Drug Updates

New Approvals

Buprenorphine Transdermal System (Butrans) has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of moderate to severe chronic pain in patients requiring around-the-clock opioid analgesia. It will be available in early 2011 at 5-µg/hour, 10-µg/hour, and 20-µg/hour dosage strengths as a Schedule III controlled substance. Each patch releases the drug continuously over seven days.¹ A dose of 20 µg/hour should not be exceeded due to the risk of QTc interval prolongation.² Other warnings and contraindications apply.

CIP-Tramadol ER, an extended-release tramadol product, has been FDA-approved for treating adults with moderate to moderately severe chronic pain.³ The product is a capsule comprising an immediate-release tablet and sustained-release beads. It can be taken without food.

Denosumab injection (Prolia) has been FDA-approved for postmenopausal women at risk for fractures.⁴ Postmenopausal osteoporosis studies were completed in 7,000 women and evaluated both hip and vertebral fractures. Denosumab is administered once every six months by injection to increase bone mass and bone strength. Common side effects reported in clinical trials included back pain, hypercholesterolemia, and bladder infections. Denosumab will cost approximately $825 per injection and will be competitively priced with orally administered osteoporosis treatments.

Methoxsalen 10 mg capsules (Oxsoralen) are available again for treating severe psoriasis.⁵ These capsules are available on a limited supply basis following a product shortage due to an unanticipated change in the active ingredient supplier.

Tramadol orally disintegrating tablets (Rybix ODT) have been FDA approved to treat moderate to moderately severe pain in patients 17 years of age and older.⁶ No studies have been completed to indicate whether tramadol ODT has a faster onset of action than orally administered immediate release tramadol tablets. The tablets contain phenylalanine.

Valacyclovir hydrochloride tablets in both 500-mg and 1,000-mg strengths are now available generically. Valacyclovir is approved by the FDA to treat cold sores (herpes labialis), initial and recurrent episodes of genital herpes in immunocompetent adults, chronic suppressive therapy of recurrent episodes of genital herpes in immunocompetent and in HIV-infected adults, reduction of transmission of genital herpes in immunocompetent adults, and treatment of herpes zoster in immunocompetent adults.⁷

Pipeline

Acetaminophen injection (Ofirmev) has received a new Prescription Drug User Fee Act (PDUFA) action date of November 4, 2010.⁸ The manufacturer (Cadence Pharmaceuticals, Inc.) received a complete response letter in February from the FDA, citing deficiencies in the production facilities. No safety issues, efficacy issues, or requests for additional clinical trials are needed prior to approval. Cadence met with the FDA in April to discuss these deficiencies, and they resubmitted their New Drug Application (NDA) in May. Intravenous acetaminophen is approved in 80 countries worldwide, including major markets in Europe.

Denosumab injection (Prolia) has been granted a priority review by the FDA for the treatment of bone metastases to reduce skeletal-related events in patients with cancer.⁹ Denosumab was studied in approximately 6,900 patients, including in head-to-head trials that compared it to zoledronic acid. This same indication has been submitted in Europe, Canada, and Australia.

DM-1796, extended-release once-daily gabapentin, has had its NDA filed with the FDA for the treatment of postherpetic neuralgia.¹⁰

Ibuprofen/famotidine (Duexa) has had its NDA filed with the FDA to reduce the risk of upper gastrointestinal (GI) ulcer development in patients with pain and arthritis.¹¹ Phase 3 clinical trials enrolled more than 1,500 patients with mild to moderate pain.¹² Patients that were treated with this combination had 50% fewer upper GI ulcers compared with patients that received ibuprofen monotherapy. The PDUFA date is anticipated to be in the first quarter of 2011.

Laquinimod is a new oral quinoline-3-carboxamide derivative that is currently in Phase 2 clinical trials to treat multiple sclerosis (MS).¹³ In addition to managing MS, this agent has shown preclinical therapeutic efficacy in models of other autoimmune diseases, including rheumatoid arthritis (RA), insulin-dependent diabetes mellitus, Guillain Barré Syndrome, lupus nephritis, and Crohn’s disease. Because of this, the manufacturer, Teva, has initiated clinical trials utilizing laquinimod in Crohn’s disease and lupus nephritis.¹⁴ Teva has begun recruitment of patients for a Phase 2 clinical trial of laquinimod in lupus patients with active lupus arthritis.¹⁵

Prednisone tablet low dose has been reformulated in a novel, modified-release preparation known as Lodotra and is currently in Phase 3 clinical trials as a circadian cytokine modulator for the treatment of RA.¹⁶ Compared with RA patients receiving placebo and ongoing disease-modifying antirheumatic drugs, Lodotra use showed a statistically significant improvement in ACR response criteria in a 12-week, double-blind trial known as CAPRA-2 (Circadian Administration of Prednisone in RA-2). A total of 350 patients were evaluated. ACR 20 and ACR 50 responses were statistically significantly better for Lodotra-treated patients compared with placebo-treated patients. The relative reduction in morning stiffness compared with baseline (134 minutes) was also statistically significantly better for active-treated versus placebo-treated patients.

Rilonacept (Arcalyst), currently in Phase 3 clinical trials to treat gout, has met its primary endpoint of decreasing the number of gout flares compared with placebo.¹⁷ Studies are still ongoing, and the manufacturer plans to file an NDA by mid-2011.

Generic rituximab is being investigated by Teva Pharmaceutical Industries, the world’s largest generic company, as a biosimilar of Rituxan/MabThera.¹⁸ A European trial is now recruiting patients with RA to compare branded rituximab to the generic copy, which is known as TL011. It is anticipated that this study, which plans to include 60 patients, will be concluded in August 2011, with a potential launch time in the second half of 2014. Teva formed a biosimilars partnership with the Swiss manufacturer Lonza to research and bring biologic generics (e.g., biosimilars, follow-on generics) to the market.

Zucapsaicin Cream 0.075% (Civamide) has had its NDA filed with the FDA for treatment of the signs and symptoms of knee osteoarthritis.¹⁹ The PDUFA date is anticipated to be in the second half of 2011; the drug will likely get a standard FDA review. Zucapsaicin is a synthetically synthesized transient receptor potential vanilloid-1 receptor modulator that selectively reduces the action of the type-C pain fibers. Zucapsaicin initiates the release of neuropeptides, substance P, and calcitonin-gene related peptide, leading to reduced pain transmission and inflammation. The most common reactions in clinical trials were burning and stinging at the site of application. Zucapsaicin has also been submitted for approval in the European Union and Canada.

Safety

The FDA has updated labelling information for colchicine (Colcrys) related to combined use with protease inhibitors to treat HIV.²⁰ The label change was prompted by results of clinical trials noting serious drug interactions between it and HIV protease inhibitors as well as some antihypertensive agents and antibiotics. The updated label notes a dose adjustment in patients taking protease inhibitors or combinations of HIV medications such as fosamprenavir calcium (Lexiva) and ritonavir. Patients who use these agents together need to follow new dosing guidelines. In addition, colchicine is now contraindicated in patients with hepatic or renal failure that also receive protease inhibitors.

Danish registry data noted that diclofenac had the highest relative risk of heart attack or stroke among nonsteroidal antiinflammatory drugs (NSAIDs) in healthy adults.^21,22 Data from more than 1 million users of NSAIDs from 1997 through 2005 were analyzed. The two NSAIDs with the greatest increased risk of cardiovascular events were diclofenac and rofecoxib. Lead investigator Emil Fosbøl, MB, noted that diclofenac has a “high COX-2 inhibiting selectivity” making it similar to rofecoxib, a COX-2 inhibitor no longer on the market. Cardiovascular events were evaluated for celecoxib, diclofenac, ibuprofen, naproxen, and rofecoxib. Results were inconclusive for celecoxib. Naproxen had the least cardiovascular risk. Other findings included a 29% increase in relative risk of fatal or nonfatal stroke with ibuprofen and a 66% increase in the risk of cardiovascular death with rofecoxib. The main limitation of the study was that it was observational.

The FDA has updated the boxed warning for leflunomide (Arava) related to the risk of severe liver injury and how to avoid it in RA patients receiving the agent.²³ This decision was based on the FDA’s review of adverse event reports between August 2002 and May 2009 that identified 49 cases of severe liver injury, including 14 cases of fatal liver failure. During this review, the greatest risk for liver injury was seen in patients receiving other potential hepatotoxins and in patients with preexisting liver disease. Information added to the boxed warning also states that leflunomide should not be used in patients with preexisting liver disease or those with elevated liver enzymes (alanine aminotransferase [ALT] levels greater than two times the upper limit of normal). Additional recommendations include monitoring liver enzymes at least monthly for three months after starting treatment and at least quarterly thereafter, and stopping leflunomide treatment if the ALT rises to greater than two times the upper limit of normal and beginning cholestyramine to expedite removal of leflunomide from the body. Another recommendation is performing weekly ALT measurements until the level is within the normal range.

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

References

1. Butrans transdermal system approved for chronic pain. www.empr.com/butrans-transdermal-system-approved-for-chronic-pain/article/173803. Published July 1, 2010. Accessed July 19, 2010.
2. Purdue Pharma L.P. receives FDA approval for Butrans (buprenorphine) transdermal system CIII. www.purduepharma.com/pressroom/news/20100701.htm. Published July 1, 2010. Accessed July 19, 2010.
3. Cipher achieves major milestone with FDA approval for CIP-TRAMADOL ER. www.cipherpharma.com/news/cipher-achieves-major-milestone-with-fda-approval-for-cip-tramadol-er. Published May 10, 2010. Accessed August 9, 2010.
4. Perrone M. FDA clears Amgen’s bone-strengthening drug, Prolia. www.businessweek.com/ap/financialnews/D9G2P0400.htm. Published June 1, 2010. Accessed July 19, 2010.
5. Oxsoralen-Ultra available again. www.empr.com/oxsoralen-ultra-available-again/article/173097. Published June 23, 2010. Accessed July 19, 2010.
6. Rybic ODT. www.empr.com/rybix-odt/drugproduct/123. Published July 15, 2010. Accessed July 19, 2010.
7. Watson’s Generic VALTREX 500 mg and 1000 mg receives FDA approval. http://ir.watson.com/phoenix.zhtml?c=65 778&p=irol-newsArticle&ID=1430538. Published May 24, 2010. Accessed August 9, 2010.
8. Cadence Pharmaceuticals announces Ofirmev NDA action date of November 4, 2010. www.drugs.com/nda/ofirmev_100517.html. Published May 14, 2010. Accessed July 19, 2010.
9. Dennis M.FDA grants priority review to Amgen’s Prolia to reduce skeletal events in patients with cancer. www.firstwordplus.com/Fws.do?articleid=26F40A2D5906449B805FADCBB79D447D. Published July 16, 2010. Accessed July 19, 2010.
10. NDA submitted for DM-1796 for postherpetic neuralgia (PHN). www.empr.com/nda-submitted-for-dm-1796-for-postherpetic-neuralgia-phn/article/167056. Published March 31, 2010. Accessed July 19, 2010.
11. FDA accepts NDA for Duexa for ulcer risk reduction in arthritis patients. www.empr.com/fda-accepts-nda-for-duexa-for-ulcer-risk-reduction-in-arthritis-patients/article/171054. Published May 26, 2010. Accessed July 19, 2010.
12. Horizon Pharma, Inc. announces FDA acceptance of DUEXA New Drug Application for filing. www.prnewswire.com/news-releases/horizon-pharma-inc-announces-fda-acceptance-of-duexar-new-drug-application-for-filing-94915659.html. Published May 26, 2010. Accessed July 19, 2010.
13. Teva R&D products auto-immune/inflammatory diseases and other. www.tevapharm.com/research/products_ai.asp. Accessed July 19, 2010.
14. Teva to launch Laquinimod lupus clinical trial. www.tradingmarkets.com/news/stock-alert/teva_teva-to-launch-laquinimod-lupus-clinical-trial-the-firm-s-new-multiple-sclerosis-drug-may-be-able-t-850328.html. Published March 16, 2010. Accessed July 19, 2010.
15. Laquinimod study in systemic lupus erythematosus (SLE) patients with active lupus arthritis. http://clinicaltrials.gov/ct2/show/NCT01085084. Published May 4, 2010. Accessed July 19, 2010.
16. Phase 3 study of Lodotra for the treatment of rheumatoid arthritis (RA). www.empr.com/phase-3-study-of-lodotra-for-the-treatment-of-rheumatoid-arthritis-ra/article/172681. Published June 17, 2010. Accessed July 19, 2010.
17. Dennis M. Regeneron’s Arcalyst meets main goal of late-stage gout trial. www.firstwordplus.com/Fws.do?articleid=DE0A30BB3ACE4F7E9A67BB3E517E588A. Published June 9, 2010. Accessed July 19, 2010.
18. Update 1: Teva tests biosimilar version of Roche’s Rituxan. www.reuters.com/assets/print?aid=USLDE64O1UB20100525. Published May 25, 2010. Accessed July 19, 2010.
19. Winston Laboratories, Inc. submits NDA for CIVANEX (Civamide Cream) for treatment of osteoarthritis. www.marketwatch.com/story/winston-laboratories-inc-submits-nda-for-civanexr-civamide-cream-for-treatment-of-osteoarthritis-2010-07-07. Published July 7, 2010. Accessed July 19, 2010.
20. Petrochko C. Gout treatment gets label update for HIV drug interaction. www.medpagetoday.com/ProductAlert/DevicesandVaccines/19999. Published May 9, 2010. Accessed July 19, 2010.
21. Peck P. Registry data point to diclofenac as deadliest NSAID. www.medpagetoday.com/Cardiology/Prevention/20558. Published June 8, 2010. Accessed July 19, 2010.
22. Fosbøl, EL, Folke F, et al. Cause-specific cardiovascular risk associated with non-steroidal antiinflammatory drugs among healthy individuals. Circ Cardiovasc Qual Outcomes. 2010; 3:395-405.
23. Arava (leflunomide): Boxed warning—risk of severe liver injury. www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm218912.htm?sms_ss=email. Published July 13, 2010. Accessed July 19, 2010.