Drug Updates

New Approvals

• Ketorolac tromethamine intranasal (Sprix) has been approved by the U.S. Food and Drug Administration (FDA).¹ Nasal ketorolac, a nonsteroidal antiinflammatory drug (NSAID), is approved for short-term (up to five days) treatment of acute moderate to moderately severe pain requiring opioid-level analgesia. Gastrointestinal hemorrhage, bleeding, and cardiovascular risks are included in the labeling. Mild, transient nasal discomfort was the most common adverse reaction in clinical trials.

Pipeline

• Belimumab (Benlysta), an investigational agent currently in phase III trials, did not show statistical significance in relation to the difference in response rates at Week 76 in seropositive patients with systemic lupus erythematosus (SLE) taking the drug compared with those who received placebo.² In the BLISS-76 study, 819 patients with serologically active SLE were enrolled. They were randomized to receive standard of care and placebo or one of two belimumab doses for 76 weeks. At Week 52, 43.2% of high-dose belimumab-treated patients had significant symptom improvement versus 34% of placebo-treated patients. At Week 76, 38.5% of patients responded to high-dose belimumab versus 32.4% of placebo-treated patients.
• Naproxcinod was evaluated in mid-May as an antiinflammatory agent to treat symptoms of osteoarthritis (OA).³ Its manufacturer stated that it has similar safety and efficacy to naproxen but that it does not have some of the same cardiovascular complications, such as blood pressure increases, associated with other NSAIDs. This is because it is metabolized to yield naproxen and a nitric oxide-donating moiety, which is believed to play an important role in controlling blood pressure. Naproxcinod appears to be safe and effective for treating OA, but its cardiovascular risks are not clear. The FDA evaluation did not conclusively show that the submitted data supports the claim of cardiovascular benefit. A final FDA decision is due by July 23.
• Ocrelizumab, a humanized anti-CD20 monoclonal antibody which was in late-phase clinical trials to treat lupus and rheumatoid arthritis (RA), has been suspended due to safety concerns.⁴ Four RA clinical trials were evaluated by a safety monitoring board in March and some serious infections in clinical trials were noted, some leading to death. The developer decided that the overall benefit-to-risk profile was not favorable, considering other agents that are currently part of the RA armamentarium. The lupus trials were discontinued in March.⁵
• Oxycodone/niacin (Acurox) was filed for FDA approval and evaluated by an FDA advisory panel in late April for the treatment of moderate to severe pain while acting as a misuse and abuse deterrent. The panel voted 19 to one against approving the agent. There were concerns related to the abuse-deterrent properties of immediate-release oxycodone and whether the addition of niacin was enough to deter abuse of the agent.⁶ The agent was developed to aggravate nasal passages if inhaled and to form a gel when dissolved in water to make it difficult to take intravenously. The company is working with the FDA to determine the next steps for this product.

Safety

The FDA has updated the warning section of the product labeling for tramadol and tramadol/acetaminophen.^7,8 This warning accentuates the risk of suicide in patients who are addiction prone and those who are also taking tranquilizers or antidepressant drugs. In addition, it warns of an overdose risk when the recommended dose is exceeded or when it is used in combination with central nervous system (CNS)–active drugs or alcohol. Tramadol-related deaths have occurred in patients with previous histories of emotional disturbances or suicidal ideation or suicide attempts, as well as in patients with a history of misuse of alcohol, tranquilizers, and other CNS-active drugs. Tramadol may produce additive effects when used with these agents, in conjunction with alcohol or with other opioids or illicit drugs that cause CNS depression. Consequences of tramadol overdose include CNS depression, respiratory depression, and death. Tramadol has mu-opioid agonist activity, is often abused, and may be subject to criminal diversion.

Biologics for Pediatric Patients with Juvenile Idiopathic Arthritis

Juvenile idiopathic arthritis (JIA) is a chronic, debilitating autoimmune musculoskeletal disease in children with onset prior to age 16.⁹ More than 50% of children who have this disease become adults with active disease. Therefore, the changing treatment paradigm is early aggressive combinations of agents to achieve disease remission. Therapy goals include allowing normal childhood activities, growth, and development, eliminating active disease, and normalizing joint function while limiting permanent disability by preventing long-term joint damage or blindness from chronic uveitis.^9,10

Using biologics in young patients raises a number of concerns for some clinicians, including questions of infection risks, possible risks of malignancy, long-term surveillance to prevent malignancy, possible neurologic side effects, and response to vaccinations. Treating these patients requires a careful risk–benefit evaluation throughout therapy. In addition, adult guidelines for tuberculosis screening with purified protein derivative prior to commencing biologic agents are recommended.

Current Agents

• Etanercept is FDA approved for treating moderate to severe polyarticular-course JIA in patients two years of age and older.¹¹ The approved dose for this tumor necrosis factor (TNF)–α antagonist in this population is 0.8 mg/kg per week subcutaneously as a single or divided dose (maximum weekly dose of 50 mg). The 50-mg prefilled syringe or SureClick autoinjector can be used for pediatric patients weighing 139 pounds or more (the 25-mg prefilled syringe is not recommended for patients weighing less than 68 pounds. Glucocorticoids, NSAIDs, or other analgesics may be continued while using etanercept. When using two subcutaneous injections a week, the injections should either be given on the same day or three or four days apart. In Dutch and German registries, the agent has shown good short-term safety and tolerability in patients with JIA.⁹ Additionally, patients who have received etanercept for more than eight years in clinical trials also have had a good response.

In February 2008, adalimumab received FDA approval for the treatment of moderate to severe active polyarticular JIA in patients age four years and older.¹² The approved dosing for this TNF-α antagonist in four- to 17-year-olds is 20 mg subcutaneously every other week (20-mg prefilled syringe) for patients that weigh 33 to 66 pounds, and a dose of 40 mg subcutaneously every other week for patients that weigh 66 pounds or more (Humira Pen or 40-mg prefilled syringe).¹³

Infliximab is not approved by the FDA for use in JIA patients; however, it is approved for treating pediatric Crohn’s disease in patients at least six years old or older. Therefore, there has been some use of infliximab in JIA, such as that reported by Rupert et al.¹⁴ In this study, 122 patients’ refractory to methotrexate (MTX) treatment were treated with infliximab 3 mg/kg/dose as an IV infusion plus MTX or placebo plus MTX for 14 weeks. They then received either infliximab 3 mg/kg/dose or 6 mg/kg/dose through Week 44. Once all patients were receiving infliximab, the ACR Pedi 30 response rate was 73%. The agent was generally well tolerated, but patients that received the higher dose tolerated the drug better. There were more serious infections and infusion reactions (e.g., vomiting, headache, fever, and hypotension) in the lower dosage–treated group. Anti-infliximab antibodies were also reported. Some of the infections included upper respiratory tract infections, herpes zoster, asymptomatic pulmonary tuberculosis, and pneumonia. Infusion reactions leading to drug discontinuation have been reported elsewhere and hinder appropriate management.⁹ Postmarketing surveillance in pediatric patients using TNF-α antagonists shows an increased risk of abscess formation and sepsis.

The selective costimulation modulator abatacept is also FDA approved to treat moderately to severely active polyarticular JIA in patients age six years and older.¹⁵ Abatacept may be used alone or in combination with MTX. Patients weighing more than 165 pounds should receive a dose of 10 mg/kg as an IV infusion based on body weight; those children weighing less than 165 pounds should be dosed following the adult regimen with a maximum dose of 1,000 mg. Following the initial dose, abatacept should be given at Weeks 2 and 4, then every four weeks thereafter. Some pediatric patients have severe anxiety associated with weekly or more frequent injections. Agents that are administered with less frequent dosing or are administered via IV infusion may ease this anxiety.¹¹

Biologics on the Horizon for JIA

No other biologic agents are approved by the FDA for the treatment of pediatric patients, but there are three agents currently under investigation for JIA. ACZ885 (canakinumab) is currently undergoing phase III clinical trials in patients with systemic JIA.¹⁶ This agent is a fully human monoclonal antibody that blocks the inflammatory protein interleukin-1b.¹⁷ This agent is already FDA approved for treating cryopyrin-associated periodic syndrome, a rare autoinflammatory disease. Novartis plans to file for the approval of canakinumab for systemic JIA in 2011.¹⁸ Certolizumab pegol (Cimzia) is also undergoing phase III clinical trials for the treatment of JIA.¹⁹ This PEGylated TNF-α antagonist is currently FDA approved for the treatment of RA and Crohn’s disease in adults.²⁰ Tocilizumab (Actemra), the humanized anti–interleukin-6 receptor monoclonal antibody, is currently in phase III clinical trials for the treatment of systemic JIA.²¹ In an ongoing clinical trial, patients aged 2 to 17 years receive IV tocilizumab 8 mg/kg (for weight 66 pounds or more) or 12 mg/kg (for weight under 66 pounds) every two weeks for 12 weeks, in addition to NSAIDs plus MTX. These patients are compared with patients receiving only NSAIDs plus MTX.²² Patients receiving tocilizumab have had a prior inadequate clinical response to NSAIDs and corticosteroids. Open-label treatment is expected through 92 weeks with an anticipated sample size of 100 to 500 patients.

If these biologic agents can meet treatment goals in children and prevent joint damage and other negative outcomes, many more treatment options become available once they are adults. All biologics require vigilance and long-term surveillance to monitor for and prevent adverse effects that can occur in the short or long term. There are numerous biologic agents for treating RA in adults and many more in earlier phases of pharmaceutical development for this patient population.²³

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

References

1. Roxro announces FDA approval of Sprix. www.sprix.com/docs/SPRIX-approval-press-release.pdf. Published May 17, 2010. Accessed May 24, 2010.
2. Roy C. GlaxoSmithKline, Human Genome Sciences’ lupus drug Benlysta fails secondary endpoint in phase III study. www.firstwordplus.com/Fws.do?articleid=EC8EA1A513274EDA94E3A541C6BE18A2&logRowId=361010. Published April 20, 2010. Accessed May 24, 2010.
3. Dennis M. FDA staff question cardiovascular risk of NicOx’s naproxcinod ahead of meeting. www.firstwordplus.com/Fws.do?articleid=215EE4F655E549B7BDF7E7080D16DF8E&logRowId=364007. Published May 11, 2010. Accessed May 24, 2010.
4. Dennis M. Roche, Biogen Idec halt development of ocrelizumab for rheumatoid arthritis. www.firstwordplus.com/Fws.do?articleid=AB3879AE22394F708E179A40E6E006F6&logRowId=365165. Published May 19, 2010. Accessed May 24, 2010.
5. Roche and Biogen Idec decide to suspend Ocrelizumab treatment-Rheumatoid Arthritis development programme on hold. www.roche.com/media/media_releases/med-cor-2010-03-08.htm. Published March 8, 2010. Accessed May 24, 2010.
6. Dane L. FDA advisory panel votes not to recommend Acura, King’s Acurox. www.firstwordplus.com/Fws.do?articleid=A2AACAE25AF042CB86175DCC0D39CE16&logRowId=361174. Published April 22, 2010. Accessed May 24, 2010.
7. U.S. Food and Drug Administration. Ultram (tramadol hydrochloride), Ultracet (tramadol hydrochloride/acetaminophen): Label change. www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm213264.htm. Published May 25, 2010. Accessed May 26, 2010.
8. U.S. Food and Drug Administration. Important drug warning. www.fda.gov/downloads/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/UCM213265.pdf. Published March 2010. Accessed May 26, 2010.
9. Hayward K, Wallace CA. Recent development in anti-rheumatic drugs in pediatrics: Treatment of juvenile idiopathic arthritis. Arthritis Res Ther. 2009;11:216.
10. Hoffart C, Sherry DD. More aggressive treatment for juvenile idiopathic arthritis. J Musculoskel Med. 2010;27:106-108.
11. Enbrel label. www.accessdata.fda.gov/drugsatfda_docs/label/2008/103795s5359lbl.pdf. Published June 23, 2008. Accessed May 26, 2010.
12. U.S. Food and Drug Administration. Humira approval letter for juvenile idiopathic arthritis. www.accessdata.fda.gov/drugsatfda_docs/appletter/2008/125057s114ltr.pdf. Published February 21, 2008. Accessed May 26, 2010.
13. Humira label with new indication for JIA. www.accessdata.fda.gov/drugsatfda_docs/label/2008/125057s114lbl.pdf. Published February 2008. Accessed May 26, 2010.
14. Ruperto N, Lovell DJ, Cuttica R, et al. A randomized, placebo-controlled trial of infliximab plus methotrexate for the treatment of polyarticular-course juvenile rheumatoid arthritis. Arthritis Rheum. 2007;56:3096-3106.
15. Orencia label. www.accessdata.fda.gov/drugsatfda_docs/label/2009/125118s0086lbl.pdf. Published August 25, 2009. Accessed May 26, 2010
16. Single-dose study to assess efficacy of canakinumab (ACZ885) in patients with active systemic juvenile idiopathic arthritis (SJIA) (β-SPECIFIC 1). www.clinicaltrials.gov/ct2/show/NCT00886769?term=acz885+and+sjia&rank=2NCT00886769. Published April 22, 2009. Updated March 24, 2010. Accessed May 26, 2010.
17. Novartis set to sustain its leading global position in oncology with portfolio targeting various tumors and life-threatening diseases. www.novartis.com/newsroom/media-releases/en/2009/1359994.shtml. Published December 9, 2009. Accessed May 26, 2010.
18. First quarter 2010 results: Novartis investors presentation. www.novartis.com/downloads/investors/sales-results/q1-2010-investor-presentation.pdf. Published April 20, 2010. Accessed May 26, 2010.
19. UCB’s new development pipeline. www.ucb.com/rd/pipeline/new-development. Published 2010. Accessed May 26, 2010.
20. Cimzia label. www.accessdata.fda.gov/drugsatfda_docs/label/2009/125160s092lbl.pdf. Published November 18, 2009. Accessed May 26, 2010.
21. Roche Pharmaceuticals pipeline. www.roche.com/research_and_development/pipeline/roche_pharma_pipeline.htm. Published April 16, 2010. Accessed May 26, 2010.
22. A study of tocilizumab in patients with active systemic juvenile idiopathic arthritis. www.clinicaltrials.gov/ct2/show/NCT00642460?term=tocilizumab+and+JIA&rank=2. Published March 19, 2008. Updated May 25, 2010. Accessed May 26, 2010.
23. Smolen JS, Aletaha D, Koeller M, Weisman MH, Emery P. New therapies for treatment of rheumatoid arthritis. Lancet. 2007;370:1861-1874.