Drug Updates - Page 2 of 5 - The Rheumatologist

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Anakinra injection (Kineret) is being evaluated for treating systemic-onset juvenile idiopathic arthritis (JIA).¹ At the recent European League Against Rheumatism meeting, De Jager et al presented results of a small open-label study in which 11 of 13 patients enrolled achieved a 90% reduction in the American College of Rheumatology pediatric criteria (ACRPed90), which occurred within three weeks of initiating treatment with anakinra.² At one year follow-up, all 11 children were still in remission. A more rigorous study with better controls needs to be performed to truly evaluate the effect of anakinra on systemic-onset JIA before more widespread use can be recommended.

Belimumab (Benlysta) has received a priority review from the FDA as a potential new treatment for systemic lupus erythematosus (SLE).³ The FDA is expected to make a decision on the drug on December 9, 2010, which is the Prescription Drug User Fee Act target date.⁴ The Biologics License Application was filed on June 9, 2010, which includes data from two phase III clinical trials involving 1,684 autoantibody positive patients with SLE. A Marketing Authorization Application (MAA) was filed with the European Medicines Agency (EMA) on June 4 for potential approval and use in European countries.

Calcitonin oral tablets are undergoing phase III clinical trials for the treatment of postmenopausal osteoporosis.⁵ Tarsa Therapeutics is investigating this once daily tablet to potentially add to the armamentarium of injectable and intranasal calcitonin products.

Canakinumab (Ilaris, ACZ885), administered as a one-time subcutaneous injection was shown to significantly reduce gout flares in a 16-week study.⁶ Canakinumab is a recombinant, human anti-human-interleukin-1β monoclonal antibody that is already FDA approved to treat cryopyrin-associated periodic syndromes in patients four years of age and older, including familial cold auto-inflammatory syndrome and Muckle-Wells syndrome.⁷ Further study is needed to fully evaluate the efficacy of this agent in treating gout patients.

The C.A.R.E.S. Alliance, a patient safety organization, was launched on September 8, 2010, to help curb the problem of misuse, abuse, and unintentional overdose associated with the use of opioid medications.

CH-4051 is an orally active, antifolate agent currently undergoing phase II clinical trials.⁸ It is being evaluated in rheumatoid arthritis patients who have had an inadequate response to methotrexate. Patient screening began in October.

Duloxetine (Cymbalta) was evaluated as a potential treatment for chronic musculoskeletal pain by the Anesthetic and Life Support Drugs Advisory Committee of the FDA.⁹ The committee voted by a slim margin to recommend use of duloxetine for this purpose. Based on three studies using different doses of duloxetine, it performed slightly better than placebo in treating chronic low back pain but not osteoarthritis pain. As for safety, hepatotoxicity may be an issue. It also appears to be associated with an increased risk of Stevens Johnson syndrome and toxic epidermal necrolysis.

Ketoprofen 10% cream (Ketotransdel) is currently undergoing phase III clinical trials as a topical therapy to reduce pain associated with soft tissue injuries.¹⁰ In a placebo-controlled study, time to onset of pain relief was about 40 minutes faster and time to end of analgesic effect was about 45 minutes longer with topical ketoprofen 10% compared with the effects of placebo.

Drug Development Setbacks

JZP-6 (Zyrem, sodium oxybate) was evaluated by the Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee for the treatment of fibromyalgia.^19,20 The committees voted 20 to 2 that the benefit-risk ratio did not support approving sodium oxybate. There was a concern for abuse of the agent and accidental overdose, even with the proposed REMS. The committees did, however, suggest that the company perform additional safety and effectiveness trials. The committees also recommended that the developer compare sodium oxybate to other agents that are currently used to treat fibromyalgia. Sodium oxybate is currently FDA approved to treat narcolepsy and is a schedule III controlled substance.

Naproxcinod, which was being developed for relieving the signs and symptoms of osteoarthritis, received a complete response letter for their New Drug Application on July 22, 2010.²¹ The FDA informed NicOx that it did not approve the application. Naproxcinod was to be a first-in-class cyclooxygenase-inhibiting nitric oxide-donating antiinflammatory. The FDA recommended that NicOx perform one or more long-term controlled studies in order to assess the cardiovascular and gastrointestinal safety of naproxcinod. NicOx still plans on discussing next steps with the FDA and continuing the European regulatory process for this agent.²² It is currently under review by the European Medicines Agency; the Marketing Authorization Application was filed in December 2009. NicOx has also announced that they will be closing their US-based headquarters.

Methylnaltrexone tablets (Relistor) are currently undergoing phase III clinical trials for the treatment of chronic nonmalignant pain in patients who experience opioid-induced constipation (OIC).¹¹ The phase III program will be international in scope and plans to enroll about 700 patients with OIC in a double-blind, placebo-controlled manner. The primary study endpoint will be the proportion of patients with a rescue-free bowel movement within four hours of receiving methylnaltrexone during an initial four-week double-blinded period. Currently methylnaltrexone is FDA approved as a subcutaneous injection for the treatment of OIC in patients with advanced illness who are receiving palliative care when they have not responded to laxative therapy. Treatment beyond four months has not been evaluated. Patients with known or suspected bowel obstruction should not use methylnaltrexone. The most common side effects in clinical trials were abdominal pain, flatulence, nausea, dizziness, diarrhea, and hyperhidrosis. Subcutaneous methylnaltrexone is also approved for use in the European Union, Canada, Australia, and Brazil.

RDEA594, an oral uric acid transporter inhibitor, is undergoing phase II clinical studies for the management of gout patients with hyperuricemia.¹² In a small four-week study, 60% of patients that had elevated uric acid levels were able to achieve a level that was less than 6 mg/dL.

Tranilast, an oral mast cell stabilizer, is being studied in the United States as a uricosuric agent.¹³ In clinical trials it was being dosed daily as 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 900 mg, or placebo; it was mostly dosed as once daily. The twice-daily dosing had no greater efficacy. Following seven days of treatment at the three highest medication doses, mean serum urate concentrations decreased, and urinary uric acid excretion values significantly increased in treated patients. Six patients developed liver transaminase elevations; four of these reactions were in placebo-treated patients.

Safety

The Collaborating and Acting Responsibly to Ensure Safety (C.A.R.E.S.) Alliance, a patient safety organization, was launched on September 8, 2010, to help curb the problem of misuse, abuse, and unintentional overdose associated with the use of opioid medications.¹⁴ Free resources are available on their website for healthcare professionals.^15,16 C.A.R.E.S. Alliance is based on the belief that the answer to effective pain management lies in education, innovation, and collaboration between healthcare professionals and patients. The mission statement of the alliance is to improve patient and societal outcomes through innovative and scientific education. Healthcare providers can download tools and resources from the website and also sign up to receive information from them.

New Approvals

Buprenorphine HCl/naloxone HCl dihydrate sublingual film (Suboxone sublingual) has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of opioid dependence.²³ This sublingual formulation provides a quick-dissolving therapeutic buprenorphine dose.

Enoxaparin sodium injection (the generic of Lovenox) has been approved by the FDA.²⁴

Oxymorphone hydrochloride extended-release tablets (the generic of Opana) in 5 mg, 10 mg, 20 mg, 30 mg, and 40 mg strengths have been approved by the FDA.²⁴

Lamotrigine (Lamictal) has been linked to the development of aseptic meningitis between one to 42 days after commencing therapy.¹⁷ There have been at least 40 cases in both adults in children. Thirty-five patients required hospitalization, and in most cases the symptoms resolved when lamotrigine was discontinued. Symptoms included headache, nausea, vomiting, fever, nuchal rigidity, photophobia, myalgias, and rash. Cerebrospinal fluid white blood cell count differentials showed a predominance of neutrophils in most cases. Some of these cases occurred in patients with SLE and other autoimmune disorders, and some patients developed renal and hepatic reactions, suggesting a hypersensitivity or drug reaction. The FDA is working with the drug’s manufacturer on a label update and patient medication guide.

Quinine sulfate (Qualaquin) continues to be used off label to manage night-time leg cramps and restless leg syndrome, yet quinine is only approved by the FDA to treat uncomplicated malaria.¹⁸ Use of quinine sulfate can cause serious and life-threatening hematologic reactions including thrombocytopenia and hemolytic-uremic syndrome/thrombotic thrombocytopenic purpura (TTP), which can result in permanent kidney damage. There have been at least 38 cases of serious adverse events, most requiring hospitalization. The median time to onset of hematologic adverse reactions was 13.5 days after starting quinine sulfate. Two deaths were reported, one due to TTP and one due to hemolysis. The risk management plan for quinine sulfate required that a patient receive a medication guide as part of the FDA’s Risk Evaluation and Mitigation Strategy (REMS). A Dear Healthcare Professional letter was also issued for this product.

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

References

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