DDMAC UNTITLED LETTERS.

The following untitled letters were issued by the Center for Drugs Division of Drug Marketing, Advertising and Communications (DDMAC). Copies of these letters are available to subscribers from our RECORD-RETRIEVE Service for $7 plus retrieval. Please reference the MACMIS ID # to order the company response.

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AstraZeneca, Wayne, PA, July 18 (DDMAC). The letter cited Zeneca for promotional labeling and advertising for Prilosec (omeprazole) that FDA insisted was misleading because the materials "use intragastric pH data from healthy volunteers to suggest that specific levels of intra-gastric pH acidity correlate with clinical efficacy." The agency insisted that there was no "substantial evidence" to back the firm's claim of increased clinical benefit in the treatment of erosive esophagitis or duodenal ulcer by increases of dosage. The letter stated that a reprint carrier made a misleading comparison in the rates of healing of erosive esophagitis between Prilosec and other proton pump inhibitors based on the "Castella study," because Zeneca did "not prominently disclose the placebo effect...at four and eight weeks" and failed to disclose the lack of statistical significance of some of the numbers shown. FDA cited several of the items for lack of fair balance, noting that a sales aid proclaimed the drug's "excellent safety record" in "large-size, colorful header font" while a statement regarding the occurrence of gastroduodenal carcinoids reported in patients with Zillinger-Ellison syndrome on long-term treatment with Prilosec was reported "in much smaller type at the bottom of the page." ID # 9086 F-B 

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AstraZeneca, Wilmington, DE, July 20 (DDMAC). FDA notified Zeneca that statements made in a brochure and a journal ad for Nolvadex (tamoxifen citrate) were misleading due to lack of context for information on efficacy in that comparison rates with placebo were not provided. The agency stated that Zeneca's statement that "women may experience some level of hot flashes and vaginal discharge" lacked fair balance given that the incidence of these events were 80% and 55%, respectively. ID # 9075 F-B

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Bausch & Lomb Pharmaceuticals, Tampa, FL, June 27 (DDMAC). The letter stated that a sales aid and a 4" x 6" magnet for Alrex (loteprednol etabonate ophthalmic suspension) contained misleading claims of superior efficacy in comparisons with several other drugs because the pieces suggested that "only Alrex is depicted to be effective for all symptoms" when only one of the other products was indicated for the same use. ID # 8889

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DuPont Pharmaceuticals, Wilmington, DE, July 18 (DDMAC). The agency cited DuPont for two professional advertisements and one consumer ad for the claim that "life goes on" which FDA insisted was misleading because "it broadens the indication for Sustiva (efavirenz) by implying that it improves survival in patients with HIV infection." FDA took exception to the claims that Sustiva "fits the way you live" and "offers convenient dosing" because the statements failed to provide the context of a prohibition against taking the drug with high fat meals and because the product insert recommends bedtime administration for the first two to four weeks to "improve the tolerability of nervous system side effects." FDA stated that all three ads failed to include adequate risk information in that contraindications and common adverse events were omitted and the risk of central nervous system (CNS) effect is understated by the description of "a small number of patients" may experience "serious psychiatric adverse experiences" when 53% had reported "a range of CNS effects." ID # 8971 F-B

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DuPont Pharmaceuticals, Wilmington, DE, July 18 (DDMAC). The letter stated that DuPont's July 18 press release for Innohep (tinzaparin sodium) lacked fair balance because it omitted the warning that the drug should not be used in patients with a history of heparin-induced thrombocytopenia. Also omitted were contraindications for patients "with known hypersensitivities to heparin, sulfites, benzyl alcohol or pork products." FDA insisted that the statement that Innohep "offers the advantage of being the only once-a-day heparin product for all patients with DVT (deep vein thrombosis)" was false or misleading because it implied that Innohep was indicated for all DVT patients when its use in outpatient populations had not been studied, that it is approved for monotherapy when it had not been approved for monotherapy, and that the drug was the only such product approved for once-a-day treatment when this was not the case. ID # 9154 F-B

The following symbols are used to flag certain warning letters containing alleged violations of specific FDA regulations and policies of current interest:

510(k)   Failure to submit a 510(k)
BiMo   Sponsor/monitor, IRB, clinical investigator issues
CAPA   Corrective and preventive action
C-H   Complaint handling
C-R   Corrections and removals
Design   Design control issues
E-Sig   Violations of Part 11
F-B   Lack of fair balance in promotion
H2O   Water quality, water for injection (WFI)
MDR   Medical device reporting requirements
NDA   No new drug application
NLEA   Labeling that violates the Nutritional Labeling and Education Act
OOS   Out-of-specification results
PMA   No premarket approval
S-HACCP   Violations of HACCP requirements for seafoods
Stab   Stability
Ster   Sterility
Val   Validation
Web   Internet promotion irregularities

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Genentech, South San Francisco, CA, July 28 (DDMAC). The letter referred to the firm's healthcare professional in-service resource kit for Nutropin (somatropin rDNA origin) which the letter stated lacked fair balance because risk information was presented on only three pages in a 30-page booklet and no information was presented on contraindications and warnings. FDA commented that the statement that "Nutropin depot represents a significant advance in terms of convenience over other currently-available growth hormone replacement therapies" because it fails to note that the once- or twice-monthly regimen may not provide the growth rates delivered by a daily injection regime and the letter commented that according to the product insert, "patients previously treated with daily growth hormone who were switched to Nutropin depot experienced a decrease in growth rate." ID # 9082 F-B

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Hoffman-La Roche, Nutley, NJ, June 28 (DDMAC). FDA cited Roche for promoting Rocephin (ceftriaxone sodium) for treatment of penicillin-resistant Streptococcus pneumoniae. ID # 8732

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Knoll Pharmaceutical, Mount Olive, NJ, Jan. 28 (DDMAC). The agency stated that "reminder advertisements for Synthroid are not permitted" because the labeling of the product includes a serious risk warning related to use and that to satisfy the requirement for fair balance, each page would have to display risk information comparable in prominence to information on safety and effectiveness. The letter indicated that the header which read "The measure of excellence" and the footer which read "The trusted standard in thyroid hormone replacement" suggested an unsubstantiated superiority claim and that the use of the term "standard" was misleading inasmuch as no levothyroxine preparations have been approved or recognized as a standard in thyroid replacement. ID # 8601

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Novartis, East Hanover, NJ, May 8 (DDMAC). FDA insisted that the firm's slide show, which stated that patients switched from Neoral (cyclosporine capsule and oral solution) to an "AB"-rated generic cyclosporine product "may not be kept within their therapeutic range" was false or misleading. The letter pointed out that "all FDA-approved dosage forms of generic drugs classified as therapeutically equivalent and coded AB can be substituted for the reference product with the full expectation" that the same effect will be achieved. ID # 8415

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Organon, West Orange, NJ, April 6 (DDMAC). The letter briefly cited Organon for a journal ad titled "Life without Depression" that FDA stated lacked fair balance due to a lack of risk information. ID # 8496 F-B

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Shire Labs, Rockville, MD, Aug. 7 (DDMAC). The agency wrote that Shire's sales aid for Fareston (toremifene citrate) was misleading because of the description of the drug as a "first-line therapy for advanced breast cancer" because it "implied usefulness in a broader population than has been demonstrated by substantial evidence." The letter stated that approved product labeling indicated that the drug was for treatment of breast cancer in post-meno-pausal women with estrogen receptor-positive or unknown tumors. The letter hit Shire for minimizing carcinogenic risks associated with the drug in statements such as "no endometrial cancers attributable to Fareston in 11 years of market experience despite approved product labeling that stated that "some patients treated with Fareston have developed endometrial cancer, but circumstances make it difficult to establish the role" of the drug. FDA cited the firm for failing to display risk information with a comparable prominence to efficacy information, which the letter stated was present with the use of graphs, pictures, bullets and large fonts. ID # 8823 F-B

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Wyeth-Ayerst, Philadelphia, PA, Jan. 27 (DDMAC). FDA deemed a journal ad and a product summary for Sonata (zaleplon) misleading because they did not state that the drug "has not been shown to increase total sleep time or decrease the number of awakenings." ID # 8573