Rheumatology Drug Updates: Labeling for Fluoroquinolones; FDA to Review Benzhydrocodone/Acetaminophen Combination

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FDA Restricts Fluoroquinolone Use

The U.S. Food and Drug Administration (FDA) has twice previously communicated safety information about systemic fluoroquinolones—in August 2013 and July 2008. The safety issues of this medication class described in its latest Drug Safety Communication were also discussed at a November 2015 FDA Advisory Committee meeting.¹ The FDA is now advising that the serious side effects associated with the use of fluoroquinolones generally outweigh the treatment’s benefits for patients with sinusitis, bronchitis and uncomplicated urinary tract infections who have other treatment options available to them. For patients with these conditions, fluoroquinolones should be reserved for those who do not have other treatment options.

The FDA safety review showed that use of fluoroquinolones—tablets, capsules and injectable—is associated with disabling and potentially permanent side effects involving the tendons, muscles, joints, nerves and central nervous system. The FDA is now requiring the drug labels and medication guides for all fluoroquinolones to be updated to reflect this new safety information. The FDA is continuing to investigate safety issues with fluoroquinolones and will update the public and the healthcare community with additional information when available.

The safety review of fluoroquinolones included ciprofloxacin (Cipro ER, Cipro), moxifloxacin (Avelox), ofloxacin (Floxin), gemifloxacin (Factive) and levofloxacin (Levaquin).

FDA Will Review Benzhydrocodone & Acetaminophen Combination

Benzhydrocodone hydrochloride (a hydrocodone prodrug) and acetaminophen combination (Apadaz) is an abuse-deterrent, immediate-release fixed-dose combination product for short-term, acute pain management.² On May 5, the FDA’s Anesthetic and Analgesic Drug Products Advisory Committee and the Drug Safety and Risk Management Advisory Committee voted in favor of approving the agent for its proposed indication. The Prescription Drug User Fee Act date of June 9, 2016, has been set.

OA Drug Enters Phase 2 Clinical Trials

GSK3196165, previously known as MOR103, is a monoclonal antibody that has begun Phase 2 clinical trials to treat patients with inflammatory hand osteoarthritis (OA).³ GSK3196165 is a monoclonal antibody against granulocyte-macrophage colony-stimulating factor (GM-CSF) cytokine.

This European Phase 2 clinical trial, titled “A Study to Investigate the Efficacy and Safety of GSK3196165 in Inflammatory Hand Osteoarthritis (NCT02683785),” is multicenter, double blind and placebo controlled.⁴ The study will investigate the safety and efficacy of subcutaneous injections of GSK3196165 in adults (n=40) with inflammatory hand osteoarthritis. This study is evaluating the efficacy potential of GSK3196165 on pain, as well as a safety assessment and compound pharmacokinetics.

GSK3196165 is also being investigated in a different Phase 2B study in rheumatoid arthritis (NCT02504671).⁵ This trial, “Study to Evaluate the Efficacy and Safety of GSK3196165 Plus Methotrexate in Subjects With Active Moderate-Severe Rheumatoid Arthritis,” began in the third quarter of 2015.

Fluoroquinolone use—tablets, capsules & injectable—is associated with disabling & potentially permanent side effects.

Fasinumab Promising for Treating OA Pain

Fasinumab is an investigational nerve growth factor antibody in Phase 2 and 3 clinical trials.⁶ This placebo-controlled, 16-week study evaluated patients (n=421) with moderate to severe hip or knee OA pain and inadequate pain relief, or intolerance to either acetaminophen and at least one oral non-steroidal anti-inflammatory drug and an opioid.

At baseline, patients had significant pain, measuring an average of 6.3 out of 10 points on the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) Index. Other measures included in the study were pain, stiffness and physical functioning (WOMAC Index). Patients were randomized into one of five treatment groups in a 1:1:1:1:1 ratio to receive 1 mg fasinumab subcutaneously, 3 mg fasinumab, 6 mg fasinumab, 9 mg fasinumab or placebo every four weeks through Week 12. Primary efficacy was measured at Week 16.

Following the 16-week study, patients were evaluated for an additional 20 weeks off-treatment. All fasinumab-treated patients showed statistically significant improvements in pain relief (the primary study endpoint) and improvements in physical function (a secondary measure).

Adverse events were similar between all fasinumab-treated patients and placebo-treated patients. Neuromusculoskeletal adverse events were more common in fasinumab-treated patients compared with placebo-treated patients (17% vs. 6%, respectively). These adverse events included arthralgia, paresthesia, hypoesthesia and peripheral edema. During the study, there were no cases of osteonecrosis, but there was one case of subchondral insufficiency fractures and one case of rapidly progressive osteoarthritis.

Bone-specific alkaline phosphatase was increased in fasinumab-treated patients because it’s a marker for osteoblast activity. There were no increases in ALT or AST enzymes.

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

1. U.S. Food and Drug Administration. Safety alerts: Fluoroquinolone antibacterial drugs: Drug safety communication—FDA advises restricting use for certain uncomplicated infections. 2016 May 12.
2. KemPharm Inc. News release: Statement regarding FDA advisory committee meeting on KemPharm’s abuse-deterrent product candidate Apadaz. 2016 May 5.
3. MorphoSys AG. News release: MorphoSys licensing partner GSK starts phase 2 study with GSK3196165 (MOR103) in hand osteoarthritis. 2016 Apr 18.
4. U.S. National Institutes of Health. A study to investigate the efficacy and safety of GSK3196165 in inflammatory hand osteoarthritis. NCT02683785. ClinicalTrials.gov. 2016 Apr 28.
5. U.S. National Institutes of Health. Study to evaluate the efficacy and safety of GSK3196165 plus methotrexate in subjects with active moderate-severe rheumatoid arthritis. NCT02504671. ClinicalTrials.gov. 2016 Jan 14.
6. Regeneron Pharmaceuticals Inc. News release: Regeneron announces positive topline results from phase 2/3 fasinumab study in patients with osteoarthritis pain. 2016 May 2.