Drug UPDATES

New Drug Approvals

New drug approvals were down in 2010, according to the U.S. Food and Drug Administration (FDA).1 Those in the agency and its drug reviewers continued to provide rigorous analyses of drug safety in 2010. Accordingly, it appears that only 21 drugs were approved in 2010, which is down from 2009 and 2008, when 25 and 24 drugs were FDA approved, respectively. Looking back over the past year, new approvals were dominated by new generic approvals, new dosage forms, and new indications. The new indications category included agents that were new molecular entities such as denosumab and new indications for those entities.2 You will see from this month’s limited list of new approvals and agents in the pipeline a pattern similar to that of 2010, with more focus on safety. In the next few years, the focus of new approvals will likely trend towards more biologics and/or specialty agents, with safety and manufacturer risk evaluation and mitigation strategies (REMS) in place to ensure that a product’s risks do not outweigh its benefits.3,4

Fentanyl transmucosal tablet (Abstral) has been FDA approved to treat breakthrough pain in cancer patients who already use and can tolerate around-the-clock opioids.5 The FDA is requiring that all patients using this agent enroll in a REMS program to prevent misuse of the agent. The REMS program consists of a Patient–Prescriber Agreement and an enrollment form. The FDA is asking that all manufacturers of opioids develop and utilize a single shared REMS implementation system. Fentanyl is already FDA approved as a buccal tablet and as a patch, but there have been a number of recalls on the patch due to drug leakage. There also have been issues related to misuse of fentanyl products. Patients who are not opioid tolerant should not use this product due to the potential for respiratory depression and/or death. In 2005, fentanyl patches had been linked to 120 deaths. Although approved in cancer patients, there is always the potential that other opioid-tolerant chronic-pain patients may receive this agent.

Pantoprazole delayed-release tablets (generic Protonix) have been FDA approved.6

Tocilizumab (Actemra) has received a supplemental approval from the FDA for inhibition and slowing of structural joint damage, improvement of physical functioning, and achieving major clinical response in adults with moderately to severely active rheumatoid arthritis (RA), when combined with methotrexate treatment.7

Pipeline

The FDA has extended the date of its priority review of belimumab injection (Benlysta) for treating systemic lupus erythematosus to March 10, 2011. The FDA had requested additional information on the drug, which its manufacturer, GlaxoSmithKline and Human Genome Sciences, has since provided.8 Final word on its approval should come soon.

A supplemental biologics license agreement has been submitted for infliximab injection (Remicade) for the treatment of moderately to severely active ulcerative colitis in pediatric patients who have not had an adequate response to conventional therapy.9 The data on which this study is based evaluated patients six to 17 years of age who had an inadequate response to agents such as 6-mercaptopurine, azathioprine, corticosteroids, and 5-aminosalycylic acid.

The new drug application (NDA) for oxycodone tablets (Remoxy) was recently resubmitted to the FDA.10 This agent is a twice-daily, long-acting formulation of the opioid oxycodone to treat continuous, around-the-clock, moderate to severe pain. This formulation consists of a high-viscosity liquid formulation in a hard gelatin capsule designed to provide steady pain relief while resisting common methods of tampering intended to result in rapid oxycodone release.

The NDA for oxycodone tablets (Acurox) has been submitted to the FDA.11 This agent is an immediate release tablet containing oxycodone for treating moderate to severe pain. This formulation also utilizes Acura’s Aversion Technology designed to deter opioid abuse by intravenous injection of dissolved tablets and snorting of crushed tablets.

Endo Pharmaceuticals has received a complete response letter from the FDA for a new crush-resistant formulation of oxymorphone hydrochloride extended-release tablets (Opana ER).12 The letter did not request additional clinical studies be conducted for approval. The manufacturer has begun to address the issues in the letter and expects to respond to the FDA by mid-2011. The current formulation of oxymorphone hydrochloride extended-release tablets are FDA-approved for relieving moderate to severe pain in patients that require continuous, around-the-clock opioid treatment for an extended period of time.13

RDEA594, a selective URAT1 inhibitor, is currently undergoing phase II clinical trials for the treatment of gout and hyperuricemia.14,15 Preliminary results from a phase IIb study of RDEA594 in combination with allopurinol showed a statistically significant improvement of 89% in reducing serum uric acid (sUA) levels after four weeks of treatment, compared with allopurinol monotherapy. Additionally, the secondary efficacy endpoint of achieving a reduction in the sUA below the clinically relevant target of less than 6 mg/mL after four weeks of combination therapy was also statistically significant compared with the combination of allopurinol and placebo. The study was a multicenter, double-blind, randomized, placebo-controlled, 28-day dose-response safety and urate-lowering efficacy trial.

The Sandoz generic division of Novartis has begun trials of their biosimilar version of Roche’s monoclonal antibody rituximab (Rituxan/MabThera), for the treatment of RA.16 When the FDA develops new biosimilar rules, companies expect they will include shortened clinical testing of products.17

A new oral anticoagulant, rivaroxaban, is being studied to treat atrial fibrillation as well as deep vein thrombosis (DVT).18 It is also being investigated to prevent recurrent DVT and pulmonary embolism in patients undergoing total knee and/or total hip replacement surgery. Rivaroxaban was compared to enoxaparin and warfarin and has shown comparable efficacy. It will likely be the second oral anticoagulant to garner FDA approval—second to dabigatran, which recently was FDA approved—in a long line of oral anticoagulants currently in the FDA pipeline.4,19

Drug Safety

The FDA is working with the Institute for Safe Medication Practices (ISMP) and the National Association of Boards of Pharmacy (NABP) to decrease the number of emergency department visits related to unintentional and intentional acetaminophen overdoses.20–23 Annually, there are more than 5,000 visits to emergency departments because patients intentionally increase their dose of acetaminophen or take different products that contain acetaminophen because they are unaware of the “duplicate” therapy and potential for serious toxicity. In view of this situation, clearer and stronger warnings appear needed on prescription and over-the-counter (OTC) product labels related to maximum safe doses. Harm can potentially be avoided if patients are better educated. In late 2009, the FDA launched the Safe Use initiative to reduce preventable medication harm in collaboration with healthcare stakeholders. These stakeholders include but are not limited to federal agencies, pharmacies, hospitals, health professionals, and professional societies. In mid-2010, two of the main goals of this initiative related to acetaminophen were to decrease confusion by encouraging the avoidance of using “APAP” as an acetaminophen abbreviation and increase awareness and education related to acetaminophen use. Patient responsibilities include identifying that their prescription or OTC analgesics contain acetaminophen; comparing active ingredients on their prescription and OTC product labels; and avoiding use of two or more medications that contain acetaminophen, which can potentially lead to hepatoxicity.

Last summer, the NABP sent a letter to the state boards of pharmacy recommending that the abbreviation “APAP” be prohibited on prescription labels and that acetaminophen be spelled out. Healthcare providers are being asked to appropriately counsel patients that APAP is acetaminophen and that they should not take different OTC or prescription medications that contain acetaminophen without first discussing it with their prescriber or their pharmacist. Patients need to be educated about how acetaminophen can cause hepatoxicity when too much is taken at one time or if it is taken within too short an interval. In another measure to curb acetaminophen-induced hepatoxicity, the FDA recently asked manufacturers of prescription acetaminophen combination products to limit the maximum amount to 325 mg per dosage unit. The FDA believes that limiting the amount of acetaminophen per dosage unit will decrease the risk of acetaminophen overdoses. Although many OTC products are available, too much acetaminophen can lead to hepatic failure, transplant, and/or death.

Morphine sulfate oral solution 100 mg/5 mL (20 mg/mL) has undergone a label revision due to inadvertent overdoses when ordered in milligrams (mg), which was later misread as milliliters (mL).24,25 This has led to 20-fold overdoses when the high-concentration product was used instead of lower-concentration products (e.g., 10 mg/5 mL or 20 mg/5 mL). Morphine sulfate oral solution is approved by the FDA to relieve moderate to severe acute and chronic pain in opioid-tolerant patients only. The product label has been revised with a bright yellow background (compared with a white background for the lower concentrations) as well as the product name being displayed in white letters on a red background. Other label revisions help to differentiate it from similar products, to help decrease medication error risks.

Michele Kaufman is a freelance medical writer based in New York City and a clinical pharmacist at New York Downtown Hospital.

References

1. FDA’s drug approval down in 2010. www.drugs.com/news/fda-s-approval-down-2010-28669.html. Published December 31, 2010. Accessed January 24, 2011.
2. FDA approves Amgen’s XGEVA (denosumab) for the prevention of skeletal-related events in patients with bone metastases from solid tumors. www.amgen.com/media/media_pr_detail.jsp?year=2010&releaseID=1498709. Published November 18, 2010. Accessed January 24, 2011.
3. U.S. Food and Drug Administration. Approved Risk evaluation and mitigation strategies. www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm111350.htm. Published January 14, 2011. Accessed January 24, 2011.
4. Perry L, Kaufman MB. Pipeline 2011. Drug Topics. 2011;155:30-40.
5. Frieden J. FDA okays another fentanyl product. www.medpagetoday.com/PainManagement/PainManagement/24242. Published January 7, 2011. Accessed January 10, 2011.
6. Dr. Reddy’s announces the launch of Pantoprazole Sodium delayed-released tablets. www.drreddys.com/media/popups/jan20_2011.html. Published January 20, 2011. Accessed January 24, 2011.
7. FDA grants supplemental approval for ACTEMRA (tocilizumab). www.gene.com/gene/news/press-releases/display.do?method=detail&id=13147. Published January 5, 2011. Accessed January 8, 2011.
8. Dane L. FDA extends review of GlaxoSmithKline, Human Genome Sciences’ Benlysta. www.firstwordplus.com/Fws.do?articleid=90722752BC6247119BB608B38FB5B7B0&logRowId=393011. Published December 3, 2010. Accessed January 24, 2011.
9. Supplemental BLA submitted for Remicade for pediatric ulcerative colitis. www.empr.com/supplemental-bla-submitted-for-remicade-for-pediatric-ulcerative-colitis/article/193430/?DCMP=EMC-MPR_WeeklyNewsbrief. Published December 29, 2010. Accessed January 3, 2011.
10. King Pharmaceuticals and Pain Therapeutics announce resubmission of new drug application for REMOXY. www.kingpharm.com/Investors/News_Details.cfm?news_item_id=568. Published December 27, 2010. Accessed January 24, 2011.
11. King Pharmaceuticals and Acura Pharmaceuticals announce submission of New Drug Application for ACUROX tablets. www.kingpharm.com/Investors/News_Details.cfm?news_item_id=567. Published December 29, 2010. Accessed January 24, 2010
12. Endo Pharmaceuticals provides regulatory update on new formulation of OPANA ER designed to be crush-resistant. http://phx.corporate-ir.net/phoenix.zhtml?c=231492&p=irol-newsArticle_print&ID=1514262. Published January 7, 2011. Accessed January 10, 2011.
13. Endo Pharmaceuticals Opana ER. www.endo.com/Opana. aspx. Accessed January 24, 2011
14. Ardea Biosciences reports positive results for RDEA594, its lead product candidate for gout, in combination with allopurinol or febuxostat. www.medicalnewstoday.com/articles/175402.php. Published January 8, 2011. Accessed January 24, 2011.
15. Phase 2b study of RDEA594 for the treatment of gout. www.empr.com/phase-2b-study-of-rdea594-for-the-treatment-of-gout/article/193868/. Published January 7, 2011. Accessed January 10, 2011.
16. Dennis M. Novartis starts mid-stage trial of biosimilar version of Roche’s Rituxan. www.firstwordplus.com/Fws.do?articleid =438774BDB43448269895FCE494E97D70. Published January 10, 2011. Accessed January 11, 2011.
17. Dennis M. Merck & Co. in deal with Parexel to develop biosimilars. www.firstwordplus.com/Fws.do?articleid=411CA68F1931475B92F0A475730DE0CA&logRowId=396586. Published January 12, 2011. Accessed January 24, 2011.
18. Dennis M. Bayer, Johnson & Johnson seek EU, US approval of Xarelto for stroke prevention. www.firstwordplus.com/Fws.do?articleid=93CCEB75BBF64F2BB3993F73EAF006F4&logRowId=395681. Published January 5, 2011. Accessed January 24, 2011.
19. Garrett AD. Pradaxa primer: A guide to treatment with dabigatran etexilate. Drug Topics. 2011;155:42-43.
20. Fritsch B. FDA’s Safe Use Initiative. Pharmacy Today. 2010 ;9:61.
21. NABP recommends boards of pharmacy prohibit use of acetaminophen abbreviation. www.nabp.net/news/nabp-recommends-boards-of-pharmacy-prohibit-use-of-acetaminophen-abbreviation. Published July 15, 2010. Accessed January 4, 2011.
22. Signals for acetaminophen, dronedarone, and botulinum toxin. ISMP Medication Safety Alert QuarterWatch Report (2010 Quarter 1). November 4, 2010;15:1-3.
23. U.S. Food and Drug Administration. Acetaminophen Information. www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm165107.htm. Last updated January 27, 2011. Accessed January 27, 2011.
24. Morphine sulfate oral solution 100 mg per 5 mL (20mg/mL): Medication use error reports of accidental overdose. www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm239559.htm. Published January 10, 2011. Accessed January 11, 2011.
25. Nelson R. Fatal medication errors seen with high-dose morphine oral solution. www.medscape.com/viewarticle/735564. Accessed January 10, 2011.