the Matter of Establishment Inspection of: Wedgewood Village Pharmacy, 270 F. Supp. 2d 525, 543-44 (D.N.J. 2003), aff'd, Wedgewood Village Pharmacy v. United States, 421 F.3d 263, 269 (3d Cir. 2005) ("The FDCA contains provisions with explicit exemptions from the new drug . . . provisions. Neither pharmacies nor compounded drugs are expressly exempted."). FDA maintains that, because they are "new drugs" under the FDCA, compounded drugs may not be introduced into interstate commerce without FDA approval.
The drugs that pharmacists compound are not FDA-approved and lack an FDA finding of safety and efficacy. However, FDA has long recognized the important public health function served by traditional pharmacy compounding . FDA regards traditional compounding as the extemporaneous combining, mixing, or altering of ingredients by a pharmacist in response to a physician's prescription to create a medication tailored to the specialized needs of an individual patient . See Thompson v. Western States Medical Center, 535 U.S. 357, 360-61 (2002). Traditional compounding typically is used to prepare medications that are not available commercially, such as a drug for a patient who is allergic to an ingredient in a mass-produced product, or diluted dosages for children.
Through the exercise of enforcement discretion, FDA historically has not taken enforcement actions against pharmacies engaged in traditional pharmacy compounding. Rather, FDA has directed its enforcement resources against establishments whose activities raise the kinds of concerns normally associated with a drug manufacturer and whose compounding practices result in significant violations of the new drug, adulteration, or misbranding provisions of the FDCA.
FDA's current enforcement policy with respect to pharmacy compounding is articulated in Compliance Policy Guide (CPG), section 460.200 ["Pharmacy Compounding"], issued by FDA on May 29, 2002 (see Notice of Availability, 67 Fed. Reg. 39,409 (June 7, 2002)).1 The CPG identifies factors that the Agency considers in deciding whether to initiate enforcement action with respect to compounding . These factors help differentiate the traditional practice of pharmacy compounding from the manufacture of unapproved new drugs. They further address compounding practices that result in significant violations of the new drug, adulteration, or misbranding provisions of the FDCA. These factors include considering whether a firm compounds drugs that are copies or essentially copies of commercially available FDA-approved drug products without a documented patient-specific medical need. The factors in the CPG are not intended to be exhaustive and other factors may also be appropriate for consideration.
1. Photocaine Gel
Like a manufacturer, you have developed a standardized anesthetic drug product called Photocaine gel . This action is not consistent with the traditional practice of pharmacy compounding, in which pharmacists extemporaneously compound reasonable quantities- of drugs upon receipt of valid prescriptions from licensed practitioners to meet the unique medical needs of individual patients.
Moreover, the agency is concerned with the public health risks associated with the compounding and sale of Photocaine gel . There have been at least two non-fatal reactions and two deaths attributed to the use of compounded topical local anesthetic creams containing high dose of local anesthetics. Local anesthetics, like Photocaine gel, may be toxic at high dosages, and this toxicity can be additive . Further, there is a narrow difference between the optimal therapeutic dose of these products and the doses at which they become toxic, i .e. they have low therapeutic index.
Adverse events consistent with high systemic exposures to these products include seizures and cardiac arrhythmias. Specifically, risk of systemic adverse events from tetracaine products includes (1) a systemic allergic response to [redacted] which, at worst, could lead to cardiac arrest ; or (2) excessive systemic absorption following repetitive or extensive application, especially for a [redacted] product, which could ultimately lead to convulsions. Tetracaine is associated with a higher incidence of allergic reactions than other anesthetics, such as lidocaine . The risk of systemic toxicity is greatest in small children and in patients with pre- existing heart disease. Factors that may increase systemic exposure are time and surface area of the exposure, particularly when the area of application is covered by an occlusive dressing. Further, patients with severe hepatic disease, because of their inability to metabolize local anesthetics, are at greater risk of developing a toxic plasma concentration of local anesthetics.
Although Section 503A of the FDCA (21 U.S.C. § 353a) addresses pharmacy compounding, this provision was invalidated by the Supreme Court's ruling in Thompson v. Western States Medical Center, 535 U.S. 357 (2002), that Section 503A included unconstitutional restrictions on commercial speech . And those restrictions could not be severed from the rest of 503A. In Thompson v. Western States Medical Center, 535 U.S. 357 (20020), the Supreme Court affirmed the Ninth Circuit ruling that the provisions in question violated the First Amendment.
The drug information sheet you provide for Photocaine gel appears to be a locally prepared document that combines safety information with a promotional advertisement. It includes claims of effectiveness for Photocaine that have not been substantiated and cautionary advice that is inadequate. No pharmacokinetic information is included to support safe use of the product and guide prescribers to reduce the risk of systemic toxicity . In addition, the drug information sheet includes advice for use on various regions of the body skin, including sensitive areas such as eyelids and genitals. Although there is a warning to use the product with caution in denuded skin or on mucous membranes, there is no specific information to guide practitioners to avoid local toxicity such as dose reduction or time of exposure. The information sheet also does not contain any warnings regarding the use of the product in certain special populations, such as the elderly or pediatric age groups.
The Photocaine gel product compounded by your firm is a drug within the meaning of section 201(g)(1) of the FDCA (21 U.S.C. § 321(g)(1)). This product is misbranded under section 502(f)(1) of the FDCA (21 U.S.C § 352(f)(1)) in that its labeling fails to bear adequate directions for its use . This product is not exempt from this requirement under 21 CFR § 201.115 because it is a new drug within the meaning of section 201(p) of the FDCA (21 U.S.C. § 321(p)) that lacks an approved application filed pursuant to section 505 of the FDCA (21 U.S.C § 355).
The Photocaine gel product compounded by your firm is also misbranded within the meaning of section 502(a) of the FDCA (21 U .S .C . § 352(a)) because its labeling is false and misleading in that it fails to reveal facts material with respects to the consequences that may result from the use of the articles under such conditions of use described in its labeling.
Your pharmacy's list of compounded biological hormones also revealed that you are compounding progesterone [redacted] and [redacted] vaginal cream, as well as progesterone, [redacted]. These formulations are copies or essentially copies of commercially available FDA-approved drug products. As stated in the CPG and noted above, FDA considers whether there is documentation of a medical need for an individual patient for the particular variation of the compounded drug. Without proper documentation of medical need, FDA typically does not exercise its enforcement discretion for the compounding of copies of commercially available FDA-approved products.
Like Photocaine, the progesterone products that your firm compounds are drugs within the meaning of section 201(g) of the FDCA. They, too, are misbranded under section 502(f)(1) of the FDCA (21 U.S.C. § 352(f)(1)) in that their labeling fails to bear adequate directions for their use. These products are not exempt from this requirement under 21 CFR § 201.115 because they are new drugs within the meaning of section 201(p) of the FDCA (21 U.S.C. § 321(p)) that lack approved applications filed pursuant to section 505 of the FDCA (21 U.S.C § 355).
Please note that, under section 301(a) of the FDCA (21 U.S.C. § 331(a)), the introduction or delivery for introduction into interstate commerce of any drug that is misbranded is prohibited. Under section 301(d) of the FDCA (21 U.S.C. § 331(d)), the introduction or delivery for introduction into interstate commerce of a new drug that has not been approved under section 505 is also prohibited.
The above violations regarding Photocaine and progesterone are not intended to be an all-inclusive list of deficiencies. You should take prompt action to correct these deviations. Failure to promptly correct these deviations may result in additional regulatory action without further notice. These actions include, but are not limited to, seizure of your products or injunction against you or your firm. Federal agencies are routinely advised of the issuance of warning. letters so that they may take this information into account when considering the award of government contracts.
Please notify this office in writing within 15 working days of receipt of this letter, of any steps you will take to correct the noted violations, including an explanation of each step being taken to prevent the recurrence of similar violations. If corrective action cannot be completed within 15 working days, please state the reason for the delay and the time frame within which the correction will be completed.
You should address your reply to this letter to the U.S. Food and Drug Administration, Denver District Office, P.O. Box 25087, Denver, CO 80225-0087, Attn: Regina Barrell.
B . Belinda Collins
Director, Denver District Office