Drug Updates: Information on New Approvals and Medication Safety

New Approvals

• Diclofenac Topical Solution 1.5% (Pennsaid Topical Solution) has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of osteoarthritis of the knee. It is expected to be available in the first half of the year.^1,2
• Lansoprazole capsules (Prevacid 24HR) were FDA-approved for use without a prescription (over-the-counter [OTC]) for the management of adults with frequent heartburn.³ They will still be available in this strength as a prescription product, as well as in the 30-mg capsule strength.
• Lansoprazole capsules 15 mg and 30 mg have been FDA-approved as a generic.⁴
• Omeprazole 20-mg/sodium bicarbonate 1100-mg capsules (Zegerid OTC) have been FDA-approved for OTC use for frequent heartburn.⁵ They will be available in the first half of this year.

Pipeline

A New Drug Application (NDA) was submitted to the FDA on December 2, 2009, for diclofenac sodium injection (Dyloject) for the treatment of moderate to severe acute pain in adults.⁶ If it receives FDA approval, it will be the first single-agent non­steroidal antiinflammatory drug to be approved for intravenous use since ketorolac was approved in 1990. Patients studied in trials included those over 65 years of age, as well as those with mild to moderate hepatic and renal insufficiency. Even patients utilizing concomitant blood thinners during post­operative care were evaluated. These are patient populations often overlooked in clinical trials. The submission of this NDA includes more than 2,000 subjects in multi-dose and multiple-day trials.

Hydromorphone HCl extended-release tablets (Exalgo) are being studied in clinical trials for the management of moderate to severe pain in opioid-tolerant patients requiring continuous, around-the-clock opioid analgesia for extended lengths of time.⁷ The FDA has stated that the NDA in its current form is not sufficient for approval of this product. The manufacturers of this agent are in discussions to resolve the details related to the approval of this agent.

Pozen Inc. has begun phase III clinical trials for PA32540, a fixed combination of enteric-coated aspirin 325 mg and immediate-release omeprazole 40 mg.⁸ PA32540 is being studied for secondary stroke and myocardial infarction prevention in patients at risk for gastric ulcers.

Genentech had hoped to receive approval of rituximab for treating patients with earlier stages of rheumatoid arthritis (RA), but the FDA declined to support wider use of the agent due to the risk of the development of progressive multifocal leukoencephalopathy.⁹

Tocilizumab (Actemra) is undergoing phase III clinical trials to treat juvenile idiopathic arthritis (sJIA).¹⁰ In a recent trial, called the TENDER study, patients treated with tocilizumab met the primary endpoint of significant improvement in disease signs and symptoms (JIA ACR30 and the absence of fever) after treatment for 12 weeks compared with placebo-treated patients. Patients received tocilizumab (or placebo) infusions every two weeks throughout the study. The drug was generally well tolerated, with an overall safety profile consistent with previously reported data from other studies of this agent. However, that this study was of a relatively short duration, so not all adverse reactions would be evident.

On the Horizon for Osteoporosis Management

The last time the Pharmaceutical Research and Manufacturers Association published a report on biotechnology medicine in development was a little over a year ago, in November 2008.¹¹ At that time, the association identified 633 biotechnology drugs in development for more than 100 diseases, including auto­immune diseases and other rheumatologic conditions, such as osteoporosis. One of the biotechnology agents submitted to the FDA for the management of postmenopausal osteoporosis is denosumab (potential brand name: Prolia). At the time of the FDA submission, Amgen, the manufacturer, was looking for approval for both the prevention and treatment of osteoporosis. However, in October 2009, the FDA requested a different clinical program for osteoporosis prevention.¹² For the treatment indication to garner an approval, the FDA is requesting more information, including postmarketing safety surveillance information. The FDA also stated that the agent, if approved, will require a Risk Evaluation and Mitigation Strategy (REMS), including a medication guide, a communication plan, and a timetable for REMS assessment. The FDA also requested all safety data related to denosumab.

Denosumab is a fully human monoclonal antibody that inhibits the receptor activator of nuclear factor kappa B ligand (RANKL).¹³ RANKL is a cytokine member of the tumor necrosis factor family and is an important mediator of osteoclast formation, function, and survival.¹⁴ Denosumab has been shown to increase bone mineral density (BMD) and suppress bone resorption in postmenopausal women with low BMD. When administered every six months via the subcutaneous (SC) route, denosumab reduced the risk of vertebral, hip, and nonvertebral fractures in postmenopausal women compared with placebo-treated women.¹⁵ When compared with alendronate, denosumab provided a greater BMD increase with greater decreases in bone turnover markers.

A major concern about long-term use of denosumab relates to its possible effects on the immune system, because RANKL is expressed not just in bone cells but also in immune cells.¹⁶ Neither Cummings et al nor Smith et al. observed an increased rate of serious infections related to denosumab.^15,17 However, Cummings et al reported significant increases in rates of eczema and hospitalizations for cellulitus in denosumab when compared with placebo. A previous study of 314 patients treated with denosumab reported that six patients developed neoplasms and three developed serious infections, whereas none of the 46 patients in the placebo group had such complications.¹⁸ Although not statistically significant, these findings support ongoing surveillance of patients receiving denosumab, particularly when the drug is used in the community setting in patients with coexisting illnesses that might have excluded them from participating in clinical trials. Finally, cost is increasingly relevant. The average wholesale price for the most direct competitor for denosumab, zoledronic acid, is approximately $1,300 per year. Given the relatively marginal clinical differences between these two drugs, a higher cost of denosumab would considerably limit its use. Denosumab is currently in clinical trials for the treatment of RA.

Compared with agents already approved for osteoporosis, denosumab may enhance compliance because in clinical trials, it was administered as a SC injection every six months. Most current treatments are administered daily, weekly, or monthly. The bisphosphonates are quite effective, but can lead to gastrointestinal toxicity or osteonecrosis of the jaw, with some studies showing decreased medication adherence due to these potential adverse events.¹⁹ The use of hormone therapies has decreased, likely reflecting concerns over data from the Women’s Health Initiative, indicating an increased risk of stroke and venous thromboembolism with estrogen use. Selective estrogen receptor modifiers (SERMs), of which raloxifene is currently the only agent FDA-approved for osteoporosis, can also increase thromboembolic events; therefore, SERMs are contraindicated in certain patient populations. Raloxifene can also increase vasomotor symptoms, such as hot flashes and leg cramping. According to the Wyeth/Pfizer pipeline, their SERM bazedoxifene has been filed for FDA approval.²⁰ A bazedoxifene/conjugated estrogen combination product is currently in phase III clinical trials. However, if approved, the use of this combination product may also be limited, because it combines estrogen and a SERM. Salmon calcitonin (Miaclacin) is administered intranasally and is a relatively low-potency agent. It is often reserved for osteoporosis patients who are unable to take other agents. Teriparatide (Forteo), a human recombinant parathyroid hormone administered as a daily SC injection, is an effective treatment modality as well. However, it is not recommended for use beyond two years because it has not been studied beyond two years. Teripartide must also be given by injection, which may decrease adherence. Dose-limiting side effects include dizziness, nausea, and leg cramps. Eli Lilly and TransPharma Medical are studying transdermal teriparatide, which is in phase II clinical trials.²¹ Use of the transdermal route will likely enhance adherence, yet there are many individuals who have difficulty tolerating adhesives in transdermal products.

A number of oral forms of calcitonin are currently in the pharmaceutical pipeline. Bone Medical Limited is currently investigating Capsitonin in phase II clinical trials for the treatment of osteoporosis.²² Tarsa Therapeutics has an investigational oral calcitonin product currently in phase III clinical trials to treat osteoporosis.²³ Finally, Novartis is investigating an oral calcitonin product to treat postmenopausal osteoporosis.²⁴

Another new class of agents to manage osteoporosis includes cathepsin K inhibitors. One agent, MK-0822 or odanacatib, is currently in phase III clinical trials.25 This agent selectively inhibits the cathepsin K enzyme, which plays a pivotal role in osteoclast function.26 Time will tell which of these new biologic or nonbiologic agents will make it through clinical trials and be approved to manage osteoporosis.

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

References

1. FDA approves Pennsaid Topical Solution. www.drugs.com/newdrugs/fda-approves-pennsaid-topical-solution-1758.html 2. Published November 5, 2009; Accessed December 2, 2009.
2. Update-1 Nuvo shares surge on FDA pain cream approval. www.reuters.com/article/email/idUSN0543459820091105. Published November 5, 2009. Accessed December 2, 2009.
3. Prevacid 24HR hr available over-the-counter. www.empr.com/prevacid-24hr-available-over-the-counter/article/157592. Published November 12, 2009. Accessed December 2, 2009.
4. Teva receives final approval for generic Prevacid delayed-release capsules. www.tevapharm.com/pr/2009/pr_882.asp. Published November 10, 2009. Accessed December 2, 2009.
5. Zegerid OTC approved for frequent heartburn. www.empr.com/zegerid-otc-approved-for-frequent-heartburn/article/158881. Published December 2, 2009. Accessed December 2, 2009.
6. Javelin Pharmaceuticals submits Dyloject New Drug Application to FDA for management of Acute Moderate-to-Severe Pain in Adults. http://ir.javelinpharmaceuticals.com/releasedetail.cfm?ReleaseID=427752. Published December 2, 2009. Accessed December 2, 2009.
7. Feedback on Exalgo NDA. www.drugs.com/nda/exalgo_091116.html. Published November 16, 2009. Accessed December 2, 2009.
8. POZEN announces start of enrollment for PA32540 Phase 3 program. http://phx.corporate-ir.net/phoenix.zhtml?c=121701&p=irol-NRText&ID=1357809&highlight=. Published November 20, 2009. Accessed December 2, 2009.
9. FDA nixes wider use of rheumatoid arthritis drug-FDA rejects expanded use of rheumatoid arthritis drug Rituxan. www.cbsnews.com/stories/2009/10/17/ap/business/main5392451.shtml. Published October 17, 2009. Accessed December 2, 2009.
10. Actemra improves signs and symptoms in children with systemic onset juvenile idiopathic arthritis. www.roche.com/investors/ir_update/inv-update-2009-11-20.htm. Published November 20, 2009. Accessed December 2, 2009.
11. Pharmaceutical Research and Manufacturer’s Association 2008 Report-Medicines in Development: Biotechnology. www.phrma.org/medicines_in_development_for_biotechnology. Published November 3, 2008. Accessed December 2, 2009.
12. Amgen provides update on status of Prolia (Denosumab) biologics license application (BLA) submitted to the U.S. Food and Drug Administration (FDA). wwwext.amgen.com/media/media_pr_detail.jsp?year=2009&releaseID=1343288. Published October 19, 2009. Accessed December 2, 2009.
13. Lewiecki EW. Current and emerging pharmacologic therapies for the management of postmenopausal osteoporosis. J Women’s Health. 2009;18:1615-1626.
14. Lewiecki EW. Denosumab update. Curr Opin Rheumatology. 2009;21:369-373.
15. Cummings SR, San Martin J, McClung MR, et al for the FREEDOM Trial investigators. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361:756-765.
16. Lacey DL, Timms E, Tan HL, et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell. 1998;93:165-176.
17. Smith MR, Egerdie B, Hernández Toriz N, et al. Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N Engl J Med. 2009;361:745-755.
18. McClung MR, Lewiecki EM, Cohen SB, et al. Denosumab in postmenopausal women with low bone mineral density. N Engl J Med. 2006;354:821-831.
19. Khosla S. Increasing options for the treatment of osteoporosis. N Engl J Med. 2009;361:818-820.
20. Wyeth Pharmaceuticals Development Pipeline. www.pfizer.com/files/research/pipeline/2009_0506/pipeline_2009_0506.pdf. Published May 6, 2009. Accessed December 2, 2009.
21. A study for the transdermal application of teriparatide. http://clinicaltrials.gov/ct2/show/NCT01011556?term=forteo+transdermal&rank=1. Published November 16, 2009. Accessed December 2, 2009.
22. Bone Medical Ltd website. www.bone-ltd.com/bn002.htm Accessed December 2, 2009.
23. Tarsa Therapeutics receives license for Phase III oral calcitonin program. www.news-medical.net/news/20091020/Tarsa-Therapeutics-receives-license-for-Phase-III-oral-calcitonin-program.aspx. Published October 20, 2009. Accessed December 2, 2009.
24. A study to evaluate oral salmon calcitonin in the treatment of osteoporosis in postmenopausal women taking calcium and vitamin D. http://clinicaltrials.gov/ct2/show/NCT00525798?term=SMC021&rank=3. Published November 13, 2008. Accessed December 2, 2009.
25. Merck October combined pipeline. www.merck.com/research/pipeline/Merck%20October%202009%20Combined%20Pipeline.pdf. Published October 15, 2009. Accessed December 2, 2009.
26. New, long-term data for odanacatib, Merck’s investigational cat K inhibitor, showed positive results in treating osteoporosis. www.merck.com/newsroom/news-release-archive/research-and-development/2009_0914.html. Published September 14, 2009. Accessed December 2, 2009.