Drug Safety Oversight Board Meeting, September 15, 2011

Public Summary

The following is a list of the Drug Safety Communications (DSC) posted since the July 21, 2011 meeting and relayed to the Drug Safety Oversight Board (DSB or Board) via memorandum:

• September 7, 2011: Drug labels for the Tumor Necrosis Factor-alpha (TNFα) blockers now include warnings about infection with Legionella and Listeria bacteria: FDA issued a communication informing healthcare professionals that the Boxed Warning for the entire class of TNFα blockers has been updated to include the risk of infection from Legionella and Listeria. In addition, the Boxed Warning and Warnings and Precautions sections of the labels for all of the TNFα blockers have been revised so that they contain consistent information about the risk for serious infections and the associated disease-causing pathogens.
• September 1, 2011: Serious allergic reactions reported with the use of Saphris (asenapine maleate): FDA issued a communication informing the public of hypersensitivity reactions, including anaphylactic reactions and angioedema, associated with Saphris. This information will be included in the Contraindications, Warnings and Precautions, Adverse Reactions, and Patient Counseling Information sections of the product labeling.
• September 1, 2011: New contraindication and updated warning on kidney impairment for Reclast (zoledronic acid): FDA issued a communication informing healthcare professionals and patients of updated labeling on the association of Reclast and renal failure in patients with a history of or risk factors for renal impairment. Cases of acute renal failure requiring dialysis or having a fatal outcome following Reclast use have been reported to FDA. The Medication Guide has also been updated and a Dear Healthcare Provider Letter will be issued.
• August 24, 2011: Abnormal heart rhythms associated with high doses of Celexa (citalopram hydrobromide): FDA issued a communication informing healthcare professionals and patients that citalopram hydrobromide should no longer be dosed at greater than 40 mg per day because it can cause QT prolongation. Previously, the citalopram drug label stated that certain patients may require a dose of 60 mg per day.
• August 4, 2011: Updated drug labels for pioglitazone-containing medicines: FDA issued a communication to update the DSC issued on June 15, 2011, regarding an ongoing safety review of Actos and increased risk of bladder cancer. This update informs the public that FDA has approved updated labeling for pioglitazone-containing medications to include safety information that the use of such drugs for more than one year may be associated with an increased risk of bladder cancer.
• August 4, 2011: Safety review update of Recombinant Human Growth Hormone (somatropin) and possible increased risk of death: FDA issued a communication to update the DSC issued on December 22, 2010, regarding an ongoing safety review of recombinant human growth hormone and possible increased risk of death. FDA determined that at this time, the evidence regarding recombinant human growth hormone and increased risk of death is inconclusive after analysis of the Sante Adulte GH Enfant (SAGhE) study, the medical literature, and reports from AERS. FDA will continue to review additional data from the SAGhE study and will update the public when new information is available.
• August 3, 2011: Use of long-term, high-dose Diflucan (fluconazole) during pregnancy may be associated with birth defects in infants: FDA issued a communication to inform the public that chronic, high doses (400-800 mg/day) of Diflucan may be associated with a rare and distinct set of birth defects in infants whose mothers were treated with the drug during the first trimester of pregnancy. Therefore, the pregnancy category for fluconazole indications (other than vaginal candidiasis) has been changed from category C to category D.
• July 26, 2011: Serious CNS reactions possible when linezolid (Zyvox) is given to patient taking certain psychiatric medications: FDA issued a communication that serious CNS reactions can occur when Zyvox is given to patients taking serotonergic psychiatric medications. Safety information about potential drug interactions and important drug usage recommendations for emergency and non-emergency settings are being added to the drug labels for serotonergic psychiatric medications and Zyvox.
• July 26, 2011: Serious CNS reactions possible when methylene blue is given to patients taking certain psychiatric medications: FDA issued a communication that serious CNS reactions can occur when methylene blue is given to patients taking serotonergic psychiatric medications. Safety information about potential drug interactions and important drug usage recommendations for emergency and non-emergency settings are being added to the drug labels for serotonergic psychiatric medications.
• July 26, 2011: FDA alerts healthcare professionals to stop performing heart scans with CardioGen-82 due to potential for increased radiation exposure in patients: FDA issued a communication to update the DSC issued on July 15, 2011, regarding increased radiation exposure due to undetected strontium breakthrough when using CardioGen-82 for cardiac PET scans. This update alerted healthcare professionals to stop using CardioGen-82 for cardiac PET scans and that Bracco Diagnostics, Inc. decided to voluntarily recall the drug.
• July 22, 2011: Chantix (varenicline) drug label now contains updated efficacy and safety information: FDA issued a communication to update the DSC issued on June 16, 2011, regarding revised labeling for Chantix. The revised labeling includes updates to the Dosage and Administration, Warnings and Precautions, Adverse Reactions, Clinical Studies, Patient Counseling Information, and Medication Guide on the following: updated information on the use of Chantix in patients with stable cardiovascular disease, information on the use of the drug in patients with COPD, and alternative directions for patients to select a quit smoking date after they have already started Chantix.
• July 21, 2011: Multaq (dronedarone) and increased risk of death and serious cardiovascular adverse events: FDA issued a communication that it is reviewing data from a clinical trial titled Permanent Atrial fibriLLAtion Outcome Study Using Dronedarone on Top of Standard Therapy (PALLAS) that evaluated the reduction of major cardiovascular events or unplanned cardiovascular hospitalization or death from any cause with Multaq in patients aged 65 and older with permanent atrial fibrillation. The study was stopped early because of a two-fold increase in death and two-fold increases in stroke and hospitalization for heart failure compared to patients taking placebo.
• July 21, 2011: Ongoing safety review of oral osteoporosis drugs (bisphosphonates) and potential increased risk of esophageal cancer: FDA issued a communication that it continues to review data from published studies to evaluate whether use of oral bisphosphonate drugs is associated with an increased risk of esophageal cancer. There have been conflicting findings from studies evaluating this risk, but FDA believes that the benefits of oral bisphosphonates in reducing the risk of serious fractures in people with osteoporosis continue to outweigh the potential risks.
• July 15, 2011: Increased radiation exposure due to undetected strontium breakthrough when using CardioGen-82 for cardiac positron emission tomography (PET) scans: FDA issued a communication informing the public and the medical imaging community about the potential for inadvertent, increased radiation exposure in patients who underwent or will be undergoing cardiac PET scans with rubidium (Rb)-82 chloride injection from CardioGen-82 (manufactured by Bracco Diagnostics, Inc.). FDA is actively investigating the root cause of this failure and will promptly notify the public with updates.

The DSB discussed three topics:

1. CDER Adoption of USP Monograph Naming Policy
2. Discuss Safety Issues/Key Messages in DSC for Prescription Sleep Aid
3. Opioid Risk Evaluation and Mitigation Strategy (REMS) Blueprint and Med Guide

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

CDER Adoption of USP Monograph Naming Policy

The Board heard presentations from Angela G. Long, M.S., Vice President, Office of the CEO, Executive Secretariat, Council of Experts of the United States Pharmacopeia (USP) and Richard Lostritto, Ph.D., Director of Division I, Office of New Drug Quality Assessment, on the Center for Drug Evaluation and Research’s (CDER) implementation of the USP Monograph Naming Policy for Salt Drug Substances in Drug Products and Compounded Preparations (“the monograph naming policy”).

Ms. Long provided an introduction to and history of USP, as well as USP’s role in drug naming. She also described in detail the monograph naming policy which will be official May 1, 2013. Ms. Long also discussed the monograph naming policy’s implementation, including proposed timeline and dissemination of key messages to targeted groups via various formats, and the challenges of implementation. Specifically, titles for drug product monographs submitted prior to the official date of May 1, 2013, will use the name approved by FDA with respect to active moiety/salt nomenclature in the title/strength terminology, except in cases where safety issues are involved or where the relevant manufactures in the United States market agree to a name that conforms to the monograph naming policy. The Nomenclature, Safety, and Labeling Expert Committee will apply the monograph naming policy to drug product titles after May 1, 2013. The policy is provided in General Chapter <1121> Nomenclature and is posted on USP’s website. Minor corrections to the policy are proposed in an update to General Chapter <1121>, which will be published for public comment in January 2012.

Dr. Lostritto provided CDER’s perspective of the monograph naming policy and its implementation process.

The Board discussed the following:

• Consideration should be given to dosing differences (mg, units) with drugs named by their active moiety versus their salt form. For example, the combination product amlodipine and benazepril hydrochloride tablet has the strength for amlodipine expressed in terms of the active moiety but the strength for benzapril is expressed in terms of the salt.
• Drug products named with one active moiety but available in multiple salt formulations and whether there will be an impact on prescribing, whether this will be interpreted to indicate/replace therapeutic equivalence, and if there will be any effects on Orange Book listings and drug marketing/promotion. If the salt is clinically relevant, the drug name will include the salt. If the salt is not clinically relevant, multiple products could share the same drug product name; however, this does not mean they are therapeutically equivalent – the Orange Book will differentiate them by listing each salt separately. An example of oxycodone and aspirin tablets was presented.
• The various interpretations of the phrase “clinically relevant effect” in the definition of “vital information from a clinical perspective.” “Vital information from a clinical perspective” means that the salt has a clinically relevant effect on absorption, metabolism, or excretion which impacts safety and/or efficacy. Determination of clinical relevancy is a review decision.
• Education for patients on medications that are therapeutically equivalent but may be different in appearance, and may have differences in dosage amounts.
• Education for prescribers and pharmacists on electronic and handwritten prescriptions to help eliminate potential delay in patients receiving medications because of confusion.
• Various communication tools and distribution methods to consider as part of the rollout plan.

Discuss Safety Issues/Key Messages in Draft DSC for Prescription Sleep Aid

The Board heard a presentation by Ronald Farkas, MD, PhD, Clinical Team Leader in the Division of Neurology Products (DNP) in CDER regarding prescription sleep aids and risk of next-morning driving impairment.

The Board discussed the following:

• Impact on next-day driving impairment by prescription sleep aids, and comparison of the drug product’s effect with that of other prescription sleep aids.
• Driving test requirements for sponsors of prescription sleep aids.
• Consideration of non-sleep aid prescription and over-the-counter drugs with longer half-lives than prescription sleep aids and their impact on next-day driving.
• The types of patients included in the driving studies, the contribution of concomitant medications to next-morning driving impairment, and other implications of the driving study results.
• Communicating a message about using prescription sleep aids wisely/as labeled.

Opioid REMS Blueprint and Med Guide

The Board heard presentations from Theresa Toigo, RPh, MBA, Associate Director for Drug Safety Operations, Office of the Center Director in CDER and Richardae Araojo, PharmD, MS, Acting Director, Division of Medical Policy Programs, Office of Medical Policy Initiatives in CDER providing updates on the Opioid REMS Prescriber Education Program (“the Blueprint”) and Medication Guide (Med Guide).  An overview of the opioid REMS was presented at the March 18, 2010, Board meeting.

The Board discussed the following:

• Relationship and collaboration with other federal agencies and programs.
• Sufficient granularity of information and criteria to complete and assess the continuing education program.
• The focus of the opioid REMS and comparison to other REMS.