Department of Health and Human Services
Public Health Service
555 Winderley Pl #200 Maitland, FL 32751
December 4, 2006
James G. Castillo, President
Tiberius, Inc. Custom Scripts Pharmacy
4600 N Habana Ave #16A
Tampa, FL 33614
Dear Mr Castillo:
On April 21, 2005, investigators from the US Food and Drug Administration (FDA) and Florida Department of Health, Division of Medical Quality Assurance., inspected Custom Scripts Pharmacy, 4600 N Habana Ave #16A, Tampa, FL. This inspection revealed that your firm compounds a drug product called Betacaine LA ointment, which contains 15% fidocaine, 5% prilocaine, and phenylephrine, and a similar drug called Betacaine Plus ointment, which contains 15% lidocaine and 5% prilocaine. The inspection also revealed that your firm offers to compound polidocanol and dinitrochlorobenzene (DNCB).
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 USC 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 US 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 US 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. Betacaine Ointments
Like a manufacturer, you have developed a standardized anesthetic drug products called Betacaine LA and Betacaine Plus. 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 of Betacaine ointments. 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. 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. Prilocaine has an additional toxicity not seen with lidocaine. This toxicity, which is known as methemoglobinemia, is an acquired decrease in the oxygen-carrying capacity of the red blood cells. It is related to the use of large doses of prilocaine. Further, patients with severe hepatic disease are at greater risk of developing toxic plasma concentrations of local anesthetics because of their inability to metabolize them. Phenylephrine is a vasoconstrictor agent that can cause serious adverse events related to hypertension and vasoconstriction at the significant dose present in your firm’s Betacaine LA ointment.
Your sheet entitled “The Recommended Procedures for Usage of Lidocaine Compounds” does not identify the risks that can reasonably be anticipated with the use of prescription preparations containing lidocaine and/or prilocaine. The sheet states “Apply the ointment to intact skin only. Once the skin surface is removed, do not apply.” This sentence is not clear as there is no warning to the patient that the product should not be applied over raw surfaces or blistered areas. Further, when using a topical local anesthetic, patients should be made aware that the production of dermal analgesia may be accompanied by the block of all sensations in the treated skin. For this reason, the patient should avoid Inadvertent trauma to the treated area by scratching, rubbing or extreme hot or cold temperatures until full sensation has returned. Also, no warning is given that this product should only be applied externally. Even though the sheet states that “due to possible side effects and allergic reactions, apply in the physician’s office if possible or have someone with you at all times. Do not drive or operate heavy machinery,” it does not state what should be done if an allergic reaction is suspected. The sheet also does not contain any warnings regarding the use of the product in certain special populations such as the elderly.
The Betacaine LA and Betacaine Plus ointments compounded by your firm are drugs within the meaning of section 201(g)(1) of the FDCA (21 USC 321(g)(1)). These products are misbranded under section 502(f)(1) of the FDCA (21 USC 352(f)(1)) in that their labeling fails to bear adequate directions for its 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 USC 321(p)) that lacks an approved application filed pursuant to section 505 of the FDCA (21 USC 355).
The Betacaine LA and Betacaine Plus ointments compounded by your firm are also misbranded within the meaning of section 502(a) of the FDCA (21 USC 352(a)) because their labeling is false and misleading in that they fail to reveal facts material with respects to the consequences that may result from the use of the article under such conditions of use described in their labeling.
2. Polidocanol and DNCB
Your firm’s promotional materials indicate that it also offers to compound polidocanol for sclerotherapy and DNCB for treatment of warts. Polidocanol and DNCB are not active ingredients contained in any FDA-approved drug product. FDA does not sanction their use in pharmacy compounding and will not exercise its enforcement discretion for compounded products containing polidocanol or DNCB.
The agency is seriously 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. Reversible cardiac arrest after polidocanol sclerotherapy has been reported. DNCB is highly toxic and may be fatal if inhaled, swallowed, or absorbed through skin. High concentrations of DNCB are also extremely destructive to tissues of the mucous membranes and upper respiratory tract, eyes, and skin. If your firm is compounding products containing polidocanol or DNCB, then those products would be drugs within the meaning of section 201(g)(1) of the FDCA (21 USC 321(g)(1)). Those products would be misbranded under section 502(f)(1) of the FDCA (21 USC 352(f)(1)) in that their labeling fails to bear adequate directions for its 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 USC 321(p)) which lack approved applications filed pursuant to section 505 of the FDCA (21 USC 355).
Finally, please note that, under section 301(a) of the FDCA (21 USC 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 USC 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 topical anethestics, polidocanol, and DNCB 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 US Food and Drug Administration, Florida District Office, 555 Winderley Pl #200, Maitland, FL 32751, Attn: Compliance Branch. If you have any further questions, please feel free to contact our Director of Compliance, Jimmy E. Walthall, at 407-475-4734.
Emma R. Singleton District Director
1 Although Section 503A of the FDCA (21 USC 353a) addresses pharmacy compounding, this provision was invalidated by the Supreme Court’s ruling in Thompson v. Western States Medical Center, 535 US 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 US 357 (2002), the Supreme Court affirmed the Ninth Circuit ruling that the provisions in question violated the First Amendment.
This page was posted on February 12, 2008.