Drug Updates

New Approvals

Earlier this year, the European Commission approved abatacept (Orencia) in combination with methotrexate (MTX) for treating moderate to severe active polyarticular juvenile idiopathic arthritis in children six years of age and older who have had an insufficient response to other disease-modifying antirheumatic drugs (DMARDs), including at least one tumor necrosis factor (TNF) α inhibitor.¹ To date, there are limited DMARD options for treating children. This approval of abatacept is based on the results of the Abatacept Withdrawal study to Assess efficacy and safety in Key Endpoints in juvenile idiopathic arthritis Not responding to current treatment (the AWAKEN study). This study evaluated the safety and efficacy of abatacept in patients six to 18 years of age. Following an initial open-label lead-in period, the overall adverse event frequency was 70%, and infections occurred at a frequency of 36%. Only patients that obtained an ACR Pediatric 30 response were randomized in the second phase, to receive either abatacept or placebo. In the double-blinded second phase, there were significantly fewer disease flares in abatacept-treated patients compared with placebo-treated patients (20% versus 53%). Adverse events in the second phase did not differ significantly between treatment groups. Acute infusion reactions occurred in 2–4% of patients. No opportunistic infections were identified. In another study, abatacept improved quality of life for children, allowing them to miss fewer school days.

Oral transmucosal fentanyl citrate lozenges have been approved by the U.S. Food and Drug Administration (FDA). It is the generic of Actiq and is available in six different doses.²

Hydromorphone extended-release tablets (Exalgo) have been approved by the FDA for treating moderate to severe pain in patients that require treatment for an unlimited period of time.³

Pipeline

The FDA is expected to review the complete response submission related to denosumab (Prolia) for the treatment of postmenopausal osteoporosis by July 25, 2010.⁴ Information submitted included more information on postmarketing surveillance and updated safety data. Denosumab, if approved, will be administered every six months as a subcutaneous injection. It is also being investigated for the treatment of rheumatoid arthritis (RA) and to delay bone metastases and treat bone destruction in patients with advanced cancer.

Hydrocodone controlled-release without acetaminophen (ZX002) has begun phase 3 clinical trials to treat moderate to severe pain in patients requiring around-the-clock opioids.⁵ There are currently no hydrocodone “monotherapies” available, nor are there any controlled-release hydrocodone products, even though hydrocodone is one of the most widely prescribed opioids in combination with acetaminophen. ZX002 is a novel, oral, controlled-release formulation using Elan’s Spheroidal Oral Drug Absorption System (SODAS).

Ocrelizumab, an investigational humanized anti-CD20 monoclonal antibody for treating RA given in combination with MTX, met its primary endpoint (an ACR20 response) in the first phase 3 trial, known as STAGE.⁶ In this trial, ocrelizumab was given to patients who had an inadequate response to MTX at both Weeks 24 and 48. STAGE was an international randomized, multicenter, three-arm, parallel-group, placebo-controlled study in over 1,000 patients with active RA. However, in March, Roche and Biogen announced the suspension of ocrelizumab clinical trials for the treatment of RA due to the safety signal of serious infections and opportunistic infections, including some deaths. It was determined that the benefits of using ocrelizumab for RA did not outweigh its risks.⁷

The fate of oxycodone/niacin (Acurox), an abuse-deterrent formulation to treat moderate to severe pain, will soon be decided.⁸ Niacin was added to this agent for the purpose of reducing oxycodone misuse.

Pirfenidone, an investigational agent to delay pulmonary function declines in patients with idiopathic pulmonary fibrosis, has been recommended for approval by an FDA advisory panel.⁹ Advisory committee members felt that the drug’s effect was modest and agreed that long-term follow-up would be needed to determine if the agent is able to extend patient survival. A final decision is expected soon.

A New Drug Application (NDA) was filed for sodium oxybate (JZP-6) for treating fibromyalgia.¹⁰ The target date for the FDA to complete its review is October 11, 2010. In clinical trials, sodium oxybate significantly decreased fatigue and pain and also improved sleep quality, daily functioning, and patient global impression of change. It was generally well tolerated, with only mild to moderate adverse effects such as nausea, dizziness, and headaches. It already has FDA approval for the treatment of excessive daytime sleepiness and cataplexy in adults with narcolepsy.

Tapentadol extended-release tablets have had their NDA filed. Tapentadol is a centrally acting oral analgesic which binds to the mu-opioid receptor and inhibits norepinephrine reuptake. It is being used to treat moderate to severe chronic pain in adults aged 18 years and older. Clinical trials studied this agent for treating osteoarthritis, low back pain, and in patients with diabetic peripheral neuropathic pain. The extended-release formulation has been designed to resist mechanical destruction that could cause abuse of the agent (e.g., crushing and chewing). An immediate-release tapentadol tablet (Nucynta) is already FDA approved and is a Schedule II agent.¹¹

A supplemental NDA was filed with the FDA for tocilizumab for preventing structural joint damage assessed by radiograph, and improving physical functioning in adults with moderate to severely active RA.¹² The Tocilizumab Safety and the Prevention of Structural Damage (LITHE) Study showed that when tocilizumab was combined with MTX, patients had significantly less joint damage at two years compared with patients that received MTX monotherapy. Physical functioning was improved at Weeks 52 and 104.

Safety

Oral bisphosphonates are undergoing a safety review related to reports of a possible increased risk of atypical subtrochanteric femur fractures.¹³ Some of these agents include risedronate (Actonel), ibandronate (Boniva), and alendronate (Fosamax). During this process, the FDA recommends that healthcare professionals be aware of the possible risk of this type of femur fractures in patients taking oral bisphosphonates, to continue to follow the prescribing recommendations in the label, to discuss the known benefits and potential risks of using oral bisphosphonates with patients, and to report any adverse reactions to the FDA’s MedWatch program.¹⁴

Rho(D) immune globulin intravenous (WinRho SDF) has received a boxed warning related to patients dying from intravascular hemorrhage (IVH) in those who have been administered this agent for managing immune thrombocytopenia purpura.¹⁵ Additional serious complications have occurred with the use of this product, including severe anemia, acute renal insufficiency, renal failure, and disseminated intravascular coagulation. Deaths have been reported most frequently in patients over age 65 years and with co-morbid conditions.¹⁶ The boxed warning informs healthcare professionals to closely monitor patients in a healthcare setting for at least eight hours after administration and perform a urinalysis (e.g., dipstick) at baseline, at two hours and four hours after administration, and prior to the end of the monitoring period. In addition, patients should be alerted to and monitored for signs and symptoms of IVH (e.g., back pain, shaking chills, fever, discolored urine, hematuria). Even if these signs or symptoms do not occur within eight hours of receiving WinRho, they can subsequently occur. If IVH is suspected after administering WinRho, post-treatment laboratory testing should be performed, including plasma hemoglobin, urinalysis, haptoglobin, lactate dehydrogenase, and plasma direct and indirect bilirubin.

A draft guidance from the National Institute for Health and Clinical Excellence (NICE)—an independent advisory groups to the National Health Service in the U.K.—recommends use of rituximab (MabThera) in combination with MTX in patients who do not respond to other therapies, including at least one TNF inhibitor. Additionally, NICE also stated that use of a second TNF inhibitor following failure of a first TNF inhibitor should only be done within the confines of a clinical trial, and that abatacept should not be used in patients with RA that have failed treatment with a TNF inhibitor. The committee does not consider abatacept to be a better therapy than rituximab. They also feel that abatacept is not a good value for the money, considering that it is also more costly.¹⁷

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

References

1. European Commission Approves ORENCIA (abatacept) in combination with methotrexate for children with moderate to severe polyarticular juvenile idiopathic arthritis (pJIA). http://investor.bms.com/phoenix.zhtml?c=106664&p=irol-newsArticle_print&ID=1378489&highlight=. Published January 25, 2010. Accessed March 17, 2010.
2. Covidien launches generic version of Actiq. www.ajc.com/business/covidien-launches-generic-version-344323.html?cxntlid=daylf_artr. Published March 3, 2010. Accessed March 17, 2010.
3. Dane L. CombinatoRx’ Exalgo garners FDA approval. www.firstwordplus.com/Fws.do?articleid=49543B75368641E1A81C6F59EF8B0C7D&logRowId=353157. Published March 2, 2010. Accessed March 17, 2010
4. FDA classifies Prolia (Denosumab) complete response submission and targets action date. www.amgen.com/media/media_pr_detail.jsp?year=2010&releaseID=1393314. Published February 19, 2010. Accessed March 17, 2010.
5. Zogenix initiates pivotal phase 3 clinical trial for novel formulation of oral controlled-release hydrocodone. www.zogenix.com/index.php/news/zogenix-initiates-pivotal-phase-3-clinical-trial-for-novel-formulation-of-oral-controlled-release-hydrocodone/. Published March 17, 2010. Accessed March 17, 2010.
6. Genentech and Biogen Idec announce positive results from first phase III trial of ocrelizumab in rheumatoid arthritis. www.gene.com/gene/news/press-releases/display.do?method=detail&id=12487. Published December 10, 2009. Accessed January 20, 2010.
7. Dennis M. Roche, Biogen Idec suspends ocrelizumab treatment in rheumatoid arthritis trials. www.firstwordplus.com/Fws.do?articleid=49796805EE5B4BB4A3E56F64ABBEAA9D&logRowId=354200. Published March 8, 2010. Accessed March 17, 2010.
8. FDA schedule joint advisory committee meeting for Acurox. http://acurapharm.com/investors/press-releases. Published March 17, 2010. Accessed March 17, 2010.
9. Dane L. FDA panel recommends approval for InterMune’s Esbriet. www.firstwordplus.com/Fws.do?articleid=DF0CC2FCF3D24EDDBE2A1EEE7994842D&logRowId=354313. Published March 9, 2010. Accessed March 17, 2010.
10. Jazz Pharmaceuticals announces FDA acceptance of its new drug application for JZP-6 (sodium oxybate) for the treatment of fibromyalgia. http://investor.jazzpharma.com/phoenix.zhtml?c=210227&p=irol-newsArticle_print&ID=1392820&highlight=. Published February 18, 2010. Accessed March 17, 2010.
11. NDA submitted for extended-release tapentadol tablets for chronic pain. www.empr.com/nda-submitted-for-extended-release-tapentadol-tablets-for-chronic-pain/article/158882. Published December 2, 2009. Accessed March 17, 2010.
12. Genentech submits supplemental Biologics License Application for ACTEMRA (tocilizumab) for prevention of structural joint damage and improvement of physical function in rheumatoid arthritis. www.gene.com/gene/news/press-releases/display.do?method=detail&id=12687. Published March 16, 2010. Accessed March 17, 2010.
13. Oral bisphosphonates: Ongoing safety review of atypical subtrochanteric femur fractures. www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm204127.htm. Published March 10, 2010. Accessed March 17, 2010.
14. FDA Drug Safety Communication: Ongoing safety review of oral bisphosphonates and atypical subtrochanteric femur fractures. www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm203891.htm. Published March 10, 2010. Accessed March 17, 2010.
15. Lowes R. FDA announces new boxed warning for WinRho SDF. www.medscape.com/viewarticle/718311. Published March 10, 2010. Accessed March 17, 2010.
16. WinRho SDF (Rho(D) Immune Globulin Intravenous (Human): Risk of intravascular hemolysis. www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm203739.htm. Published March 10, 2010. Accessed March 17, 2010.
17. Dennis M. NICE releases draft guidance on use of anti-TNF therapies in rheumatoid arthritis. www.firstwordplus.com/Fws.do?articleid=7EE99FCAA87740958A6D883B4DCA5B35&logRowId=353557. Published March 3, 2010. Accessed March 17, 2010.