Drug Updates

Safety Issues: Interactions, Label Changes, and Warnings

Anti-Epileptic Drugs (AEDs): In 2008, the Food and Drug Administration (FDA) informed healthcare professionals that they were analyzing reports of suicidality (suicidal behavior or ideation) from placebo-controlled trials of 11 AEDs.¹ These agents are used to treat psychiatric disorders, pain, epilepsy, and other conditions. In the FDA analysis, they found that patients treated with AEDs had about twice the risk of suicidal behavior or ideation (0.43%) compared with patients receiving placebo (0.22%). This was noted as soon as one week after starting therapy until 24 weeks of therapy. The results were relatively consistent among all agents. The relative risk for suicidality was higher in epilepsy patients compared with patients using an AED for another condition.²

Based on these outcomes (completed in December 2008), the FDA mandated that all manufacturers of AEDs include a label warning and develop a medication guide for patients dispensed these agents, informing them of these risks. The complete list of AEDs includes:

• carbamazepine (Carbatrol, Equetro, Tegretol, Tegretol XR);
• clonazepam (Klonopin);
• clorazepate (Tranxene);
• divalproex sodium (Depakote, Depakote ER, Depakene);
• ethosuximide (Zarontin);
• ethotoin (Peganone);
• felbamate (Felbatol);
• gabapentin (Neurontin);
• lamotrigine (Lamictal);
• lacosamide (Vimpat);
• levetiracetam (Keppra, Keppra XR);
• mephenytoin (Mesantoin);
• methsuximide (Celontin);
• oxcarbazepine (Trileptal);
• phenytoin (Dilantin Suspension);
• pregabalin (Lyrica);
• primidone (Mysoline);
• rufinamide (Banzel);
• tiagabine (Gabitril);
• topiramate (Topamax);
• trimethadione (Tridione);
• and zonisamide (Zonegran).³

Bisphosphonates (BPs) and Osteonecrosis of the Jaw (ONJ): Sedghizadeh et al. reported on their single-institution, retrospective evaluation of the electronic medical records at the University of Southern California (USC) in Los Angeles for patients that were diagnosed with ONJ and had received or were receiving alendronate.⁴ Their intent was to determine if ONJ occurrence is more common than had been suggested by the FDA or the American Dental Association’s (ADA’s) expert panel. Initially reported as a rare occurrence at an incidence of 0.7 per 100,000 person-years of exposure or 170 cases worldwide, these investigators identified 208 patients with a history of alendronate use. Of these 208 patients, nine had active ONJ and were being treated in the USC dental clinic. These nine patients corresponded to one in 23 patients receiving alendronate, or about 4% of the population. All cases occurred after tooth extraction or denture trauma resulting in jawbone exposure. BPs are thought to inhibit osteoclast function, leading to cell death and an overall decrease in bone breakdown. Once BPs are integrated into mineralized bone, they stay in the bone for a long time; due to their long half-lives, ONJ can occur long after patients have discontinued BP treatment as well as while they are on therapy. Most ONJ cases have occurred in the newer generation nitrogen-containing BPs which include alendronate, ibandronate, pamidronate, risedronate, and zoledronate.⁵ The ADA Scientific Affairs Council states that routine dental treatment should not be changed based on BP use.⁶