Rheumatology Drug Updates

Pipeline & Approvals

Anakinra (Kineret) has been approved by the Food and Drug Administration (FDA) to treat adults and children with neonatal-onset multisystem inflammatory disease (NOMID), the most severe form of cryopyrin-associated periodic syndromes (CAPS).¹ Prior to this approval, anakinra was available under an Orphan Drug Designation. This is its first approval for use in children. NOMID is associated with an overproduction of interleukin-1 (IL-1) that, when left untreated, leads to hearing and visual loss, cognitive dysfunction, joint contractures, bone loss, and cartilage loss.

Bazedoxifene/conjugated estrogen had its New Drug Application (NDA) filed on December 13, 2012.² The FDA Prescription Drug User Fee Act (PDUFA) date is October 3, 2013. It was submitted for the treatment of moderate to severe vasomotor symptoms, vulvar and vaginal atrophy associated with menopause, and also to prevent postmenopausal osteoporosis in nonhysterectomized women. Bazedoxifene is a selective estrogen receptor modulator that has been studied in over 7,500 postmenopausal women in the Selective estrogens, Menopause And Response to Therapy (SMART) trials. The most common adverse reactions in clinical trials were abdominal pain, muscle spasms, and vaginal yeast infection.

Canakinumab (ACZ885) is a fully human monoclonal antibody that inhibits IL-1 beta. It is currently in phase III clinical trials for treating systemic juvenile idiopathic arthritis (SJIA).³ Recent data show that it led to substantial symptom relief in young patients with SJIA (n=84). In one trial known as beta-SPECIFIC 1, 84% of canakinumab-treated SJIA patients had at least a 30% improvement in symptoms (JIA ACR30) versus 10% of placebo-treated patients. This occurred after 15 days of treatment. This benefit continued beyond 29 days (P<0.001). This was a randomized, double-blind, placebo-controlled, four-week study. In beta-SPECIFIC 2, of 177 patients who were prescribed corticosteroids, 45% of canakinumab-treated patients were able to reduce their steroid use, with 33% of patients able to completely discontinue steroids. These patients were almost three times less likely to experience a new flare. Seventy-four percent of canakinumab-treated patients remained flare-free versus 25% of placebo-treated patients (P=0.003).

Fostamitinib is an oral spleen tyrosine kinase inhibitor currently in phase III clinical trials for the treatment of rheumatoid arthritis (RA).⁴ Fostamatinib blocks signalling in multiple cell types involved in inflammation and tissue degradation in RA and may delay disease progression. The phase III trials, the results of which are expected by mid-2013, are known as, Oral Syk Inhibition in Rheumatoid Arthritis (OSKIRA). Three pivotal studies are ongoing: two are examining fostamatinib in patients who have had an inadequate response to disease-modifying antirheumatic drugs (DMARDs). These trials, OSKIRA-1 and OSKIRA-2, are both 12-month studies; one six-month study, OSKIRA-3, is studying patients who have had an inadequate response to anti–tumor necrosis factor therapy. A long-term extension study will also examine ongoing tolerability and safety. The primary study endpoints of OSKIRA 1 to 3 include the proportion of patients with ACR20 response criteria versus placebo. The OSKIRA-1 study also has a co-primary endpoint of change from baseline to week 24 in the modified total Sharp score.

FDA reviewers expressed concern over the potential rate of abuse with hydrocodone bitartrate extended-release capsules (Zohydro ER); they are currently reviewing an NDA for the drug.⁵ The makers of hydrocodone extended-release are seeking the drug’s approval for the management of moderate to severe chronic pain when an around-the-clock opioid analgesic is needed for a prolonged time. If approved, it will be a controlled substance Class II. Part of the advisory group discussion was related to not having an abuse-deterrent in this formulation and the potential for abuse of a single-entity hydrocodone product. Data showed that oxycodone combination products led to about twice as many emergency department (ED) visits than hydrocodone combination products, and that oxycodone-only products led to about six times as may ED visits compared to hydrocodone combination products. A vote was postponed due to Hurricane Sandy but is expected soon.

Lansoprazole has been FDA approved as a generic for Prevacid. It is available as both 15-mg and 30-mg delayed-release capsules.⁶

Otrexup was developed to more easily administer subcutaneous (SC) methotrexate (MTX).⁷ It is a combination product to deliver MTX using Medi-Jet technology. This would make self-administration easier than using intramuscular injections, and potentially improve patient outcomes. Premarketing clinical trials already conducted indicate that RA patients find this delivery system is safe and easy to use to self-administer precise SC MTX doses. This administration also has shown to have improved systemic availability compared to oral dosing.

Tabalumab, an anti–B cell–activating factor (BAFF) monoclonal antibody, is still in phase III clinical trials for RA; however, one trial (FLEX-M) was stopped due to lack of efficacy.⁸ This agent is also still being investigated for systemic lupus erythematosus (SLE). The company believes that the RA data do not reflect negatively on the SLE data. BAFF promotes B cell survival, proliferation, and activation. In the presence of excess BAFF, B cells are not correctly removed by the immune system and may contribute to RA development. Tabalumab is a human immunoglobulin G subclass 4 monoclonal antibody that inhibits soluble and membrane-bound BAFF.

Tocilizumab (Actemra) received an expanded indication for the treatment of adults with moderately to severely active RA who have had an inadequate response to one or more DMARDs.⁹ Tocilizumab has been approved for use as monotherapy or in combination with MTX or other DMARDs.

Varicella zoster immune globulin (VZIG; Varizig) has been FDA approved to reduce chicken pox (varicella zoster virus) infection severity in high-risk patients if administered within four days following exposure to varicella zoster virus.¹⁰ This is the only immune globulin product approved for this use. In 2006, an earlier FDA-approved varicella zoster immune globulin product was removed from the market. The currently approved VZIG product has been available for use under an investigational expanded access protocol. Susceptible individuals treated in the expanded access protocol had low rates of severe VZV infection compared with untreated individuals. Patients without varicella zoster virus immunity who become exposed are at risk of developing severe infections that may be fatal. This product provides a treatment to lower the risk of severe, potentially fatal varicella infections in vulnerable patients, which include patients who are immunocompromised, pregnant women, and infants exposed during pregnancy or after birth. The most common side effect reported was pain at the injection site.

Drug Safety

New data show that evening dosing of any formulation of zolpidem leads to high morning blood levels in some patients. This may lead to impairment of mental alertness, including impairments to driving.¹¹ The data also show who has the highest risk when using the extended-release forms of these drugs, with women appearing more vulnerable due to slower zolpidem elimination compared to men. Manufacturers of brand name products of zolpidem are being mandated by the FDA to lower the recommended dose. For the immediate-release product, the recommended dose for women will be lowered from 10 mg to 5 mg, and the recommended dose for the extended-release products will be lowered from 12.5 mg to 6.25 mg. The lower dose Intermezzo product will not undergo a label change. The same lower doses are also recommended for men. In the pharmacokinetic data reviewed by the FDA, zolpidem blood concentrations exceeding 50 ng/mL approximately eight hours postdosing were found in approximately 33% of women and 25% of men. In addition, approximately 5% of patients had blood levels greater than or equal to 100 ng/mL. Zolpidem blood levels above 50 ng/mL seem capable of impairing driving, increasing motor vehicle accident risk. The FDA is evaluating next-morning impairment with other hypnotic agents.

Michele B. Kaufman, PharmD, BSc, RPh, is a freelance medical writer based in New York City, a clinical pharmacist at New York Downtown Hospital, and adjunct faculty at Touro College of Pharmacy.

Pipeline & Approvals

Drug Safety

References

Drug UPDATES

Information on New Drug Approvals and Medication Safety

Drug Updates: Information on New Approvals and Medication Safety

Drug Updates

Pipeline & Approvals

Drug Safety

References

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