Rheumatology Drug Updates

Pipeline and Drug Approvals

In late July, an independent advisory panel to the Food and Drug Administration (FDA) voted against approving adalimumab for treatment of nonradiographic (early-stage) axial spondylarthritis that has not responded to other treatments.¹ This panel recommended additional trials in order to prove efficacy of adalimumab for treating early-stage spondylarthritis. The FDA panel will use this information in their final consideration about whether to approve this agent.

Buprenorphine/naloxone sublingual tablets have been approved by the FDA for individuals with opioid dependence.² This combination agent should be used as part of a complete treatment plan, including counselling and psychosocial support. According to its manufacturer, this new menthol product has higher bioavailability and a faster dissolution time. It also has a smaller tablet size compared to similarly available products.

An advisory panel to the FDA recommended approving certolizumab for treatment of active axial spondylarthritis, ankylosing spondylitis, and nonradiographic axial spondylarthritis.³ The panel unanimously voted in support of the drug’s safety profile.

In late June, Sandoz (the generic division of Novartis) began a phase III clinical trial with a biosimilar version of etanercept for treatment of patients with moderate to severe chronic plaque psoriasis.⁴ This study is evaluating the biosimilarity between this “biogeneric” and etanercept (brand) regarding efficacy, safety, and immunogenicity.

Golimumab (Simponi Aria), the tumor necrosis factor inhibitor (TNF), has been FDA approved as an intravenous (IV) infusion for treating moderate to severe rheumatoid arthritis (RA) for those patients with an inadequate response to methotrexate (MTX).⁵ Approval was based on the results of the Golimumab, an Anti-TNF-alpha Monoclonal Antibody, Administered Intravenously, in Subjects with Active Rheumatoid Arthritis Despite Methotrexate Therapy (GO-FURTHER) trial in 592 patients in a multicenter, double-blind, randomized, placebo-controlled trial. The approved regimen includes a 2-mg/kg IV infusion over 30 minutes. This is administered at baseline, after Month 1, and every two months thereafter.

Oxymorphone hydrochloride extended-release tablets (generic Opana ER) have been FDA approved.⁶ The following strengths are available: 5 mg, 10 mg, 20 mg, 30 mg, and 40 mg. The branded product is FDA approved for treating moderate to severe pain in adults requiring around-the-clock opioid treatment for an extended period.

Paroxetine mesylate (Brisdelle), the selective serotonin reuptake inhibitor, has been FDA approved as the first nonhormonal treatment to relieve moderate to severe vasomotor symptoms with menopause (e.g., hot flashes).⁷ It is available in a 7.5-mg capsule and should be taken daily at bedtime without regards to food.

The FDA has accepted the New Drug Application (NDA) for lower dose submicron indomethacin, a nonsteroidal antiinflammatory drug (NSAID) with a proposed indication of treating adults with mild to moderate acute pain.⁸

Drug Safety

Last month, the FDA issued a safety communication related to the appearance of serious but rare dermatologic reactions with acetaminophen including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and acute generalized exanthematous pustulosis (AGEP).⁹ The FDA is now requiring that a warning be added to the prescription drug product labels containing acetaminophen. Over-the-counter acetaminophen manufacturers will also be required to add a warning about these serious reactions to these products. NSAIDs already have a similar warning on their labels. Evidence supporting causality of these reactions is mostly from a small number of cases published in the medical literature where patients were rechallenged with acetaminophen, and had a recurrence of the skin reaction. The FDA Adverse Event Reporting System (FDA AERS) database and case-control studies provided additional case information. There were three cases of a positive rechallenge in the FDA data. In the medical literature, there were additional cases of SJS, AEP, and TEN (in 3, 6, and 17 patients, respectively) where the only administered drug before the reaction occurred was acetaminophen, or acetaminophen hypersensitivity was confirmed by skin testing or other means. In a review of the FDA AERS (1969 to 2012), there were 16 cases of AGEP and 91 cases of SJS/TEN, resulting in 67 hospitalizations and 12 deaths. Most of these cases were for single-ingredient acetaminophen products. Of the 91 cases of SJS/TEN cases, six were determined to be probably associated with acetaminophen, the rest of the cases were categorized as possibly related to acetaminophen use.

In late July, the FDA took several actions related to ketoconazole (Nizoral) oral tablets with label changes and a new medication guide.¹⁰ Topical ketoconazole formulations are not affected by this safety update. The FDA’s actions include limiting the use of oral ketoconazole due to its ability to cause severe hepatotoxicity and adrenal insufficiency, as well as the potential to cause significantly harmful drug interactions. Through its inhibition of the cytochrome P450 3A4 isoenzyme (CYP3A4) system, ketoconazole can block adrenal steroid production, potentially leading to male gynecomastia and menstrual irregularities, particularly at high doses. Additionally, clearance of coadministered drugs that are metabolized by CYP3A4 are decreased by ketoconazole and can result in increased plasma drug concentrations leading to potentially serious adverse reactions including QT prolongation. Some drug combinations with ketoconazole are therefore restricted or contraindicated (check the drug’s interactions and contraindications section of the label to determine which agents). The new ketoconazole oral tablets labeling states that it should not be a first-line treatment for any fungal infection. Oral ketoconazole is not indicated for the treatment of fungal skin or nail infections. Oral ketoconazole should only be used for the treatment of blastomycosis, coccidioidomycosis, histoplasmosis, chromomycosis, and paracoccidioidomycosis in patients where other treatments have failed or have not been tolerated. Oral ketoconazole is also contraindicated in patients with acute or chronic liver disease, and with other hepatotoxins. Alcohol should be avoided while taking this agent. When evaluating any potential patient for use of oral ketoconazole, all the patient’s concomitant medications should be evaluated, to prevent any potentially serious outcomes. Patients with adrenal insufficiency or with borderline adrenal function should be closely monitored, as should patients under extended stress periods.

Tocilizumab (Actemra) has undergone a label revision with respect to changes in neutrophil count, platelet count, lipid values, and liver enzymes.¹¹ It is recommended that laboratory monitoring be performed due to potential consequences of treatment-related changes in these tests. It has most commonly been seen in polyarticular (PJIA) and systemic juvenile idiopathic arthritis (SJIA).

In The Literature

Berry et al published data on the relationship between the use of nonbenzodiazepine sedative hypnotics and hip fractures in nursing home residents.¹² They conducted a case-crossover study looking at the nonbenzodiazepine agents zolpidem tartrate, zaleplon, and eszopiclone (Ambien/CR, Edluar, Intermezzo, Zolpimist; Sonata; and Lunesta, respectively), and their propensity for increasing the hip fracture risk in a nationwide sample of long-stay nursing home residents. Patients were stratified by individual and facility-level characteristics. Participants (n=15,528) aged 50 and older and that had suffered a hip fracture documented through Medicare Part A and D medical claims were evaluated. Days before and after the fracture were evaluated for nonbenzodiazepine hypnotic drug use. The mean age of study participants was 81 years, of which 78% were female.

Eleven percent of study participants (n=1,715) were dispensed a nonbenzodiazepine hypnotic prior to the hip fracture. The risk for hip fracture was elevated among these patients with an odds ratio (OR) of 1.66. In new users of nonbenzodiazepine hypnotics, the association with hip fracture was greater (OR 2.20). Additionally, the association with hip fracture was also slightly greater in residents with normal or mild cognition impairment (OR 1.86) compared to participants with moderate to severe impairment (OR 1.43). Participants with moderate functional status impairment had an OR of 1.71, and were at greater risk for having a hip fracture compared to more functionally debilitated patients (OR 1.16). Those who were more independent had less of a risk of hip fracture compared to those who required some assistance with moving (OR 2.02). These results are consistent with those of prior studies showing an increased risk of falls and fracture with nonbenzodiazepine hypnotics in older patients. This study confirmed a 66% increase in hip fracture risk within 30 days of using one of these agents.

Many patients are prescribed nonbenzodiazepine sleep medications that have mechanisms of action and metabolism similar to benzodiazepines. Patients have difficulty sleeping from pain, psychiatric/mood, or other reasons. Giving an older patient a long-term (or short-term) prescription for zolpidem without working up the issue can often lead to more harm than good, noted Berry et al, especially in more cognitively impaired, less mobile individuals and those taking many different medications.

Michele Kaufman is a freelance medical writer based in New York City, a pharmacist at New York Presbyterian–Lower Manhattan Hospital, and adjunct faculty at Touro College of Pharmacy.

Pipeline and Drug Approvals

Drug Safety

In The Literature

References

Unexpected Benefits of Bisphosphonates after Hip Fracture

Drug Updates

Drug UPDATES

Patients with OA Respond to Low-Dose SoluMatrix Meloxicam; Off-Label Use of Ketoconazole Results in Death

Pipeline and Drug Approvals

Drug Safety

In The Literature

References

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