Last year, on September, Xarelto has been approved in Japan. The Ministry of Health, Labor and Welfare gave its good-to-go to the famous anticoagulant drug, approving it for the prevention and treatment of several conditions such as venous thromboembolism, pulmonary embolism, and deep vein thrombosis. Also known as rivaroxaban, the new Bayer’s medicine is a drug from the Novel Oral Anticoagulants (NOACs) group which is marketed by Janssen Pharmaceuticals. To support the blood thinner’s safety and effectiveness to the Japanese regulatory agency, the pharmaceutical companies issued two large clinical trials, the J-EINSTEIN PE and the J-EINSTEIN DVT programs. Both the two trials have been performed in Japan in 2014 and included more than 8,000 subjects to compare Xarelto’s anticoagulant performance to a double-drug regimen consisting of a Vitamin K antagonist (VKA) and a low-molecular-weight heparin (LMWH). Researchers also measured rivaroxaban’s effectiveness alone in treating and preventing recurrent pulmonary embolism and deep vein thrombosis.
The Japanese equivalent of the Food and Drugs Administration (FDA), the Pharmaceutical and Food Safety Bureau (PMDA) already granted approval to rivaroxaban in January 2012. However, it was only indicated to prevent stroke in patients affected by atrial fibrillation. Bayer’s new drug was thoroughly tested during another Japanese-specific program, the J-ROCKET AF trial. Together with the newer indications, the Japanese Ministry of Health now approved rivaroxaban for seven indications in total.
The Japanese blood thinners’ market is rapidly increasing, and experts predicted it’s going to reach its peak growth in the upcoming four years. In America, however, Xarelto’s purported safety has been put under scrutiny by many agencies and physicians. Unlike many other anticoagulants currently used to treat patients, the effects of the various NOACs cannot be reversed since no antidote has ever been released. Even a minor trauma or a gastrointestinal bleeding during treatment with Xarelto, Pradaxa and Eliquis may cause an internal bleeding for which there’s no treatment available, with potentially fatal consequences.
Back before Xarelto was approved, in August 2011, a report from the PMDA indicated Pradaxa (in Japan named “Prazaxa”) as the cause of five patient’s deaths. Another group of 81 subjects also suffered from serious adverse reactions and severe injuries. The pharmaceutical company that manufactures the NOAC, Boehringer-Ingleheim Inc., was requested to add a new warning on the medication’s label, to warn patients about a risk of potentially lethal hemorrhages linked with the use of dabigatran. The advisory board also requested doctors to keep all patients treated with this medication under constant monitoring, paying careful attention to signs of renal impairment, anemia or bleeding. Recently, a new paper published in the Journal of Cardiology showed that in 136 elderly patients coming from Japan, Xarelto’s anticoagulant properties were far above the supposed level. The blood thinner’s effects were prolongated, increasing the risk of potential bleeding accidents and requiring additional monitoring by healthcare professionals. Bayer and Janssen always advertised rivaroxaban as a more convenient medication since it didn’t require any form of blood test or monitoring, though. The FDA published a warning letter to the drugmakers, pointing out that their marketing campaign misleadingly minimized the dangers of their medication, and did not provide the public with adequate information about its risks.
1. Nakano Y, et al. Clinical usefulness of measuring prothrombin time and soluble fibrin levels in Japanese patients with atrial fibrillation receiving rivaroxaban. J Cardiol. 2015 Mar;65(3):185-90. doi: 10.1016/j.jjcc.2014.07.021. Epub 2014 Sep 2.
2. US Food and Drugs Administration (FDA). Warning Letter – RE: NDA #202439 XARELTO (rivaroxaban) tablets MA #215. www.fda.gov (Accessed October 2015)
3. Pharmaceutical and Food Safety Bureau, Ministry of Health, Labour and Welfare. Press release, Severe haemorrhages in patients treated with an anticoagulant “Prazaxa capsules”. Retrieved at: https://www.pmda.go.jp/files/000153497.pdf. (Accessed August 2015).
4. Yamada N, et al. Oral rivaroxaban for Japanese patients with symptomatic venous thromboembolism – the J-EINSTEIN DVT and PE program. Thromb J. 2015 Jan 17;13:2. doi: 10.1186/s12959-015-0035-3. eCollection 2015.