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Executive Summary

Searle should prepare a "Dear Prescriber" letter on phototoxicity and potential photocarcinogenicity associated with its broad spectrum quinolone antimicrobial Maxaquin (lomefloxacin), the combined Anti-Infective Drugs and Dermatologic Drugs Advisory Committees agreed unanimously March 31. In addition, the committee recommended by a 12 to one vote that information on photosensitivity/phototoxicity associated with Maxaquin be disseminated to patients. Possible methods of distribution would include a patient package insert or a Searle information sheet given to patients by their doctors. Searle received approval for Maxaquin in February 1992 ("The Pink Sheet" March 2, 1992, T&G-1) and began marketing the drug in May 1992. ICI has co-promoted the drug since September. "The issue of phototoxicity is unusual from reading the reports, in that some patients who were exposed to relatively small amounts of light seemed to have reactions that were incongruent to what we would expect," committee guest John DiGiovanna, MD, National Cancer Institute Dermatology Branch, said. "I think that the cautionary note that has been sounded here today will be heard for quite some time with the quinolones and fluoroquinolones," Dermatologic Drugs Advisory Committee Chairman Arnold Schroeter, MD, said. The joint committee expressed its support for two statements: that fluoroquinolones as a class are photosensitizing or phototoxic drugs, and that lomefloxacin has an enhanced risk of phototoxicity/photosensitization. The March 31 meeting was prompted by spontaneous reporting to FDA of phototoxicity reactions with Maxaquin and by a 1990 Roche animal photocarcinogenicity study of five quinolones, including Maxaquin, versus a known tumor promoter, 8 methoxypsoralen (8- MOP). Roche submitted the study to FDA in December 1992 as part of an NDA for its quinolone antibiotic Megalone (fleroxacin). The joint committee voted 12 to two that information on phototoxicity be included in the warning section of Maxaquin labeling, but was split seven to seven on whether to "black box" the warning. Most Dermatologic Drug Committee members voted against a black box warning, and most Anti-Infective Drugs Committee members voted in support of the stronger warning. Boxing the warning "seems to me to be overkill," committee guest Frederick Urbach, MD, Temple University, suggested. "Certainly lomefloxacin is more phototoxic than others, but to rank that to the point where you're going to advise people that this is a very serious hazard, both to the physicians and to the patients in advertising, really appears to be more than is justified. It is not in my opinion a major health hazard of the kind let's say that anaphylaxis would be or that agranulocytosis would be...even though it's obviously a lot more frequent." Anti-Infective Drugs Committee member Franklyn Judson, MD, on the other hand, favored conservative use of lomefloxacin: "I think the desirable outcome [of a black box] is that there will be less of this drug used, especially for individuals who are at risk for phototoxicity reactions and who...have plenty of alternatives." Maxaquin is marketed by Searle as the only approved once-a-day quinolone; the drug also differs from other quinolones in that it has no adverse reaction with theophylline and is indicated for the prevention of infection for three to five days after transurethral surgery. Another difluourinated quinolone, Abbott's Omniflox (temafloxacin), approved by FDA in January 1992, was withdrawn in June due to serious multisystem adverse reactions ("The Pink Sheet" June 8, 1992, T&G-1). Phototoxicity is currently addressed in the precautions section of Maxaquin labeling. The package insert, using clinical trial data though February 1992, lists phototoxity as the third most frequent adverse event, at a rate of 2.4%. In July 1992, FDA received results from a 703-patient Swedish trial of lomefloxacin that reported a 10% rate of photosensitivity in patients on a seven-day Maxaquin regimen and a 4% rate in those on a three-day regimen. In February, Searle proposed stronger labeling to the FDA that would recommend that patients be told to avoid "to the maximum extent possible sunlight during treatment with lomefloxacin and for a few days after therapy and to discontinue therapy as soon as phototoxicity (sunburn) occurs." Lomefloxacin has the largest number of spontaneous reports of phototoxicity submitted to FDA from start of marketing through March 1993: 238, compared to 156 for piroxicam (Pfizer's Feldene and generics), 113 for the sunscreen ingredients avobenzone/padimate O, 97 for fluoxetine (Lilly's Prozac) and 73 for isotretinoin (J&J's Retin-A). Anti-Infective Drugs Division Director Murray Lumpkin, MD, stressed that reporting data, which contains duplication, should not be used quantitatively, but "may signal a problem." FDA has reports of 182 individual patients (including international cases) experiencing phototoxicity associated with Maxaquin in its database, compared to exposure of 259,000 U.S. prescriptions for Maxaquin written since approval. Of the 182 cases, seven were classed as "serious." Searle uses a larger database, estimating 1.17 mil. exposures through the end of January based on U.S. scripts and samples, and includes U.S. phototoxicity reports through the end of January totaling 191. In that time period, there were also 23 international reports of phototoxicity, Searle said. Searle estimated that in the U.S. two samples have been distributed for every one prescription. Maxaquin is approved in Japan, Italy, and some Latin American countries. Searle withdrew an application for approval in Sweden "for business reasons," the firm said. The committee unanimously agreed that a bold-type section including results of the Roche study suggesting possible enhanced animal photocarcinogenicity be added to the precautions section of labeling. The precaution section "will probably give [prescribers] at least a level of suspicion following their patients. But more than that it will send a message to [Searle] to look further into this and to come back to us or the FDA with more definitive studies," voting dermatologic committee consultant Wilma Bergfeld, MD, said. In the Roche toxicity study, conducted in Basel, Switzerland, hairless mice were dosed five times every two weeks with either lomefloxacin, fleroxacin, ofloxacin (Ortho's Floxin), ciprofloxacin (Miles' Cipro), nalidixic acid, or 8-MOP and exposed to one and one-half hours of UVA radiation. Lomefloxacin produced 29 squamous cell carcinomas, compared to 12 due to 8-MOP and one due to fleroxacin. Lomefloxacin also showed a shorter mean latency period (the time period until at least half of the animals studied have any type of tumor) of 22 weeks, compared to 38 weeks for fleroxacin and 66 weeks or more for the other drugs. Searle consultant Robert Stern, MD, Harvard Medical School, questioned the study's methodology and applicability, telling the committee that "the conditions of this experiment, especially the wavelengths of light used and the variations in drug dosage, do not permit determination of the relative photocarcinogenic potential of the various quinolones in conditions of human use. Given that quinolones are prescribed for relatively short periods of time, and considering exposure parameters of this experiment, the absolute and attributable risk of skin cancer due to quinolone exposure in humans is unlikely to be measurable and not clinically relevant." Searle is willing to discuss with FDA undertaking an animal photocarcinogenicity study that "has more relevance" and "is properly done," the firm said. Schroeter said he "would like to see this study in mice repeated with more specific light spectrums that are in the absorption area of those particular quinolones." He also suggested that data and skin samples from the Roche study be looked at by more pathologists and dermatologists to better define the types of tumors found. Chronic use photocarcinogenicity data could be relevant in the context of off-label use, Schroeter said: "There is a huge volume of use which we have to admit is outside the labeling and it's long term and prophylactic and at maximum dose." Schroeter and Beam listed applications such as the treatment of chronic prostatitis, which Beam estimated would receive six to 12 weeks of therapy or more, and complications of osteomyelitis and infectious eczematoid dermatitis.

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