Since its approval in 2011, the U.S. Food & Drug Administration has continued to monitor the severe side effects of Xarelto. Based on these reports and its own investigations, the FDA has issued multiple warnings over the last several years regarding safety concerns with the anticoagulant’s active ingredient, rivaroxaban.

One of the main benefits of Xarelto is that it works quickly, but it also can cause uncontrollable bleeding, a situation that has led to much controversy and thousands of Xarelto lawsuits. Research also shows the drug may increase the risk of wound complications in patients recovering from lower-limb surgeries, as well as those who have had spinal taps or epidurals.

Has Xarelto Been Recalled?

Various lawsuits have called for the FDA to issue a Xarelto recall until a safe and effective reversal agent for its side effects becomes available. Despite this, the FDA has not required Janssen/Bayer to remove the drug from the market.

Acknowledging the side effects, however, the agency has released many important safety warnings, including two black box warnings – the strictest of its alerts, placed on the drug label to notify patients of serious or potentially life-threatening side effects.

Timeline of FDA Warnings for Xarelto

While the FDA approved Xarelto in 2011, it determined after the fact that Janssen and Bayer did not sufficiently warn consumers about the side effects of rivaroxaban, the main ingredient in the drug. As a result, the federal agency sent a warning letter to Johnson & Johnson – the parent company of Janssen – in June 2013.

As a result of the insufficient warning, the FDA issued the first black box warning for Xarelto in August 2013. The warning stated that patients who discontinued Xarelto usage prematurely were at a higher risk for developing blood clots, deep vein thrombosis, and an epidural or spinal hematoma.

In 2014, the FDA demanded new language be added to the warnings and precautions for Xarelto, including at least one update to the black box warning. The additional information concerned:

  • Uncertainty about the best timing for the application of Xarelto in relation to neuraxial procedures (regional anaesthetic techniques)
  • Warning of the risks of using Xarelto with epidural anesthesia and spinal puncture
  • Results from a study of Xarelto on renal functionality
  • Lack of an antidote to treat excessive bleeding
  • Caution against using Xarelto with combined P-gp and strong CYP3A4 inhibitors, such as ritonavir, itraconazole, ketoconazole, conivaptan, lopinavir/ritonavir, and indinavir
  • Incomplete data regarding Xarelto’s effects on people with heart valves
  • Thrombotic events upon early discontinuation of Xarelto

More FDA Warnings Against Xarelto

The next update arrived in December 2014 when the FDA added thrombocytopenia (platelet deficiency) and hepatitis to the list of postmarketing adverse reactions. This addition also updated the description of cytolytic hepatitis to hepatitis, including hepatocellular injury.

Xarelto recallThe FDA issued another warning in that year regarding drug interactions, listing several drugs that should never be taken with Xarelto, including:

  • Itraconazole – Sporanox and Onmel
  • lopinavir – Kaletra
  • Ritonavir – Norvir
  • Indinavir – Crixivan
  • Conivaptan – Vaprisol
  • Carbamazepine – Tegretol, Tegretol-XR, Equetro, Carbatrol, Epitol, and Teril
  • Phenytoin – Dilantin
  • Rifampin – Rifater, Rifamate, Rimactane, and Rifadin
  • St. John’s wort – Hypericum Perforatum

Controversy Around Xarelto Clinical Trials

The approval of Xarelto for prevention of DVT and PE stemmed from clinical trials known as the Regulation of Coagulation in Orthopedic Surgery to Prevent Deep Venous Thrombosis and Pulmonary Embolism studies (RECORD). These studies found that Xarelto outperformed its comparison drug, enoxaparin, in preventing clot formations after hip and knee replacement surgery, although it did show an increased risk of Xarelto initiating bleeding that could decrease hemoglobin levels necessitating transfusions.

As for Xarelto’s approval for reducing the risk of stroke and embolism in patients with non-valvular atrial fibrillation, a clinical trial known as the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation study (ROCKET AF) was the basis. In comparison to warfarin, researchers found that Xarelto was not inferior, but there was a greater frequency of gastrointestinal bleeding, and bleeding leading to a drop in hemoglobin levels.

Many scientists opposed the approval of Xarelto following these trials, questioning the design of the ROCKET AF trial and arguing that patients could be “at greater risk of harm from stroke and/or bleeding” if they took Xarelto than if they were skillfully treated with warfarin.

Scientists weren’t alone in their skepticism. Scandal surfaced when Katie Thomas of the New York Times discovered a footnote buried in a legal briefing that Janssen/Bayer may have misled editors at one of the world’s most renowned medical journals. The Duke University researchers who were hired by Janssen/Bayer published an analysis in the New England Journal of Medicine, leaving out critical laboratory data. In thousands of lawsuits, Janssen/Bayer are accused of being complicit in the omission because they knew about the missing data but remained silent. This elusive data could have illuminated how the blood readings from one device compare to another.

Compounding the controversy was the revelation that faulty equipment was used in the warfarin side of ROCKET AF. This came to light when regulators notified the FDA that the device used in the trial had been recalled in 2014 for understating patients’ risk of bleeding. Regulators investigated whether the malfunctioning device led doctors to give patients the wrong dose of warfarin, which could have led to additional bleeding events, giving Xarelto an unfair advantage.

All of this calls into question the legitimacy of the trial findings, as detailed in a study that appeared in February 2015 in the Journal of the American Medical Association. But in October 2016, the FDA reaffirmed the safety and efficacy of Xarelto after its analyses concluded the drug’s clinical trial results were not affected by faulty monitoring device.