Hydrocodone Bitartrate, Secukinumab, Varenicline Updates, Trials, Approvals

Hydrocodone bitartrate (Zohydro ER) with modified formulation designed with abuse-deterrent properties has been submitted to the FDA as a supplemental New Drug Application (sNDA).¹ This new capsule formulation contains additional inactive ingredients that are intended to make the product more difficult to abuse by injection and nasal insufflation. The manufacturer anticipates review of their submission in the first quarter of 2015. If approved, this product will replace the currently marketed product that does not have abuse-deterrent properties. The product is indicated for managing pain severe enough to require daily, around-the-clock, long-term opioid treatment for which alternative treatment options are not adequate.

Secukinumab (AIN457) is a fully human monoclonal antibody that selectively blocks IL-17A.² Secukinumab in patients with adult-onset psoriatic arthritis (PsA) has met primary and major secondary endpoints in two pivotal Phase 3 clinical trials (FUTURE 1 and FUTURE 2), showing superiority to placebo in over 1,000 patients. Endpoints included improving PsA signs and symptoms, preventing joint damage and improving peripheral joint disease, compared with placebo. While at the same time, patients had clear or almost clear skin (Psoriasis Area Severity Index 90). Both FUTURE 1 and 2 are randomized, placebo-controlled, multicenter studies designed to establish secukinumab efficacy in PsA patients in comparison to placebo. In addition, the studies were designed to assess secukinumab tolerability and safety. The ACR20 was the primary endpoint in these trials, and the agent was well tolerated. No new safety signals were identified. It is also being investigated to treat ankylosing spondylitis (AS), moderate-to-severe plaque psoriasis and rheumatoid arthritis (RA).

On Sept. 18, a combined Meeting of the Bone, Reproductive and Urologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee Meeting Announcement of FDA met to discuss limitation on the use of testosterone products.³ They unanimously voted on modifying product labeling for testosterone-replacement products used for men with congenital or acquired primary hypogonadism, including such conditions as cryptorchidism, Klinefelter’s syndrome or testicular damage from chemotherapy or heavy metals. These uses were not questioned.

The benefit of [testosterone-replacement products] is unknown in patients with idiopathic hypogonadism.

Use for “age-related or idiopathic” hypogonadism was questioned. This is currently worded as “hypogonadotropic hypogonadism (congenital or acquired): Idiopathic gonadotropin or luteinizing-hormone–releasing (LHRH) deficiency or pituitary-hypothalamic injury from tumors, trauma, or radiation.” The panel recommended the completion of large studies to show both clinical benefit and product safety. Currently, the benefit is unknown in patients with idiopathic hypogonadism. The ambiguous wording has led to increased testosterone use in men with potentially low testosterone (low-T) who have signs and symptoms of age-related low levels, but many have normal levels or have not had their levels tested. In addition, studies have shown that testosterone use may increase cardiovascular risk in men who use the product. Additionally, in 25% of testosterone-replacement product users, no levels were obtained prior to treatment, and 21% of users never had levels checked during treatment.

An FDA analysis showed an increase of 65% of testosterone product usage from 2009 through 2013.

Varenicline, used for smoking cessation, was the subject of a recent Institute for Safe Medication Practices (ISMP) Medication Safety Alert.⁴ The ISMP reassessed adverse drug event (ADE) data from 2007 through the third quarter of 2013. The assessed endpoints included suicidal thoughts, self-injury and homicide. Their analysis showed that varenicline use was accompanied by more cases of homicidal thoughts, self-injury or suicide than any other drug during that timeframe.

Since its approval in 2007, varenicline has been the primary suspected drug in 293 completed suicides and another 490 attempted suicides. For homicidal ideation, varenicline had a fivefold margin over quetiapine. Of 10 drugs that were ranked for these psychiatric ADEs, all but one (isotretinoin, ranked at 7) had wider patient exposure due to the number of dispensed outpatient prescriptions according to IMS Health. Other drugs in the ranking from 2 through 10 were montelukast (ranked at 2), paroxetine (ranked at 3), quetiapine (ranked at 4), venlafaxine (ranked at 5), interferon beta (ranked at 6), duloxetine (ranked at 8), pregabalin (ranked at 9) and bupropion (ranked at 10).

The FDA met to reassess the varenicline data in a meeting of two advisory boards held in mid-October. Of 18 voting members, 11 noted that the agent should continue to carry the boxed warning about the risk of severe neuropsychiatric events, of which six panel members suggested strengthening the boxed warning.⁵ The boxed warning should remain until the outcome of a prospective trial currently underway to assess varenicline’s psychiatric risks is known. FDA reviewers suggested that some of the studies cited by the manufacturer of the agent defending its safety profile may have deterred patients at high risk for neuropsychiatric adverse events from being enrolled. The manufacturer has cited research that suggests minimal or no psychiatric risk due to the drug. However, most of this was in the form of observational studies and meta-analyses. The manufacturer was told when the prospective postmarketing study was requested that observational studies would not be acceptable to assess these safety risks. The results are expected in 2015.

Only time will tell.

Michele B. Kaufman, PharmD, CGP, RPh, is a freelance medical writer based in New York City and a pharmacist at New York Presbyterian Lower Manhattan Hospital.

References

Ixekizumab Clinical Trials Continue; FDA Updates Warning Label for Varenicline

Second Biosimilar Equivalent to Adalimumab

Secukinumab Effective Across the Spectrum of Psoriatic Arthritis

Drug Updates

References

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