Drug Updates

Earlier this year the Food and Drug Administration (FDA) mandated stricter warnings for acetaminophen-containing products stemming from a lack of consumer awareness regarding the dangers of too much acetaminophen. Patients take different products containing acetaminophen, in some cases believing that “more is better”—but this is not true in the case of acetaminophen.¹ The FDA knows that acetaminophen-containing products are extensively used, which makes hepatotoxicity a great public health concern. The FDA continuously sponsors consumer education campaigns, yet unintentional and intentional overdoses leading to hepatotoxicity continue to occur.

Although most resources state taking more than 4 g per day of acetaminophen can lead to hepatoxicity in adults, the toxic dose of acetaminophen after a single acute ingestion is 150 mg/kg, or approximately 7 g in adults. This may be even lower in certain patient populations, such as those who abuse alcohol, are malnourished, have viral illness, or are dehydrated. The risk of hepatotoxicity is very small when acetaminophen is accurately dosed.²

Some suggestions to improve the safety of acetaminophen use include reducing the maximum adult dose to not greater than 3,250 mg daily, but lowering this dose in patients that also concomitantly consume three or more alcoholic beverages daily; and limiting the immediate-release tablet strength to up to 325 mg, and a single adult dose to 650 mg rather than 1000 mg. It is important to remember that a large number of prescription analgesics often include acetaminophen and physicians and patients must be vigilant in calculating total daily acetaminophen doses. Some examples of acetaminophen containing prescription products include tramadol/acetaminophen, hydrocodone/acetaminophen, and acetaminophen/codeine. There are also many over-the-counter (OTC) cough and cold products containing acetaminophen.

In June, a joint FDA advisory committee meeting was convened to discuss how to address the problem of hepatotoxicity related to the use of acetaminophen in both OTC and prescription products.³ The FDA recognizes that acetaminophen is an important drug and does not want to remove it from the market, but acknowledges that something needs to be done to prevent additional patient harm from its use.

Label Changes and Warnings

The immunosuppressant drugs sirolimus (Rapamune), cyclosporine (Sandimmune and generics), cyclosporine modified (Neoral and generics), mycophenolate mofetil (Cellcept and generics), and mycophenolic acid (Myfortic) have undergone a label change regarding the increased risk of developing opportunistic infections.⁴ Some infections identified in patients who had kidney transplants and who were taking these agents included activation of latent viral infections including BK virus–associated nephropathy. BK virus–associated nephropathy is associated with tacrolimus use (marketed as Prograf) and is already included in its label. Therapy adjustment should be considered for any patient that develops BK virus–associated nephropathy while receiving any of these agents. In transplant patients, loss of graft may ensue. The FDA is continuing to review the safety of these agents. Although they are used in renal transplantation, the agents are also used in other immune-mediated disease. Therefore, it is critical to identify patients that may develop opportunistic infections, so that the patient can be managed appropriately. The FDA urges healthcare professionals and patients to report adverse effects from immunosuppressant agents to the MedWatch Adverse Event Reporting program.

A boxed warning has been added to the labels for the smoking cessation products, varenicline (Chantix) and bupropion (Zyban and generics).⁵ This is due to postmarketing data noting a risk of developing serious neuropsychiatric symptoms when using these products. These symptoms include behavior changes, agitation, hostility, depressed mood, suicidal thoughts and behavior, and suicide attempts, which have occurred in patients with and without a neuropsychiatric history.⁶ Healthcare professionals need to monitor patients and advise them to stop taking bupropion or varenicline if they experience agitation, depressed mood, or any behavior changes not typical of nicotine withdrawal. Patients also need to contact their healthcare provider immediately if they develop any of these symptoms, particularly if they experience suicidal thoughts or suicidal behavior. If either drug is discontinued due to the development of neuropsychiatric symptoms, the patient should be monitored closely until the symptoms abate. Caregivers and family members should also be alerted to the potential mood and behavior changes that may occur in patients taking these agents and notify the appropriate authority, should these symptoms occur.

Pipeline

Cadence Pharmaceuticals received notification that its new drug application (NDA) for intravenous (IV) acetaminophen (Acetavance), its investigational agent to treat acute pain and fever, has been accepted for filing by the FDA and designated as a priority review.⁷ Worldwide, IV acetaminophen is one of the most commonly used injectable analgesics.

Apremilast (CC-1004), a novel oral antiinflammatory and antitumor necrosis factor–α antagonist, is undergoing phase 2 clinical trials for treating adults with psoriatic arthritis.⁸ The study met its primary endpoint of assessment of ACR 20 at 12 weeks. Two different regimens were administered in a randomized, placebo-controlled manner: 20 mg twice daily and 40 mg once daily. Significant improvement was noted for both regimens 43.5% and 35.8%, respectively, versus 11.8% for placebo.⁹ Common adverse effects were nausea, diarrhea, headache, nasopharyngitis, and fatigue. There was no significant difference in the number of infections between active and placebo-treated patients. This agent is also being studied in patients with moderate to severe plaque psoriasis.

An NDA for a low-dose aspirin and esomeprazole magnesium combination product has been submitted to the FDA for risk reduction of low-dose aspirin-associated gastric and/or duodenal ulcers in at-risk patients.¹⁰

Belimumab (Benlysta, formerly Lymphostat-B), an IV BLyS-specific inhibitor, is undergoing phase 3 clinical trials for treating systemic lupus erythematosus.¹¹ In phase 3 trials, a statistically significant improvement in patient response was seen at Week 52 in belimumab-treated patients compared to placebo-treated patients. Belimumab was generally well tolerated, with an adverse event rate similar to placebo. No malignancies were reported. In the long-term continuation phase of a phase 2 extension study (n= 296), from Week 52 to Week 208, an increased response rate was noted from 46% to 57% with an overall decrease in frequency of lupus flare-ups from 62% to 16%.¹² Severe lupus flares decreased from 8% to 1%, as well.

Denosumab as a treatment for osteoporosis was the topic of discussion at an FDA advisory committee meeting on August 13, 2009.¹³ Safety issues were the main cause for concern with this agent. Most at the meeting agreed that it should be approved for the treatment of osteoporosis in postmenopausal women for those who have failed other treatments, at least until long-term safety data are available. Panelists were also in favor of initial approval to treat bone loss in men with prostate cancer undergoing hormone ablation therapy. Potential safety issues include tumor metastates and endocarditis. Hence, approval for other treatments may not happen until later, if at all. A boxed warning or a risk evaluation and mitigation strategy (REMS) is likely for denosumab, once approved. Post-approval studies will be conducted. Denosumab advantages include bi-yearly subcutaneous administration, superiority in fracture prevention, and clinical trial program involving more than 20,000 patients worldwide for different indications. A final decision on the osteoporosis indications is expected by October 19, 2009 (the Prescription Drug User Fee Act date).¹⁴

Denosumab advantages include biyearly subcutaneous administration, superiority in fracture prevention, and clinical trial program involving more than 20,000 patients worldwide for different indications. Because there have been newer concerns about long-term side effects of bisphosphonates (including osteonecrosis of the jaw), this may improve the outlook for a positive decision for denosumab’s approval first for osteoporosis and subsequently for other indications.

Oxycodone/niacin tablets (Acurox) has received a complete response letter from the FDA regarding its NDA. The letter raises issues regarding the potential abuse deterrent benefits of this combination product. The proposed use of oxycodone/niacin is in the treatment of moderate to severe pain, it has been scheduled a C-II. It was developed using an aversion technology designed to deter the intentional swallowing of excessive doses, IV injection of dissolved tablets, and/or snorting of crushed tablets. The original NDA was accepted earlier this year with a priority review designation.¹⁵

Pegloticase (Krystexxa) received a recommendation for marketing approval by the Arthritis Advisory Committee of the FDA.16 Pegloticase is a biologic, PEGylated, uricase enzyme, evaluated for the treatment of refractory chronic gout. Of concern were safety issues related to cardiovascular complications.¹⁶

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

References

1. Reinberg S. FDA report urges tougher acetaminophen warning. http://healthday.com/printer.asp?AID=627508. Published May 28, 2009. Accessed July 28, 2009.
2. Farrell SE. Toxicity acetaminophen. http://emedicine.medscape.com/article/820200-overview. Published October 3, 2007. Accessed July 28, 2009.
3. June 29–30, 2009: Joint Meeting of the Drug Safety and Risk Management Advisory Committee with the Anesthetic and Life Support Drugs Advisory Committee and the Nonprescription Drugs Advisory Committee: Meeting announcement. www.fda.gov/AdvisoryCommittees/Calendar/ucm143083.htm. Published July 7, 2009. Accessed July 28, 2009.
4. El-Hinnawy P. FDA requires labeling change for some drugs used to prevent kidney rejection of kidney transplants. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm171775.htm Published July 15, 2009. Accessed July 28, 2009.
5. Information for healthcare professionals: Varenicline (marketed as Chantix) and bupropion (marketed as Zyban, Wellbutrin, generics) FDA Alert. www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm169986.htm. Published July 1, 2009. Accessed July 27, 2009.
6. FDA Web site: Varenicline (marketed as Chantix) and bupropion (marketed as Zyban, Wellbutrin, and generics). www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm170090.htm. Published July 1, 2009. Accessed July 27, 2009.
7. Cadence Pharmaceuticals announces priority review and acceptance of NDA submission for Acetavance for treatment of acute pain and fever. www.drugs.com/nda/acetavance_ 090715 .html. Published July 15, 2009. Accessed July 27, 2009.
8. Dennis M. Celgene’s apremilast improved symptoms of psoriatic arthritis in mid-stage trial. www.firstwordplus.com/Fws.do?articleid=A3E421298FFD43BEA1FD64C6E5DE39BA&logRowId=311088. Published June 16, 2009. Accessed July 28, 2009.
9. Celgene announces positive top line data from randomized controlled phase ii study of Apremilast in psoriatic arthritis. http:// ir.celgene.com/phoenix.zhtml?c=111960&p=irol-newsArticle&ID=1299205&highlight=. Published June 15, 2009. Accessed July 28, 2009.
10. AstraZeneca submits NDA for low dose aspirin/esomeprazole combination product. Also submits supplemental new drug application (sNDA) for NEXIUM capsules for risk reduction of low-dose aspirin-associated peptic ulcer disease. www.astrazeneca-us.com/about-astrazeneca-us/newsroom/all/5762542?itemId=5762542. Published May 4, 2009. Accessed July 27, 2009.
11. Human Genome Sciences and GlaxoSmithKline announce positive phase 3 study results for Benlysta in systemic lupus erythematosus. www.gsk.com/media/pressreleases/2009/2009_pressrelease_10074.htm. Published July 20, 2009. Accessed July 27, 2009.
12. Todoruk M. Long-term data for GlaxoSmithKline, Human Genome’s lupus drug presented at EULAR. www.firstwordplus.com/Fws.do?articleid=801205B919DB4990981A76569BCACD93. Published June 11, 2009. Accessed July 27, 2009.
13. Dimond P. Denosumab—great expectations for Amgen and Osteoporosis Market. www.genengnews.com/specialreports/sritem.aspx?oid=57062429. Published June 26, 2009. Accessed July 27, 2009.
14. Boggs J. Split Panel Vote Takes Shine off Denosumab: Is PMO Only So-So? www.bioworld.com/servlet/com.accumedia.web.Dispatcher?next=bioWorldHeadlines_article&forceid=51802. Published August 17, 2009. Accessed August 18, 2009.
15. Acura and King receive FDA complete response letter regarding Acurox. www.kingpharm.com/Investors/News_Details.cfm?news_item_id=519. Published July 2, 2009. Accessed July 27, 2009.
16. FDA Appointed Arthritis Advisory Committee Recommends U.S. Food and Drug Administration Approval for KRYSTEXXA(TM) for Refractory Chronic Gout. http://investor.savient.com/ReleaseDetail.cfm?ReleaseID=390150. Published June 16, 2009. Accessed July 27, 2009.
17. Bratulic A. FDA panel recommends approval of Savient’s Krystexxa. www.firstwordplus.com/Fws.do?articleid=2AFF4DD597D24220887613900343426C&logRowId=311087. Published June 16, 2009. Accessed July 27, 2009.
18. FDA approves Zipsor. www.drugs.com/newdrugs/xanodyne-receives-approval-u-s-food-administration-zipsor-diclofenac-potassium-liquid-filled-1469.html. Published June 17, 2009. Accessed August 7, 2009.
19. Xanodyne receives approvable letter from the U.S. Food and Drug Administration for Zipsor (diclofenac potassium) capsules. www.xanodyne.com/newsroom_details.asp?NewsId=48. Published July 22, 2009. Accessed August 7, 2009.
20. Facts and Comparisons. www.factsandcomparisons.com/News/ArticlePage.aspx?cat=update&id=8448. Published July 27, 2009. Accessed August 7, 2009.
21. New drug is first injectable product approved for sale in the United States for treatment of pain and fever. www.drugs.com/newdrugs/cumberland-pharmaceuticals-announces-fda-approval-caldolor-1447.html. Published June 11, 2009. Accessed August 7, 2009.
22. Nucynta. www.empr.com/nucynta/drugproduct/69. Published July 2, 2009. Accessed July 27, 2009.
23. New Drug: Nucynta (tapentadol). Pharmacist’s Letter/Prescriber’s Letter 2009;25(7):250711.