Drug Safety Oversight Board Meeting, September 16, 2010

Public Summary

The Executive Director updated the Drug Safety Oversight Board (DSB or Board) on Drug Safety Communications posted and in development since the July 15, 2010 meeting. The following is a list of the posted risk communications:

Drug Safety Communications Posted since the July 15, 2010 DSB meeting:

• July 15, 2010: Ongoing safety review of the angiotensin receptor blockers and cancer: FDA issued a DSC to inform health care professionals and the public that it is conducting a review of the class of medications known as angiotensin receptor blockers (ARBs) after a recently published study suggested they may be associated with a small increased risk of cancer.
• July 29, 2010: Eosinophilic pneumonia associated with the use of Cubicin (daptomycin): FDA issued a DSC to inform health care professionals and patients about the potential for developing eosinophilic pneumonia during treatment with Cubicin (daptomycin), an intravenous antibacterial drug.
• July 29, 2010: Ongoing safety review of Evamist (estradiol transdermal spray) and unintended exposure of children and pets to topical estrogen: FDA issued a DSC to inform health care professionals and the public that it is reviewing reports of adverse effects from Evamist in children who may have been unintentionally exposed to the drug through skin contact with women using this product. FDA has also received reports of inadvertent exposure in pets.
• August 2, 2010: Serious medication errors from intravenous administration of nimodipine oral capsules: FDA issued a DSC to alert health care professionals that nimodipine capsules should be given only by mouth or through a feeding tube (nasogastric tube). This oral medication should never be given by intravenous administration. FDA continues to receive reports of intravenous nimodipine use, with serious, sometimes fatal, consequences. Intravenous injection of nimodipine can result in death, cardiac arrest, severe falls in blood pressure, and other heart-related complications.
• August 12, 2010: Aseptic meningitis associated with use of Lamictal (lamotrigine): FDA issued a DSC to inform health care professionals and the public that Lamictal (lamotrigine), a medication commonly used for seizures in children two years and older, and bipolar disorder in adults, can cause aseptic meningitis. FDA is revising the Warnings and Precautions section of the drug label and the patient Medication Guide to include information about this risk.
• August 20, 2010: Ongoing Safety Review of Stalevo and possible increased cardiovascular risk: FDA issued a DSC to inform health care professionals and the public that it is evaluating clinical trial data that suggest patients taking Stalevo (a combination of carbidopa/levodopa and entacapone) may be at an increased risk for cardiovascular events (heart attack, stroke, and cardiovascular death) compared to those taking carbidopa/levodopa (sold as the combination product, Sinemet).
• September 1, 2010: Increased risk of death with Tygacil (tigecycline) compared to other antibiotics used to treat similar infections: FDA issues a DSC informing health care professionals and the public about a recent pooled analysis of 13 trials with patients given Tygacil for approved and unapproved indications. The analysis showed an increase in all-cause mortality in patients taking tigecycline compared to patients taking comparator drugs with a risk difference of 0.6 (95% CI 0.1 - 1.2). The cause of the excess death in uncertain but is most likely related to progression of infection in patients with sever infections. The greatest risk was seen in patients with ventilator-associated pneumonia, an unapproved use.
• September 9, 2010: Gadolinium-based contrast agents and class labeling changes: FDA issued a DSC to inform health care professionals and the public about required label changes for gadolinium-based contrast agents (GBCAs) to minimize the risk of nephrogenic systemic fibrosis (NSF), a rare, but serious, condition associated with the use of GBCAs in certain patients with kidney dysfunction. The label changes include contraindicating Magnevist, Optimark, and Omniscan in patients with acute kidney injury or chronic kidney disease with a GFR <30 mL/min.
• September 15, 2010: New dosing recommendations to prevent potential Valcyte (valganciclovir) overdose in pediatric transplant patients: FDA issued a DSC to inform health care professionals and the public about new pediatric dosing recommendations for Valcyte (valganciclovir hydrochloride) oral tablets and solution. The change is being made to prevent potential overdosing with valganciclovir in children with low body weight, low body surface area, and below normal serum creatinine.

The DSB discussed three topics:
1. Update on Risk Evaluation and Mitigation Strategies (REMS)
2. Stalevo and cardiovascular safety
3. Update on the Safe Use Initiative

The views expressed by non-CDER employees are those of the individual and not necessarily the opinion of their respective government agency.

Update on Risk Evaluation and Mitigation Strategies (REMS)

A REMS is a required risk management plan that uses risk minimization strategies beyond professional labeling. FDA can require a REMS if they believe it is necessary to ensure that the benefits of a drug outweigh its risks.

FDA was given the authority to require REMS in March 2008 under the Food and Drug Administration Amendments Act. The Office of Surveillance and Epidemiology (OSE) presented the DSB with an update on CDER’s experience with REMS during the past 30 months.

The Board discussed the following:

• A brief overview of the REMS program
• The challenges associated with implementing REMS
• The importance of developing REMS that effectively minimize potential risks of using a drug while imposing the least burden
• The challenges associated with review of REMS assessments and development of assessment surveys
• Metrics for REMS assessment and the challenge of determining metrics for success when baseline data are difficult to obtain or are not available
• The challenge of reducing the burden of REMS on the health care system

Stalevo and Cardiovascular Safety

Stalevo is a triple combination product with entacapone, carbidopa, and levodopa approved in 1999 for the treatment of Parkinson’s disease (PD). Entacapone lacks an anti-Parkinson’s effect on its own, but increases the peripheral and brain levodopa availability. Levodopa relieves some of the symptoms of Parkinson’s disease.

On August 20, 2010, FDA posted a Drug Safety Communication (DSC) to inform healthcare professionals and the public about a possible increased risk of cardiovascular (CV) adverse events with the use of Stalevo. FDA Drug Safety Communication: Ongoing Safety Review of Stalevo and possible increased cardiovascular risk.

Board discussed the DSC and any impact it may have had on healthcare professionals and the public.

The Federal Partners with hospitals and clinics provided Stalevo usage patterns including any information about CV adverse events in their patients using Stalevo. The Board invited a guest expert in cardiovascular studies, Dr. Michael Lauer, from the National Heart Lung and Blood Institute (NHLBI) at the National Institutes of Health (NIH). Dr. Lauer provided a research perspective on the use of Stalevo and the risk of CV adverse events.

The Board discussed the following:

• A brief overview of the use of Stalevo and its components: entacapone, carbidopa, and levodopa in patients with PD
• A brief overview of the mechanism of action of entacapone, carbidopa, and levodopa in relieving symptoms of PD
• The current drug label for Stalevo
• Clinical data from the STRIDE-PD randomized trial and epidemiologic data reporting an association of CV risk with Stalevo
• A meta-analysis of 15 clinical trials looking at CV risk with use of Stalevo or its entacapone component.
• The challenges associated with interpreting the meta-analysis given much of the potential signal for CV risk comes from the STRIDE-PD trial.
• The August 20, 2010 DSC on Stalevo and CV risk and its main messages
•  Possible approaches to further evaluating the potential signal for CV risk with Stalevo

Update on the Safe Use Initiative

Safe Use is a FDA initiative to reduce risks from prescription and OTC medications; promote drug safety outside of the usual regulatory authorities, such as REMS or labeling; and form collaborations with health care stakeholders to address preventable harm from a broader perspective.

The priorities for Safe Use are issues that are associated with preventable harm, have an impact on public health, are amenable to a collaborative approach to harm reduction, are measureable, and complement ongoing regulatory activities.

The Board discussed the following:

• A brief overview of the Safe Use program
• Current issues being address by the Safe Use team
• The challenges associated with developing collaborative partnerships
• Future plans for the Safe Use initiative