The FDA has accepted the New Drug Application (NDA) for lower dose submicron indomethacin, a nonsteroidal antiinflammatory drug (NSAID) with a proposed indication of treating adults with mild to moderate acute pain.8
Drug Safety
Last month, the FDA issued a safety communication related to the appearance of serious but rare dermatologic reactions with acetaminophen including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and acute generalized exanthematous pustulosis (AGEP).9 The FDA is now requiring that a warning be added to the prescription drug product labels containing acetaminophen. Over-the-counter acetaminophen manufacturers will also be required to add a warning about these serious reactions to these products. NSAIDs already have a similar warning on their labels. Evidence supporting causality of these reactions is mostly from a small number of cases published in the medical literature where patients were rechallenged with acetaminophen, and had a recurrence of the skin reaction. The FDA Adverse Event Reporting System (FDA AERS) database and case-control studies provided additional case information. There were three cases of a positive rechallenge in the FDA data. In the medical literature, there were additional cases of SJS, AEP, and TEN (in 3, 6, and 17 patients, respectively) where the only administered drug before the reaction occurred was acetaminophen, or acetaminophen hypersensitivity was confirmed by skin testing or other means. In a review of the FDA AERS (1969 to 2012), there were 16 cases of AGEP and 91 cases of SJS/TEN, resulting in 67 hospitalizations and 12 deaths. Most of these cases were for single-ingredient acetaminophen products. Of the 91 cases of SJS/TEN cases, six were determined to be probably associated with acetaminophen, the rest of the cases were categorized as possibly related to acetaminophen use.
In late July, the FDA took several actions related to ketoconazole (Nizoral) oral tablets with label changes and a new medication guide.10 Topical ketoconazole formulations are not affected by this safety update. The FDA’s actions include limiting the use of oral ketoconazole due to its ability to cause severe hepatotoxicity and adrenal insufficiency, as well as the potential to cause significantly harmful drug interactions. Through its inhibition of the cytochrome P450 3A4 isoenzyme (CYP3A4) system, ketoconazole can block adrenal steroid production, potentially leading to male gynecomastia and menstrual irregularities, particularly at high doses. Additionally, clearance of coadministered drugs that are metabolized by CYP3A4 are decreased by ketoconazole and can result in increased plasma drug concentrations leading to potentially serious adverse reactions including QT prolongation. Some drug combinations with ketoconazole are therefore restricted or contraindicated (check the drug’s interactions and contraindications section of the label to determine which agents). The new ketoconazole oral tablets labeling states that it should not be a first-line treatment for any fungal infection. Oral ketoconazole is not indicated for the treatment of fungal skin or nail infections. Oral ketoconazole should only be used for the treatment of blastomycosis, coccidioidomycosis, histoplasmosis, chromomycosis, and paracoccidioidomycosis in patients where other treatments have failed or have not been tolerated. Oral ketoconazole is also contraindicated in patients with acute or chronic liver disease, and with other hepatotoxins. Alcohol should be avoided while taking this agent. When evaluating any potential patient for use of oral ketoconazole, all the patient’s concomitant medications should be evaluated, to prevent any potentially serious outcomes. Patients with adrenal insufficiency or with borderline adrenal function should be closely monitored, as should patients under extended stress periods.
