Expanded approval on rivaroxaban, reassurance on dabigatran

This regulatory update covers an expanded indication for rivaroxaban and an announcement that bleeding rates do not appear to be higher with dabigatran than with warfarin.

Recalls, warnings and label changes

The 32-mg, single intravenous dose of ondansetron hydrochloride (Zofran) has been pulled from the market due to its cardiac risks, the FDA recently announced.

The agency had previously warned that this dose of the anti-nausea drug should be avoided due to the risk of QT-interval prolongation, which can lead to torsades de pointes. Now, the pre-mixed 32-mg solutions, which also contain either dextrose or sodium chloride, are being recalled by the branded and generic manufacturers.


The FDA continues to recommend an intravenous regimen of 0.15 mg/kg administered every four hours for three doses to prevent chemotherapy-induced nausea and vomiting, but no single intravenous dose should exceed 16 mg, according to the agency's drug safety communication online.

A recall of all products distributed by Ameridose, LLC, due to a lack of sterility found in an ongoing FDA inspection. No infections have been reported with any of Ameridose's products. Six of the recalled products are on the FDA critical shortage list: injections of sodium bicarbonate, succinylcholine, atropine sulfate, bupivacaine hydrochloride, lidocaine hydrochloride and furosemide.

A class I recall of Baxter Healthcare Corporation's buretrol solution sets because the ball-valve component is allowing air to flow past the valve and enter the tubing once the premeasured amount of fluids is completely administered to the patient. If the air is not removed, the air present in the tubing may enter the patient's vascular system, potentially causing an air embolism and serious adverse health consequences, including death.

A recall of some of Ventlab Corporation's manual resuscitators, which have been found to potentially deliver little to no air/oxygen through the patient valve to the patient and could result in life-threatening health consequences including hypoxia and hypoventilation.

A class I recall of Hospira's Symbiq infusion systems because infusion pump LCD touch screens may not respond to user selection, possibly resulting in a delayed response and/or the screen registering a different value from the value selected by the user.

A class I recall of Ethicon Endo-Surgery circular stapler sets because of difficulty users have had firing the stapler devices, resulting in incomplete firing stroke and incomplete staple formation, which can result in severe pain, sphincter dysfunction, rectal wall damage, sepsis, bleeding, and occlusion of the rectal canal.


An expanded indication for rivaroxaban (Xarelto) to include treating deep venous thrombosis (DVT) or pulmonary embolism (PE) and to reduce the risk of recurrent DVT and PE following initial treatment. The drug is already approved to reduce the risk of DVTs and PEs after knee or hip replacement surgery and the risk of stroke with nonvalvular atrial fibrillation. Approval is based on three studies finding that rivaroxaban was as effective as the combination of enoxaparin and a vitamin K antagonist for treating DVT.

Tofacitinib (Xeljanz) to treat adults with moderately to severely active rheumatoid arthritis who have had an inadequate response to, or who are intolerant of, methotrexate. A pill taken twice daily, it works by blocking Janus kinases. Safety and effectiveness were evaluated in seven clinical trials in which patients experienced more improvement in clinical response and physical functioning than on placebo. The drug carries a boxed warning about the risk of serious infections.

Perampanel (Fycompa) to treat partial onset seizures in patients with epilepsy ages 12 years and older. Three clinical trials showed improvement in seizure control compared to placebo. The most common adverse reactions reported in clinical trials include dizziness, drowsiness, fatigue, irritability, falls, upper respiratory tract infection, weight increase, vertigo, ataxia, gait disturbance, balance disorder, anxiety, blurred vision, dysarthria, asthenia, aggression and hypersomnia. The drug carries a boxed warning about the risk of serious neuropsychiatric events.

An expanded indication for the Sapien Transcatheter Heart Valve (THV) to include patients with aortic valve stenosis who are eligible for surgery but who are at high risk for serious surgical complications or death. The Sapien THV was approved in 2011 for patients with inoperable aortic valve stenosis. The expanded approval was based on a study of surgical patients who received the Sapien THV and similar patients who received aortic valve replacement through open-heart surgery. Both groups had similar death rates at one month, one year, and two years after the procedures.

Ocriplasmin (Jetrea), the first drug approved to treat symptomatic vitreomacular adhesion (VMA). An enzyme that breaks down proteins in the eye responsible for VMA, ocriplasmin is an alternative to vitrectomy. Safety and effectiveness were established in two clinical studies in which 26% of patients randomly assigned to receive a single injection of the drug had VMA resolve compared to 10% with placebo.

Omacetaxine mepesuccinate (Synribo) to treat adults with chronic myelogenous leukemia. The drug is intended to be used in patients whose cancer progressed after treatment with at least two tyrosine kinase inhibitors. It was approved under the FDA's accelerated approval program.


Bleeding rates do not appear to be higher with dabigatran (Pradaxa) than warfarin (Coumadin, Jantoven, and generics), the FDA recently announced. The agency conducted an assessment of serious bleeding associated with the medications using insurance claims and administrative data from FDA's Mini-Sentinel pilot of the Sentinel Initiative. The results indicated that bleeding rates with new use of dabigatran do not appear to be higher than bleeding rates with new use of warfarin, which is consistent with observations from the large clinical trial used to approve dabigatran (the RE-LY trial). The FDA is continuing to evaluate multiple sources of data in the ongoing safety review of this issue but has not changed its recommendations regarding the drug. Dabigatran provides an important health benefit when used as directed, the agency said. Health care professionals should carefully follow the dosing recommendations on the drug label, especially for patients with renal impairment, to reduce the risk of bleeding.