Inspections, Compliance, Enforcement, and Criminal Investigations
Triangle Compounding Pharmacy 04-Dec-06
Department of Health and Human Services
Public Health Service
Atlanta District Office
December 4, 2006
VIA FEDERAL EXPRESS
Jose M. Cabaleiro, Owner
Triangle Compounding Pharmacy
550 New Waverly Place, Suite 110
Cary, North Carolina 27511
Dear Mr. Cabaleiro:
On February 17, 2005, investigators from the U.S. Food and Drug Administration (FDA) and the North Carolina Board of Pharmacy inspected Triangle Compounding Pharmacy, 550 New Waverly Place, Suite 110, Cary, NC. This inspection revealed that your firm compounds a drug product called Lasergel, which contains 10% lidocaine/10%o tetracaine, and a similar drug called Lasergel Plus 10110, which contains 10% Iidocaine/10% tetracaine/0.5% phenylephrine. Lasergel Plus 10/10 is associated with the death of a 22 year old female on January 5, 2005. The inspection also revealed that your firm compounds tetracaine lollipops and polidocanol drug products.
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 an FDA sanctioned investigational new drug application (IND). The factors in the CPG are not intended to be exhaustive and other factors may also be appropriate for consideration.
Like a manufacturer, you have developed a line of standardized anesthetic drug products called "Lasergel" and "Lasergel Plus 10/10." In some instances, you provide samples of these products at no charge to encourage future sales. These actions are 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 Lasergel and Lasergel Plus 10/10. There have been at least two non- fatal reactions and two deaths attributed to the use of compounded topical local anesthetic creams containing high doses of local anesthetics . Local anesthetics, like Lasergel Plus 10/10, 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.
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.
Adverse events consistent with high systemic exposure to these products include seizures and cardiac arrhythmias. Specifically, risk of systemic adverse events from tetracaine products includes (1) a systemic allergic response to p-aminobenzoic acid (PABA) which, at worst, could lead to cardiac arrest ; or (2) excessive systemic absorption following repetitive or extensive application, especially for a 10% 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 the time and surface area of exposure, particularly when the area of application is covered by an occlusive dressing, as was the case here. Further, patients with severe hepatic disease are at greater risk of developing a toxic plasma concentration of local anesthetics because of their inability to metabolize them. In addition, phenylephrine, a vasoconstrictor agent present in the Lasergel Plus 10/10, can cause serious adverse events related to hypertension and vasoconstriction.
The patient information sheet that you provide for Lasergel/Lasergel Plus 10/10 appears to be an edited version of the [redacted] (an FDA-approved drug) package insert. Apart from using Lasergel/Lasergel Plus 10/10 in place of [redacted], no changes have been made to the [redacted] package insert. But there are fundamental pharmacological differences between the two products: Lasergel/Lasergel Plus 10/10 and [redacted] are combinations of different local anesthetics: [redacted] contains lidocaine with prilocaine; Lasergel products contain lidocaine with tetracaine. In addition, Lasergel products include phenylephrine, a vasoconstrictor that is not found in [redacted]. Consequently, the Lasergel products information sheet includes warnings and other information that are not appropriate for these products.
The Lasergel/Lasergel Plus 10/10 products compounded by your firm are drugs within the meaning of section 201(g)(1) of the FDCA (21 U.S.C. § 321(g)(1)). These products 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. They 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 Act (21 U.S.C. § 355).
In addition, your compounded Lasergel and Lasergel PIus10/10 products are misbranded within the meaning of section 502(a) of the FDCA (21 U.S.C. § 352(a)) because their labeling is false and misleading in that it fails to reveal the consequences that may result from the use of these articles under the conditions of use described in their labeling. Please also be aware that FDA analyzed a sample of your firm's Lasergel Plus 10/10 Gel product, lot 36955-52. This sample was found sub-potent for both active ingredients, lidocaine and tetracaine, when compared to the amount of these two active ingredients included in your firm's formulation . According to your firm's label and formulation, this product should contain 10% lidocaine and 10% tetracaine: FDA laboratory analysis found that the amount of lidocaine ranged from 7.4% to 9.15%, and the amount of tetracaine ranged from 7.2% to 8.9%. Accordingly, this product was adulterated within the meaning of section 501(c) of the FDCA (21 U.S.C. § 351(c)) in that its strength differed from that which it purported or represented to possess.
2. Tetracaine lollipops
Your firm's dispensing log reports that you compound and sell tetracaine HCI [redacted] base lollipops. The agency is concerned with the public health risks associated with the compounding of tetracaine lollipops. The rapid absorption of local anesthetics through the mucous membranes of the mouth and nose may lead to convulsions. In addition to the toxicity that may accompany the rapid absorption of tetracaine, there is a concern that the local anesthetic action within the oral cavity will depress the normal reflexes that protect a patient's airway. This could result in the aspiration of secretions (vomitus or even normal feedings), especially in children. This is a particular hazard for children recovering from tonsillectomies or other intra-oral or intra-nasal ear, nose, and throat surgical procedures. Postoperative bleeding is not uncommon and swallowed blood can lead to stomach irritation and vomiting, thereby raising the hazard of aspiration and possible blockage of the airway.
Like your Lasergel products, the tetracaine lollipop products compounded by your firm are drugs within the meaning of section 201(g)(1) of the FDCA (21 U.S.C. § 321(g)(1)). These products are also 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).
FDA's inspection revealed that you offer to compound products containing polidocanol. The agency is very concerned about the public health risks associated with the compounding of polidocanol injection. Known adverse events include deep venous thromboses, necrosis, and ulceration at the treated site. Additionally, reversible cardiac arrest after polidocanol sclerotherapy has been reported.
Polidocanol is not an active ingredient contained in any FDA-approved drug product. FDA does not sanction its use in pharmacy compounding and will not exercise its enforcement discretion for compounded products containing polidocanol.
If your firm is compounding products containing polidocanol, then these products would be drugs within the meaning of section 201(g) of the FDCA (21 U.S.C. § 321(g)). These products would be misbranded under section 502(f)(1) of the FDCA (21 U.S.C. § 352(f)(1)) in that their labeling would fail to bear adequate directions for their use. These products would not be exempt from this requirement under 21 CFR § 201.115, because they would be 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).
Finally, 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 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 and our 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, Atlanta District Office, 60 Eighth St. NE, Atlanta, GA 30309, Attn: Philip Campbell. If you have any further questions, please feel free to contact Mr. Campbell at (404) 253-1280.
Dawn Todd-Murrell for Mary H. Woleske
Atlanta District Office