FDA has cited a number of unresolved consumer safety concerns in GlaxoSmithKline's Rx-to-OTC switch application for weight-loss drug Alli ( Xenical /orlistat 60 mg) stemming from self-selection issues observed in the drug's actual use study.

The primary self-selection concerns center around patients taking contraindicated drugs and improper multivitamin supplementation, FDA Reviewer Karen Feibus, MD, explains in a clinical review of the switch application released Jan. 20.

"Preliminary evidence suggests that nonprescription labeling may not adequately direct the safe use of orlistat," clinical reviewer Julie Golden, MD, adds in a same-day briefing document.

The review documents were released prior to an evaluation of the switch application by the Nonprescription Drugs and Endocrinologic & Metabolic Drugs advisory committees scheduled for Jan. 23.

The drug facts label in the actual use study instructs potential users not to use orlistat if they are taking prescription diabetes medication, warfarin or cyclosporine.

However, in the actual use study "after reading the Drug Facts sheet for nonprescription orlistat, only 35% of subjects taking medication for diabetes mellitus correctly stated that the drug was not appropriate for their use. Moreover, 50% of patients on cyclosporine or warfarin failed to realize that they should not take orlistat while on these medications," Golden states.

Additionally, nearly 90% of subjects taking other weight-loss agents incorrectly self-selected the drug. The label instructed potential users to consult a doctor or pharmacist before use if they were taking other weight loss medications or supplements.

Some of the warnings on the label used in the actual use study, such as those for people with hypertension, more than 30 pounds to lose or on a doctor-recommended diet are not included on the drug facts label submitted with GSK's switch application, making improper selection based on those criteria moot.

"However, the behavioral disregard for the label warnings on this product is concerning, as it may reflect a general behavioral pattern among consumers who would use this product regardless of actual label warnings," Feibus points out.

Proper multivitamin supplementation with orlistat is another safety concern pointed out by reviewers.

Taking a multivitamin is recommended for orlistat users since the drug can inhibit the absorption of fat soluble vitamins such as vitamins A, D, E and beta carotene.

Additionally, orlistat users are instructed to take the multivitamin at least two hours before or two hours after taking orlistat to ensure proper absorption of the fat soluble vitamins.

In the actual use study, 75%-86% of orlistat users took a multivitamin and approximately 80% of the multivitamin users took the multivitamin daily.

"However, only 38%-53% of study participants interviewed timed the [multivitamin] correctly with their orlistat," according to the review.

Incorrect multivitamin use during the actual use study may be due to consumer confusion about instructions for use on the multivitamin label that conflict with multivitamin use on the orlistat label, Feibus suggests.

Information about multivitamin use was moved to the "Directions" section of the label for the label comprehension study whereas in the actual use study it was located at the bottom of the Drug Facts label under the heading "Other Information."

However, only 47%-48% of the general population group and 34%-36% of the low literacy group correctly responded that orlistat users should take a daily multivitamin two hours before or after taking orlistat to ensure adequate vitamin absorption despite the more prominent placement of the multivitamin instructions.

Additionally, chances of vitamin deficiency could increase if consumers take orlistat OTC for longer than the recommended six months.

One way to combat potential deficiency of fat soluble vitamins in orlistat users is for GSK to consider co-packaging a multivitamin with OTC orlistat, Feibus suggests.

"If co-packaging does not occur, the sponsor should provide explicit instruction to consumers about when to take the multivitamin and what the multivitamin should contain," Feibus asserts.

- Jessica Lake

Self-Selection Doubts Are No Friend To Alli As Xenical Heads For Switch Panel

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