Drug Updates

Safety Warnings and Label Changes

A possible market withdrawal may be imminent for propoxyphene-containing products. In December 2008, the American Society of Health-Systems Pharmacists (ASHP) sent a petition to the Food and Drug Administration (FDA) asking for the removal of propoxyphene-containing products from the US market due to poor effectiveness and safety profiles.¹ On March 2, 2009, the ASHP reported a close vote of 14 to 12 in favor of the removal of propoxyphene-containing products from the US market based on testimony from a joint meeting of the FDA’s Drug Safety and Risk Management and Anesthetic and Life Support Drugs Advisory Committees on January 30.² Issues included are its relationship to drug-related deaths, limited analgesic usefulness, and unfavorable risk-to-benefit ratio. At press time, a final decision had not been made.

Wearing medicated transdermal patches while undergoing magnetic resonance imaging (MRI) scans can cause skin burns on the direct patch area.³ Some transdermal patches contain metallic backing or other layers that can overheat during an MRI scan. Patches have many indications including anti-emetics (e.g., granisetron), antidepressants (e.g., selegiline), hormone replacement (e.g., estrogen, testosterone), analgesia (e.g., fentanyl), and smoking cessation (e.g., nicotine). The FDA is evaluating patch contents and labeling to ensure that patients receive this warning about burns. Until the FDA makes a final decision, healthcare providers are asked to warn patients wearing a medicated patch to remove and dispose of it prior to undergoing an MRI. After the scan, the patch should be replaced. When filling out the health history questionnaire at the time of an MRI, patients should include information about medicated transdermal patches.⁴

Genentech is voluntarily withdrawing efalizumab (Raptiva), a medication for treatment of psoriasis, from the U.S. market due to a potential risk to patients of developing progressive multifocal leukoencephalopathy (PML).⁵ The phased withdrawal will run through June 8, 2009, at which time the drug will no longer be available in the United States. Physicians are being asked not to start any new patients on efalizumab and to discuss alternate therapies with their patients currently taking efalizumab.

Bisphosphonate-associated Osteonecrosis

Around the time that Sedghizadeh et al were conducting and reporting on bisphosphonate-related osteonecrosis of the jaw (BRONJ) [See “Reading Rheum,” p. 20], the American Dental Association Council on Scientific Affairs updated their recommendations for managing patients taking oral bisphosphonates.^6-7 They note that the risks of developing BRONJ from oral bisphosphonate therapy remains small compared with the risk associated with IV bisphosphonates, a comparison of approximately 0.04% and 20%, respectively. Management of general dentistry for patients taking oral bisphosphonates should include routine dental examinations and routine dental care. Those patients taking oral bisphosphonates who do not receive regular dental care should and would benefit from a comprehensive oral examination. Patients taking oral bisphosphonates should be informed of the following:

• That they are at a low risk of developing BRONJ of the jaw (estimates of zero to 1 in 2,260 cases);
• The low BRONJ risk may be minimized but not eliminated;
• The optimal approach to lowering BRONJ risk may be via good oral hygiene practices and usual care;
• No validated diagnostic techniques are available to determine who is at increased risk of BRONJ;
• Discontinuing bisphosphonates may not eliminate the risk of BRONJ;
• A dentist should be consulted if there are any oral cavity–related problems that develop while receiving bisphosphonate therapy; and
• Any discussions about whether or not to continue bisphosphonate therapy should be held with the prescribing physician. The risk–benefit ratio of oral bisphosphonate therapy should be evaluated, because the benefit often might outweigh the risk.

The goal in BRONJ prevention is to limit the possibility of extensive involvement. The advisory statement discusses management of periodontal disease, implant placement/maintenance, and other dental-related procedures. It is available at http://jada.ada.org/cgi/reprint/139/12/1674.

Bisphosphonates and Esophageal Cancer

In the January 1, 2009 issue of the New England Journal of Medicine, Diane Wysowski, PhD, from the FDA, reported on information regarding esophageal cancer in U.S. patients treated with bisphosphonates. Data from October 1995 through mid-May 2008 were analyzed.⁸ Dr. Wysowski reported that there have been 23 cases (eight of them fatal) of esophageal cancer associated with alendronate. Alendronate was the suspect drug in 21 cases and used as concomitant therapy in two. No other esophageal cancer cases were reported with other oral bisphosphonates. Abroad, an additional 31 cases (six of them fatal) were reported in Europe and Japan. In these cases, alendronate was the suspect drug in 21 cases. For remaining cases, the following drugs were implicated: risedronate, ibandronate, etidronate, or a combination of these. Four cases noted “bisphosphonates” without specifying the drug. The majority of cases were women (>71%) with median ages of 74 years (US) and 68.5 years (abroad). The median exposure time from alendronate use to diagnosis was 2.1 years (US) and 1.3 years (abroad). Barrett’s esophagus was diagnosed near the time of the esophageal cancer diagnosis in three patients. Five patients had squamous-cell carcinoma and six had adenocarcinoma.

The author noted that esophagitis has been associated with oral bisphosphonates and this usually occurs when drug administration directions are not closely followed. Additionally, crystalline material that looked like ground alendronate tablets was found on the biopsies of patients with erosive esophagitis, and ongoing mucosal irregularity had been seen in some of these same patients.⁹ This information suggests a potential for carcinogenic effects.

Dr. Wysowski recommends that physicians not prescribe oral bisphosphonates to patients with Barrett’s esophagus. Merck has stated that over 150-million prescriptions for alendronate have been written in the US. They note that in their clinical database of pre- and postmarketing patients that received the medication for three to 10 years (n=3,800), the data do not suggest an association between alendronate and esophageal cancer.

Further studies need to be performed that include oral bisphosphonates as a possible risk factor for esophageal cancer.

FDA Drug Safety Efforts

In an ongoing effort to improve drug safety and pursuant to Title IX, Section 921 of the FDA Amendments Act (FDAAA) of 2007, each quarter the FDA will be publishing a new list of potential signals of serious risks and new safety information for drugs identified. The FDAAA directs the FDA to regularly screen the Adverse Event Reporting System (AERS) database for any new safety information or potential signals of serious risks identified within the last quarter. This information may include new safety information such as that derived from postmarketing adverse-event reports or from drugs with Risk Evaluation and Mitigation Strategy (REMS).¹⁰ However, an identified safety issue does not mean that causality has been identified between the drug and the listed risk.¹¹ The FDA will communicate new information identified from their review as it completes each evaluation.

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

References

1. Coffey J. FDA petition letter to remove propoxyphene from the market. Published December 5, 2008; www.ashp.org/DocLibrary/Advocacy/Propoxyphene.aspx. Accessed April 8, 2009.
2. Traynor K. Close vote by FDA advisers favor propoxyphene withdrawal. Published March 2, 2009; www.ashp.org/import/news/HealthSystemPharmacyNews/newsarticle.aspx?id=3037. Accessed April 8, 2009.
3. FDA. Transdermal drug patches with metallic backings. Published March 5, 2009; www.fda.gov/medwatch/safety/2009/safety09.htm#Transdermal. Accessed April 8, 2009.
4. FDA. FDA warns about wearing medicated patches during MRIs. Published March 5, 2009; www.fda.gov/bbs/topics/NEWS/2009/NEW01967.html. Accessed April 8, 2009.
5. FDA. Raptiva (efalizumab). Published April 8, 2009; www.fda.gov/medwatch/safety/2009/safety09.htm#Raptiva. Accessed April 13, 2009.
6. Sedghizadeh PP, Stanely K, Caliguir M, Hofkes S, Lowry B, Shuler CF. Oral bisphosphonate use and the prevalence of osteonecrosis of the jaw: An institutional inquiry. J Am Dent Assoc. 2009;140:61-66.
7. Edwards BJ, Hellstein JW, Jacobsen PL, et al. Updated recommendations for managing the care of patients receiving oral bisphosphonate therapy: An advisory statement from the American Dental Association Council on Scientific Affairs. J Am Dent Assoc. 2008;139:1674-1677.
8. Wysowski D. Reports of esophageal cancer with oral bisphosphonate use. N Engl J Med. 2009;360:89-90.
9. Chustecka Z. Esophageal cancer in patients taking oral bisposphonates. Published December 31, 2008; www.med scape.com/viewarticle/586127. Accessed April 8, 2009.
10. FDA. Potential signals of serious risks/new safety information identified from the Adverse Event Reporting System (AERS) between January–March 2008. Updated February 4, 2009; www.fda.gov/Cder/aers/potential_signals/potential_signals_2008Q1.htm. Accessed April 8, 2009.
11. Fischer A. FDA posts drugs under review over possible safety concerns. Published February 5, 2009; www.firstwordplus.com/Fws.do?articleid=AE4EA7AB7202473B8DC3548A74AA4F57&logRowId=282534. Accessed April 8, 2009.
12. Paddock C. FDA approves first gout drug for 40 years. Published February 16, 2009. www.medicalnewstoday.com/articles/139130.php. Accessed April 8, 2009.
13. FDA approves Genzyme’s Synvisc-One for osteoarthritis of the knee. Published February 26, 2009; www.genzyme.com/corp/investors/GENZ%20PR-022609.asp. Accessed April 8, 2009.
14. Additional strengths of Avinza available. Published February 5, 2009. www.empr.com/Additional-strengths-of-Avinza-available/article/126905. Accessed April 8, 2009.
15. Scytera Foam available for chronic psoriasis. Published January 26, 2009. www.empr.com/Scytera-Foam-available-for-chronic-psoriasis/article/126384. Accessed April 8, 2009.
16. UCB receives complete response letter from US FDA for use of Cimzia in rheumatoid arthritis patients. Published January 5, 2009; www.pharmasentry.com/news/newsletter.cfm?linkid=B1776F25-1372-54C2-6119BA974B2E09CC. Accessed April 8, 2009.
17. UCB’s meeting with U.S. FDA defines path forward for Cimzia in rheumatoid arthritis. Published February 6, 2009; www.ucb.com/news/newsdetail.asp?newsid=1287988. Accessed April 8, 2009.
18. Acurox tablets new drug application accepted for filing with a priority review classification. Published March 3, 2009; www.globenewswire.com/newsroom/news.html?d=160640. Accessed April 8, 2009.