Inspections, Compliance, Enforcement, and Criminal Investigations
Custom Scripts Pharmacy, Company Response
Custom Scripts Pharmacy
4600 North Habana Avenue
Tampa, Florida 33614
January 4, 2007
By Overnight Delivery
Emma R. Singleton ERS 1/5/07
Director, Florida District
U.S. Food and Drug Administration
Florida District Office
555 W Winderley Place, Suite 200
Maitland, Florida 32751
Attn: Compliance Branch
Re: Warning Letter to Custom Scripts Pharmacy, FLA-07-O5
Dear Ms. Singleton:
This letter is written in response to the Warning Letter issued to Custom Scripts Pharmacy dated December 4, 2006. Thank you for extending our response due date to January 5, 2007. Custom Scripts is committed to complying, with applicable laws and regulations and to ensuring high quality care for our patients. We appreciate the opportunity to clarify the nature of our pharmacy operations ,and to respond to the issues raised in the Warning Letter.
The Warning Letter is based on an inspection of our pharmacy conducted on Apri1 21, 2005, eighteen months ago. FDA did not contact us during this period to check to see if its information was now out of date. Due to the lengthy delay between the inspection and the Warning Letter, some of the letter's assertions no longer apply to Custom Scripts' operations.
We are also puzzled by the timing of the issuance of the Warning Letter. The five most recent Warning Letters issued by FDA's Florida District Office to non-pharmacy recipients were sent, on average, 114 days after the recipients' facilities had been inspected. The Warning Letter we received arrived 592 days after FDA's one-day inspection of our pharmacy. The eighteen month delay, which is well over a year longer than the District's recent average, does not comport with FDA's internal procedures, which establish that decisions to issue Warning letters are to be made in a timely fashion, because they are "the agency's principal means of notifying regulated industry of violations and achieving prompt voluntary correction."1 The Warning Letter also mentions FDA's concerns about potentially serious health risks associated with the misuse by physicians and patients of compounded topical anesthetic drug products. We assume that if the potential risk to the public health were in fact dire, FDA would not have waited 18 months to issue the letter.
The Warning Letter also states that it is FDA's position that the agency has jurisdiction over compounded drugs because such drugs are "new drugs" within the meaning of Section 201(p) of the Food, Drug, and Cosmetic Act (FDC Act). However, although the Warning Letter cites several court cases, it ignores the fact that this position was rejected by the only federal court to have directly considered the issue. In Medical Center Pharmacy v. Gonzales the federal District Court for the District of Western Texas granted the plaintiff pharmacies' summary judgment on their "claim that compounded drugs do not fall under the [FDC Act's] new drug definitions."2 The court based this conclusion on "relevant case and statutory law, as well as legislative intent."3
The Warning Letter also refers to the Supreme Court's pharmacy compounding decision in Thompson v. Western States Medical Center, 4 but fails to mention that the Medical Center Pharmacy court's opinion stated that "the langua.ge of Western States demonstrates that compounding is a process that has been approved by the Supreme Court."5 We find it curious that in referencing court cases, the Warning Letter omits the decision that is most on point.
Contrary to the Warning Letter's assertion, Custom Scripts does not introduce unapproved new drugs into interstate commerce, does not manufacture drugs, and does not need approved NDAs before dispensing its compounded medications. Nor are our compounded medications misbranded. Custom Scripts only compounds medications extemporaneously upon the receipt of valid prescriptions for identified patients or in limited quantities in anticipation of prescriptions based on physician's prescribing history. We are engaged in the practice of pharmacy and in compliance with the Florida Board of Pharmacy's laws and rules, which is the kind of activity that the Medical Center Pharmacy court determined does not result in the introduction of new drugs into interstate.
Topical Analgesic Ointments
The letter asserts that Custom Scripts has developed a standardized line of topical anesthetic drug products. This statement is inaccurate. Custom Scripts compounds a number of different topical anesthetic formulas containing a variety of component ratios, depending on the prescribing physicians' requests. Although it has been our experience that physicians request certain formulations more than others, this does not mean we compound only a limited number of formulas.
We have assigned shorthand names for some of these formulations, for example Betacaine LA and Betacaine Plus, but only as a convenience to the physicians and as a way of avoiding prescribing confusion. The shorthand naming of formulas is a standard of practice in pharmacy, and does not mean that a pharmacy is manufacturing drugs. Pharmacists and physicians routinely refer to compounds such as Castellani's paint, Lugol's solution, Brompton's cocktail, and Lassar's paste by those shorthand names and not by the compounds' chemical formulations. We believe that using shorthand names is appropriate and helpful. Nonetheless, to address FDA's concerns on this point, we will no longer assign shorthand names to our compounded medications and instead will require physicians to specify the desired chemical formulation in each prescription.
The letter also notes that Custom Scripts has obtained patents for two of the formulations we are frequently asked by physicians to compound, and asserts that the issuance of patents is not consistent with the traditional practice of pharmacy compounding." This statement is incorrect. Custom Scripts' patent covers a range of formulation component ratios and not a specific product. Patent No. 5,993,836 states that"[t]he formulation of the present invention preferably contains from 10% to 20% by weight lidocaine and 1% to 5% by weight prilocaine based upon the total weight of formulation." The patent further provides:
In addition to the above described-preferred embodiment, which contains lidocaine and prilocaine, alternative embodiments include all formulations comprising a eutectic mixture of at least one first pharmaceutically active anesthetic selected from the group consisting of benzocaine, lidocaine, bupivacaine, dibucaine, mepivacaine, etidocaine, tetracaine, butanilicaine and trimecaine and at least one second pharmaceutically active anesthetic selected from the group consisting of prilocaine; tetracaine, butanilicaine and trimecaine, said first and second pharmaceutically active agents present in a weight ratio of from about 15:1 to about 2:1 in a lipophilic base, and said anesthetic(s) selected from the first group differing from the anesthetic(s) selected from the second group, and at least one of said anesthetics preferably being eight prilocaine or lidocaine.
The patent also states that "[a]s lipophilic base, the present invention is not particularly limited, and any of those known in the pharmaceutical and cosmetic industries may be employed. . . ." Thus, the patent covers not only these formulations, but thousands of other formulas. In addition, the Warning Letter fails to recognize that patents do not convey the right to make something, but only a vehicle for prohibiting others from making something. We have never exercised that vehicle.
We obtained this patent for potential future business purposes and have never attempted to enforce it. Thus, the patent is in no way indicative that we are a manufacturer.
Your letter refers to two non-fatal reactions and two deaths associated with compounded local anesthetic products, and implies that there is a similarity between the formulations associated with those adverse events and Custom Scripts' compounded topical anesthetic medications. However, it is our understanding that those four adverse events resulted either from physician misuse of the medications, or from the patients' disregard for the instructions for use as conveyed by the treating physicians. It is also our understanding that the compounded medications associated with the four adverse events contained tetracaine, and that the potential for systemic toxicity associated with the use of tetracaine is significantly different from that associated with the use of lidocaine and prilocaine. Custom Scripts does not use tetracaine in its topical analgesic compounding operations. Thus, the events cited in the Warning Letter were associated with compounds containing different active ingredients.
The Warning Letter next refers to the risk of seizures and cardiac arrhythmias associated with high systemic exposure to compounded topical anesthetics. We only use lidoaine and prilocaine in our compounded products. Both are amides, which do not involve such risks. In addition, it is the physicians' choice to have us compound these drugs. It is the physician who directs us to compound with these active ingredients. Furthermore, we are not aware of any statement by FDA, as asserted in the letter, that pharmacists may not compound a drug product because there may be toxicities. Nor are we aware of any statement by FDA with statutory basis directing pharmacists to provide detailed warnings to the dispensing/prescribing physician. To the extent FDA is suggesting that it is improper to compound drugs with potential toxicities or that these products require detailed warnings, we believe the agency is seeking to impose new requirements.
Custom Scripts also believes that the document entitled "Recommended Procedures for Usage of Lidocaine Compounds," which we send with every dispensed tube of topical anesthetic medication, does address many of the concerns raised in the Warning Letter relating to the potential risk. The Warning Letter, for example, states that the risk of toxicity is highest in small children and in patients who have pre-existing heart disease. However, the letter fails to mention that our Recommended Procedures document already states that the medications are "[n]ot recommended for use on children except under direct and immediate physician supervision." Our document also already warns that our lidocaine-prilocaine-phenyleprhine medications should not be used on patients who "have hypertension, hyperthyroidism, diabetes, high blood pressure or heart disease," because of the potential vasoconstriction effects phenyleprhine might have in those patient populations.
In addition, the Warning Letter states that factors such as the frequency of application, the time and surface area of exposure, and the coverage of the treatment area with an occlusive dressing can increase the risk of the onset of systemic toxicity. The Warning Letter overlooks the fact that our Recommended Procedures document warns, among other things, that the medications: (1) are to be applied only 30 to 45 minutes in advance of the associated procedure, during which time the treated area is to "remain undisturbed and uncovered," and that "[o]cclusion is NOT needed;" (2) are not to be applied more than once in a single day; (3) are not to be used for pregnant or lactating patients; (4) "are intended for use as an anesthetic for procedures only" and "NOT recommended for use . . . for the relief of symptoms or for long-term use;" and (5) should not be applied "to an area larger than 300 cm2[,] about 6 inches square." This last warning also appears on the label affixed to every tube of topical analgesics dispensed by Custom Scripts. We strive to further reduce the risks of physician or patient misuse of these medications by using a safety closure on each tube and by limiting the size of each dispensed tube to either 15- or 30-grams.
Finally, the Warning Letter also asserts that Custom Scripts' topical analgesics Recommended Procedures document should clarify or enumerate additional possible risks associated with the medications' uses. For example, it recommends that we clarify our warning that such products should not be applied over raw or blistered surfaces. The document, however, already warns that the medications are to be applied to "intact skin only," which we believe conveys the message that they are not to be applied to raw or blistered skin. The letter also requests that we include instructions that the medications are for external use only. The Recommended Procedures document, however, warns against allowing the product to enter the eye and instructs physicians not to apply it to mucous membranes, which we believe impart the message that the medications are for external use only.
As a legal matter, we believe that FDA lacks the authority to prescribe the wording of informational sheets for compounded drugs. Indeed, given the variable formulas prescribed by physicians, we believe that imposing such a requirement would be antithetical to the nature of compounded drugs. Custom Scripts has voluntarily developed medication information sheets, but that is different from saying compounding pharmacies are legally required to provide detailed labeling. Custom Scripts nevertheless will voluntarily clarify or include the additional warnings to more directly address FDA's concerns. Effective immediately, we will make the following revisions to our Recommended Procedures document. First, the "intact skin" warning will be changed to read: "Apply the ointment to intact skin only. Do not apply to compromised, raw, inflamed, or blistered skin. Once the skin surface has been removed, do not apply." Second, the document currently instructs that less than 7 grams be used per application and states, "Occlusion is NOT needed," but we will change this to read "[u]se no more than 5 grams per application. Do NOT cover treated area with an occlusive dressing." Third, we will revise the document to include the statement: "For external use only." Fourth, we will add the warning that "Topical application of local anesthetics may lead to temporary, reduced or blocked sensation in the treated skin. Therefore, avoid trauma to the treated area, which might result from scratching, rubbing, or exposing the treated area to extreme temperatures or to excessive sunlight before complete sensation has returned." Finally, the Recommended Procedures document will be revised to instruct that use of the medication should be stopped and the treating physician should be contacted immediately if symptoms suggestive of an allergic reaction occur, such as dizziness, numbness of the tongue, lethargy, muscle contractions, visual disturbances, or signs of respiratory or cardiac distress.
Polidocanol and DNCB
Custom Scripts has not filled a prescription for polidocanol since December 2005. Without agreeing with the correctness of FDA's position regarding the legality of the use of polidocanol in pharmacy compounding, however, Custom Scripts decided a year ago to refrain from dispensing any polidocanol medications.
Similarly, Custom Scripts stopped filling prescriptions for DNCB medications quite some time ago.
* * *
We believe that this response to FDA's Warning Letter of December 4, 2006 addresses FDA's concerns in full. We understand that FDA has a policy whereby responses to Warning Letters will be posted on the FDA website at the Warning Letter recipient's request. We therefore request that this letter be posted on FDA's website. We have enclosed with the copy of the letter delivered to you via overnight delivery, a computer diskette containing an electronic version of this response in PDF format for the purposes of redaction and website posting.
We thank you again for this opportunity to clarify the nature of our compounding pharmacy operations.
1 FDA, Regulatory Procedures Manual4-10 (March 2006).
2 Med. Ctr. Pharmacy v. Gonzales, 451 F. Supp. 2d 854, 865 (W.D. Tex 2006),
appeal docketed, No. 06-51583 (5th Cir. Dec. 11, 2006).
3 Id. at 858.
4 535 U.S. 357 (2002) .
5 451 F. Supp. 2d at 864 .