Drug Safety Oversight Board Meeting, November 17, 2011

Public Summary

The following is a list of the Drug Safety Communications (DSC) posted since the October 20, 2011 meeting and relayed to the Drug Safety Oversight Board (DSB or Board) via memorandum:

• November 9, 2011: Review update of Trilipix (fenofibric acid) and the ACCORD Lipid trial: FDA issued a communication informing the public that the cholesterol-lowering medicine Trilipix (fenofibric acid) may not lower a patient's risk of having a heart attack or stroke. This is based on data from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid trial, which evaluated the efficacy and safety of fenofibrate plus simvastatin combination therapy versus simvastatin alone in patients with type 2 diabetes mellitus. FDA reviewed this trial as part of its ongoing investigation of the safety and efficacy of Trilipix.
• November 4, 2011: Reminder to healthcare providers and patients to enroll in the Avandia-Rosiglitazone Medicines Access Program: FDA issued a communication reminding healthcare providers and patients about the need to enroll in the Avandia-Rosiglitazone Medicines Access Program by November 17, 2011 in order to continue prescribing and receiving rosiglitazone-containing medicines (Avandia, Avandamet, and Avandaryl). After November 18, 2011, rosiglitazone medicines will no longer be available through retail pharmacies and will only be available by mail order through specially certified pharmacies participating in the program.
• November 3, 2011: UPDATE on Tumor Necrosis Factor (TNF) blockers and risk for pediatric malignancy: FDA issued a communication updating the public about its ongoing safety review of Tumor Necrosis Factor (TNF) blockers and malignancy (cancer) in children, adolescents, and young adults (30 years of age or younger). FDA is requiring the manufacturers of TNF blockers to perform enhanced safety surveillance for these products.
• November 1, 2011: Safety Review Update of Medications used to treat Attention-Deficit/Hyperactivity Disorder (ADHD) in children and young adults: FDA issued a communication updating the public that a large, recently-completed study in children and young adults treated with medication for Attention-Deficit/Hyperactivity Disorder (ADHD) has not shown an association between use of certain ADHD medications and adverse cardiovascular events. These adverse cardiovascular events include stroke, heart attack (myocardial infarction or MI), and sudden cardiac death.
• October 27, 2011: Updated information about the FDA-funded study on risk of blood clots in women taking birth control pills containing drospirenone: FDA issued an update in follow-up to the FDA Drug Safety Communication posted on 9/26/2011. FDA is continuing its review of the potential increased risk of blood clots with the use of birth control pills containing drospirenone. FDA is releasing the final report of the FDA-funded study that evaluated the risk of blood clots in users of several different hormonal birth control products (contraceptives).
• October 25, 2011: Voluntary market withdrawal of Xigris [drotrecogin alfa (activated)] due to failure to show a survival benefit: FDA issued a communication informing healthcare professionals and the public that on October 25, 2011, Eli Lilly and Company announced a worldwide voluntary market withdrawal of Xigris [drotrecogin alfa (activated)]. In a recent study, Xigris failed to show a survival benefit for patients with severe sepsis and septic shock. Xigris treatment should not be started in new patients. Xigris treatment should be stopped in patients being treated with Xigris. All remaining Xigris product should be returned to the supplier from whom it was purchased.
• October 24, 2011: Safety review update of Chantix (varenicline) and risk of neuropsychiatric adverse events: FDA has reviewed the results from two FDA-sponsored epidemiological studies that evaluated the risk of neuropsychiatric adverse events associated with the smoking cessation drug Chantix (varenicline). Neither study found a difference in risk of neuropsychiatric hospitalizations between Chantix and nicotine replacement therapy (NRT; e.g., NicoDerm patches). However, both studies had a number of study design limitations, including only assessing neuropsychiatric events that resulted in hospitalization, and not having a large enough sample size to detect rare adverse events
• October 20, 2011: Updated information about the drug interaction between linezolid (Zyvox) and serotonergic psychiatric medications: FDA issued a communication updating the public on the potential drug interaction between linezolid and serotonergic psychiatric medications. FDA is providing additional information about the reports of serotonin syndrome. Not all serotonergic psychiatric drugs have an equal capacity to cause serotonin syndrome with linezolid. Most cases from the FDA's Adverse Event Reporting System (AERS) of serotonin syndrome with linezolid occurred in patients taking specific serotonergic psychiatric drugs, namely a selective serotonin reuptake inhibitor (SSRI) or a serotonin norepinephrine reuptake inhibitor (SNRI)
• October 20, 2011: Updated information about the drug interaction between methylene blue (methylthioninium chloride) and serotonergic psychiatric medications: FDA issued a communication updating the public on the potential drug interaction between methylene blue and serotonergic psychiatric medications. FDA is providing additional information about the reports of serotonin syndrome. Most cases from the FDA's Adverse Event Reporting System (AERS) of serotonin syndrome in patients given serotonergic psychiatric medications and methylene blue occurred in the context of parathyroid surgery, which involved the intravenous administration of methylene blue as a visualizing agent.

The DSB discussed five topics:

1. Patient Provider Agreements
2. Risk Evaluation and Mitigation Strategy (REMS) for a New Drug Application under review.
3. Bar Codes
4. Updates
5. Simvastatin Dosing with Amiodarone

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

Patient Provider Agreements

The Board heard a presentation from Dale Slavin, Ph.D., Safe Use Initiative, Center for Drug Evaluation and Research (CDER), on Patient Provider Agreements (PPAs). Dr. Slavin also provided an overview of FDA’s Safe Use Initiative.

The safe use of opioids and patient prescriber agreements came out of the Risk Evaluation and Mitigation Strategy advisory committee meeting held in July 2011. The issues that lead to preventable harm from opioids include: drug choice, abuse recognition, number of pills being prescribed (dose and schedule), patient taking too many pills, patient sharing and the level of information given to the patient.

The model PPA will be created for any prescriber who prescribes an opioid, a person who might become a long term pain patient, a person who is using opioids for acute pain, and a person who is a long term pain patient. The PPA agreement strawman contains 1) a checklist of all the information regarding risks (including addiction), benefits and limitations of opioid treatment and 2) information on how to safely use opioids. The model PPA agreement will involve implementation and metrics.

The Board discussed the following:

• How will a PPA be used in a patient provider interaction?
• The board members do have experience with these agreements.
• There is a range as to how PPAs are implemented.
• Pill counts and urine testing may be useful.
• Patients who truly want to circumvent the system will find a way to do so.
• PPAs are important.

REMS for a New Drug Application Under Review

The Board heard a presentation from Kim Lehrfeld, PharmD, Division of Risk Management, CDER, about the impact on healthcare facilities of a REMS for a new drug currently under review. The safety issue of concern is bronchospasm.

The Board discussed the following concerning a REMS for the new drug:

• Several board members suggested that accurate medical records for patients will determine who is at risk for lung disease.
• Workflow improvements could help, perhaps pop-ups in electronic health record.
• If the population treated with this product is limited, there may not be much impact from the REMS on the healthcare system.
• Consider reaching out to members of the relevant medical specialty group for their perspective concerning the proposed REMS.

Bar Codes

The Board heard a presentation from Rikin Mehta, Office of Compliance, CDER and Ben Chacko, Regulations and Policy Staff, Center for Biologics Evaluation and Research.

• In May 2001, the U.S. Secretary of Health and Human Services Tommy Thompson, in an appearance before a Senate committee, noted that technology, such as bar codes, could help save lives and money. In July 2011, the American Society of Health System Pharmacists asks Secretary Thompson to have FDA “develop regulations that mandate that drug manufacturers provide a standardized machine-readable code (bar coding) on all drug containers….”. In late 2001, the Department of Health and Human Services directs FDA to begin working on a bar code proposal. FDA published a proposed rule on March 14, 2003 (68 Fed. Reg. 12500). FDA published a final rule on February 26, 2004 (69 Fed. Reg. 9120). The purpose of the bar code rule is to help reduce the number of medication errors in hospital and health care settings. On Aug.11, 2011, FDA published a final guidance: “Guidance for Industry: Bar Code Label Requirements—Questions and Answers” The Agency will now consider requests from vaccine manufacturers who request to use alternate coding technologies, such as two-dimensional symbology.
• On October 26, 2011, FDA published a FR Notice (76 FR 66237) “Bar Code Technologies for Drugs and Biological Products; Retrospective Review Under Executive Order 13563; Request for Comments”. The Agency will use information received (responses to questions in docket and/or other related questions) to assess whether the bar code rule should be modified.

The Board discussed the following:

• A two-dimensional barcode or different barcode maybe preferable to a linear barcode because the linear bar code is hard to read on IV bags and fluids.
• The lot number and expiration date are important information to capture with barcoding.
• One concern about moving to a two-dimensional barcode is the expense of the equipment.

Updates

• Dr. Throckmorton shared some updates with the group concerning several upcoming advisory committee meetings and the number of approvals in fiscal year 2011.

Simvastatin

The Board heard a presentation from Mary Parks, MD, CDER.

One of the Federal partners communicated with FDA concerning the muscle toxicity labeling change for simvastatin. As a result of FDA’s review of a large randomized controlled trial, a DSC was issued in June 2011 concerning the risk of muscle toxicity for simvastatin 80 mg. The DSC referenced recommended dose caps for simvastatin when given with other medications, including a dose cap for amiodarone that was incorrectly listed at 10 mg. The dose limitation decrease associated with amiodarone (lowered from 20 mg to 10 mg) was in error. There were pharmacokinetic and/or clinical trial data to support the revised dose limitations associated with the other interacting drugs, however there were no such data to support lowering the maximum dose of simvastatin when it is taken with amiodarone. FDA has since evaluated the available data on simvastatin and amiodarone and has determined that the dose limitation should remain 20 mg. An addendum to the June 2011 review updated the labeling to correctly reflect that the amiodarone dose cap is 20 mg. FDA is planning to update the DSC and will send the draft communication to the Federal Board members for feedback before public issuance.

The Board discussed the following:

• FDA communications directly impact healthcare facilities.
• Information sharing between FDA and its Federal Partners is important.