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

BPs and Atrial Fibrillation: In November, the FDA reported on evaluated data regarding the potential increased risk of atrial fibrillation in patients treated with BPs.⁷ Data reviewed included that of 19,687 BP-treated patients and 18,358 placebo-treated patients who were followed for six months to three years.⁸ The FDA has found no clear relationship between BP use and the rate of any type of atrial fibrillation.

According to a study presented at the American Heart Association meeting in November 2008, utilizing proton pump inhibitors (PPIs) along with clopidogrel may increase the risk of major cardiovascular (CV) events (e.g., stroke, hospitalization, angina, myocardial infarction or coronary bypass graft).⁹ A retrospective cohort of patients (n=14,383) that received clopidogrel to prevent coronary stent re-thrombosis during the year 2005–2006 was evaluated. Patients were followed for the one-year incidence of major adverse CV events in those that took clopidogrel alone (n=9,862) compared with those that took clopidogrel and a PPI (n=4,521). In patients with no preceding CV events, the incidence of a major CV event was 33% in those who took a PPI with clopidogrel versus 21% in those who did not. A more distinct effect was seen in patients with a prior CV event. The risk of a major CV event was 50% higher and the relative risk for a myocardial infarction was 74% higher in the patients taking both drugs together. The FDA’s clinical pharmacology division is evaluating how the two drug classes can be safely used together.¹⁰

A Web Site to Help Prevent Medication Errors

A new Web site was developed by the Institute for Safe Medication Practices (ISMP) to empower patients and the healthcare community to prevent medication errors and adverse drug events.¹¹ Through this new site, the ISMP hopes to collect and analyze reports of medication-related problems (MRPs); disseminate timely medication safety information; educate consumers and healthcare providers; collaborate with other groups to improve medication safety; promote adopting safe medication standards by accrediting bodies, manufacturers, policy makers, regulatory agencies, etc.; and other related endeavors. There is a user-friendly tool to directly report medication errors or adverse drug reactions (by the patient or the healthcare provider). Alerts can be customized to include a list of commonly used medications or a patient’s own medications, or it can be checked for individual patients prior to prescribing. The site and alerts routinely check the safety of medications and screen for drug–drug and drug–disease interactions to help patients and their healthcare providers keep abreast of changing drug information.

New Approvals

Milnacipran (Savella), a new selective serotonin and norepinephrine reuptake inhibitor (SNRI), was approved by the FDA for treating fibromyalgia.¹² Milnacipran is similar to other SNRIs used for depression or other psychiatric disorders.¹³ Life-threatening serotonin syndrome may occur when combining it with SNRIs or similar agents (e.g., selective serotonin reuptake inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors, triptans, tramadol, tapentadol, or other drugs which impair serotonin metabolism). In trials, patients reported pain relief, improved functional ability, and an improved sense of well-being. Mild alanine aminotransferase and aspartate aminotransferase elevations have been reported. The most common side effects in clinical trials were constipation, hot flush, hyperhidrosis, vomiting, palpitations, increased heart rate, dry mouth, and hypertension. Practitioners should monitor a possibly increased blood pressure and heart rate prior to initiating therapy and periodically throughout treatment. This agent should be prescribed with caution in patients with a seizure disorder or with any condition that puts a patient at risk for seizures. Other cautions and contraindications exist.

Naproxen sodium controlled release (Naprelan) is now also available in 500- and 750-mg strengths in addition to the original 375-mg strength.¹⁴

Tapentadol, a new immediate-release centrally acting oral analgesic, was FDA-approved in late November to treat moderate to severe acute pain in adult patients. As of late January 2009, it had not yet been assigned a brand name.¹⁵ It is both a mu-opioid receptor agonist and a norepinephrine reuptake inhibitor and will be available in 50-, 75-, and 100-mg tablets. It is currently being evaluated by the FDA for scheduling. The most common adverse events in studies were nausea, dizziness, vomiting, somnolence, and headache. Life-threatening serotonin syndrome may also occur with this agent, similar to the information reported above for milnacipran. This agent should also be used cautiously in any patient with a history of seizures or with any condition that puts that patient at risk for seizures. Other cautions and contraindications exist.

Tramadol HCl extended release (Ryzolt) has been FDA approved as a once-daily treatment for moderate to severe chronic pain in adults who require 24-hour pain management.¹⁶ The formulation is composed of immediate- and extended-release layers of tramadol. It is anticipated that it will be available in the second quarter of 2009 and in 100-, 200-, and 300-mg doses.

In the Pipeline

On July 29, 2008, the Arthritis Advisory Committee of the FDA voted 10–1 to recommend approval of tocilizumab (Actemra, Roche), a humanized interleukin-6 receptor-inhibiting monoclonal antibody.¹⁷ As a result of the FDA’s evolving Risk Evaluation and Mitigation Strategy (REMS) requirements, a REMS plan will be required for tocilizumab. Additionally, based on the newer requirements for approving new biologics, the FDA has asked Roche to provide more nonclinical animal model data than was provided in their original biologics license application.¹⁸ Roche is performing the needed studies, noting that the drug does not affect peri- and post-natal development and fertility. According to one source, this is a potential 12- to 18-month setback for Roche in the United States. Tocilizumab received a positive opinion in November by European regulators for use in combination with methotrexate to treat adults with moderate to severe rheumatoid arthritis who have not responded to other treatments. Tocilizumab was approved in Europe on January 21, 2009.^{19, 20}

Michele Kaufman is a freelance medical writer based in New York City.

Safety Issues: Interactions, Label Changes, and Warnings

A Web Site to Help Prevent Medication Errors

New Approvals

In the Pipeline

References

Reading Rheum

Osteonecrosis of the Jaw

Drug Updates

Drug Updates

Safety Issues: Interactions, Label Changes, and Warnings

A Web Site to Help Prevent Medication Errors

New Approvals

In the Pipeline

References

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