Information on New Drug Approvals and Medication Safety

Drug Safety

Pegloticase (Krystexxa), the Food and Drug Administration (FDA)–approved intravenous (IV) treatment for refractory chronic gout has a Risk Evaluation and Mitigation Strategy (REMS) to ensure benefits of drug use outweigh its risks related to anaphylaxis, infusion reactions, and contraindications in patients with glucose-6-phosphate dehydrogenase deficiency.¹ The agent should be administered in healthcare settings and by providers prepared to manage both anaphylaxis and infusion reactions. The “Dear Healthcare Provider” letter, which was part of the initial REMS approval, was issued on October 31, 2011, and summarizes the REMS information. It states that anaphylaxis was reported in 6.5% of patients treated with pegloticase in clinical trials, and that all of these patients received pretreatment medication. Additionally, infusion reactions occurred in 26% of patients who received 8 mg every two weeks and in 41% who received 8 mg every four weeks (versus 5% of placebo-treated patients). Management recommendations include monitoring the serum uric acid (sUA) levels prior to infusions and discontinuing treatment when the sUA is greater than 6 mg/dL. To prevent infusion reactions, all patients should be premedicated with antihistamines and corticosteroids and observed for an appropriate time following drug administration. A medication guide accompanies the full prescribing information for the agent and should be given to patients every time pegloticase is administered. The FDA and the manufacturer encourage healthcare professionals to report adverse events associated with this agent by either calling 1-888-578-7839, 1-800-FDA-1088, or visiting https://www.accessdata.fda.gov/scripts/medwatch.

The FDA has approved changes to the warning sections of the package inserts for IV methotrexate (MTX) sodium products related to concomitant administration of proton pump inhibitors.² Specifically, the new text includes the information related to case reports and published population pharmacokinetic studies suggesting that combined use of some proton pump inhibitors (e.g., omeprazole, esomeprazole, pantoprazole) along with MTX (mostly high dose) causing decreased MTX (and/or hydroxymethotrexate, its metabolite) elimination and the potential for serious toxicity resulting from elevated serum drug levels.

REMS Resource Center and Database: The American Society of Health-System Pharmacists (ASHP) has created a REMS Resource Center that links with the FDA REMS Center.³ The FDA information is accessible to all; however, certain information in the ASHP database is available to members only. The site can be accessed at: www.ashp.org/menu/PracticePolicy/ResourceCenters/REMS.aspx.

Pipeline

BCX4208 is a next-generation, once-daily, oral, purine nucleoside phosphorylase inhibitor being developed for the chronic treatment of gout.⁴ It is being studied as an add-on therapy working synergistically with xanthine oxidase to lower sUA production. Results of a 24-week blinded phase IIb study showed that BCX4208, in combination with allopurinol 300 mg daily, was superior to allopurinol monotherapy in patients who had failed to reach an sUA goal of less than 6 mg/dL, in 279 randomized gout patients. There were five study arms (BCX4208 at doses of 5 mg, 10 mg, 20 mg, and 40 mg, and placebo). The primary endpoint was the proportion of patients, at Day 85, who had an sUA less than 6 mg/dL. The BCX4208 response rates ranged from 33% to 49%, with approximately double the proportion of patients reaching goal versus allopurinol monotherapy (18%). Adverse events were similar between treatment groups. It was well tolerated at all of the studied doses.

Fostamatinib is currently in phase III trials for the treatment of F (RA).⁵ Fostamatinib is an oral spleen tyrosine kinase (syk) inhibitor that reversibly blocks signaling in different cell types associated with inflammation and tissue degradation in RA patients.⁶ Current trials are evaluating the long-term safety and efficacy of fostamatinib monotherapy in RA patients. Two different dosing regimens are being studied in patients who have had an inadequate response to disease-modifying antirheumatic drugs (DMARDs) or tumor necrosis factor–α inhibitors; it is also being compared with adalimumab.⁷

Sarilumab, previously known as REGN88, is a novel, high-affinity, subcutaneous, fully human antibody to the interleukin 6 receptor (IL-6R) that is currently in phase III clinical trials for the treatment of active, moderate to severe RA.^8,9 The phase IIb results showed that when combined with MTX (in patients who had an inadequate response to MTX monotherapy), sarilumab+MTX–treated patients demonstrated reduction in signs and symptoms of RA. Also, adverse effects were similar to those previously reported with IL-6 inhibition. In this study, patients (n=306) were randomized to receive sarilumab 100 mg every other week (q2w), sarilumab 150 mg q2w, sarilumab 100 mg weekly (qw), sarilumab 200 mg q2w, sarilumab 150 mg qw, or placebo. The ACR20 response at Week 12 was numerically higher than placebo in all sarilumab-treated groups, and significantly greater in the 150 mg qw sarilumab arm (72%) (versus 46%, placebo; P=0.02). Treatment with sarilumab also increased the total cholesterol, low-density lipoprotein levels, and high-density lipoprotein levels.

The new drug application for tofacitinib, a novel, oral, janus-associated kinase (JAK) inhibitor-3 for treating moderate to severe active RA, has been accepted by the FDA.¹⁰ More than 300 patients (mostly women) were randomized to treatment with tofacitinib 5 mg or 10 mg twice daily for three months. All patients had at least four tender and swollen joints, and persistent disease despite treatment with at least one DMARD. Tofacitinib-treated patients had statistically significant decreases in patient’s global assessment of disease activity compared with placebo-treated patients (P<0.0001).¹¹ The anticipated Prescription Drug User Fee Act (PDUFA) date is August 2012. Tofacitinib has also been submitted for approval in Japan.

Drug Approvals

Glucarpidase (Voraxaze) has been FDA approved as a treatment for the rapid and sustained reduction of toxic MTX levels due to impaired renal function.¹² If patients have impaired renal function or their renal function becomes impaired, they may be at increased risk of MTX toxicity. This mostly occurs in oncology patients, but since MTX is used for autoimmune diseases, these patients may also benefit from this treatment. Glucarpidase is a recombinant enzyme that rapidly lowers serum MTX levels to below the toxicity threshold to prevent renal and hepatic damage, as well as aphthous ulcers, intestinal lining damage, skin rashes, and low blood counts. It is administered intravenously and has been granted orphan drug status in the U.S. and the European Union.

Oxymorphone extended-release (Opana ER) was FDA approved in December 2011 to treat adults with around-the-clock, moderate to severe pain expected to last for an extended time.^13,14 Oxymorphone ER is not for “as-needed pain” and is now crush-resistant to prevent tampering. However, any tablet alteration could result in potential overdose or death. This year, the manufacturer, Endo Pharmaceuticals, plans on transitioning from the older formulation to this new formulation. Both formulations will look alike with similar packaging and tablet color and identification.

Rivaroxaban (Xarelto), a new oral anti-Xa inhibitor that recently received FDA approval, is seeking another indication, that of treatment of acute coronary syndrome. Currently, rivaroxaban is FDA approved for the prophylaxis of deep vein thrombosis that may lead to pulmonary embolism in patients undergoing knee or hip replacement surgery and for treating atrial fibrillation.¹⁵

Ruxolitinib is the first JAK inhibitor to be FDA approved. This agent was approved on November 16, 2011 to treat the orphan bone marrow disease myelofibrosis.¹⁶ This agent is similar in mechanism to tofacitinib that is currently being reviewed at the FDA, except that this agent inhibits JAK-1 and JAK-2 enzymes. These kinases are also responsible for causing anemia, splenomegaly, nights sweats, and joint and bone pain. Patients in these clinical trials received ruloxitinib, placebo, or conventional therapy consisting of chemotherapy, hydroxyurea, or corticosteroids. The agent is taken orally twice daily.

Tocilizumab has been recommended by the National Institute and Clinical Excellence final guidance for reimbursement to the National Health Service in Great Britain for use in young patients two years of age and older with systemic juvenile idiopathic arthritis (SJIA) where prior therapies have not yielded a satisfactory response.¹⁷ It is not recommended for patients whose disease has not been treated with MTX or patients who are responding to MTX. In August, tocilizumab was approved in Europe for use in patients two years of age and older with SJIA, but who have not satisfactorily responded to prior therapy with nonsteroidal antiinflammatory agents and systemic steroids.

Michele B. Kaufman, PharmD, BSc, RPh, is a freelance medical writer based in New York City and a clinical pharmacist at New York Downtown Hospital.

References

1. Krystexxa (pegloticase) REMS. Available at www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM227955.pdf. Accessed February 14, 2012.
2. Methotrexate IV updated label. Available at www.accessdata.fda.gov/drugsatfda_docs/appletter/2011/011719s117ltr.pdf. Published September 1, 2011. Accessed February 3, 2012.
3. American Society of Health-Systems Pharmacists REMS Resource Center. Available at www.ashp.org/menu/PracticePolicy/ResourceCenters/REMS.aspx. Accessed January 27, 2012.
4. BCX4208 (PNP Inhibitor). Available at www.biocryst.com/bcx_4208. Accessed January 30, 2012.
5. Rigel. More than 2 million suffer from rheumatoid arthritis. Available at www.rigel.com/rigel/rheumatoid_arthritis. Accessed February 14, 2012.
6. Rigel. Rigel earns milestone payments from AstraZeneca Fostamatinib (R788) enters phase 3 clinical program. Available at http://ir.rigel.com/phoenix.zhtml?c=120936&p=irol-newsArticle&ID=1475814&highlight=. Published September 29, 2010. Accessed January 30, 2012.
7. Fostamatinib trials. Available at www.clinicaltrials.gov/ct2/results?term=oskira. Updated January 11, 2012. Accessed January 30, 2012.
8. Sarilumab/REGN88 (IL-6R Antibody). Available at www.regeneron.com/regn88. Published 2012. Accessed January 31, 2012.
9. Positive phase 2b results with sarilumab in rheumatoid arthritis to be presented as a late-breaking poster at the 2011 American College of Rheumatology Annual Meeting. Available at http://newsroom.regeneron.com/releasedetail.cfm?releaseid=618491. Published October 27, 2011. Accessed January 31, 2012.
10. Medical News. FDA accepts Pfizer’s tofacitinib NDA for review. Available at www.news-medical.net/news/20111221/FDA-accepts-Pfizers-tofacitinib-NDA-for-review.aspx. Published December 21, 2011. Accessed January 31, 2012.
11. Walsh N, Agus ZS. ACR: RA patients improved markedly on tofacitinib. Available at www.medpagetoday.com/MeetingCoverage/ACRMeeting/29619. Published November 11, 2011. Accessed January 31, 2012.
12. Nelson R. FDA approves glucarpidase to reduce toxic methotrexate levels. Available at www.medscape.com/viewarticle/757023?sssdmh=dm1.751129&src=nl_newsalert. Published January 17, 2012. Accessed January 31, 2012.
13. FDA approves Endo Pharmaceuticals’ crush-resistant Opana ER. Available at http://online.wsj.com/article/BT-CO-20111212-706944.html?mod=dist_smartbrief. Published December 12, 2011. Accessed December 13, 2011.
14. Opana ER Extended-Release tablets. Available at www.drugs.com/cdi/opana-er-extended-release-tablets.html. Accessed February 3, 2012.
15. Xarelto: Highlights of prescribing information. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2011/022406s000lbl.pdf. Published July 1, 2011. Accessed January 31, 2012.
16. Jefferson E. FDA approves first drug to treat a rare bone marrow disease. Available at www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm280102.htm. Published November 16, 2011. Accessed February 2, 2012.
17. Dennis M. Roche’s RoActemra backed by NICE for some with juvenile arthritis. Available at www.firstwordpharma.com/print/934701?tsid=17. Published December 14, 2011. Accessed December 14, 2011.