Rivaroxaban was patented in 2007 and approved for medical use in the United States in 2011.[10] In the United States, it will not be available as a generic medication until 2024.[11][12] It is on the World Health Organization's List of Essential Medicines.[13] In 2022, it was the 90th most commonly prescribed medication in the United States, with more than 7million prescriptions.[14][15]
When undergoing surgeries, due to the concern over managing bleeding, rivaroxaban can be discontinued 24 hours prior to low-bleeding risk surgery and 48-72 hours prior to high-bleeding risk surgeries.[19][20] Once the surgery is over, it can be recommenced after 1 to 3 days with doctor consultation.[19][20]
Dosing recommendations do not recommend administering rivaroxaban with drugs known to be strong combined CYP3A4/P-glycoprotein inhibitors because this results in significantly higher plasma concentrations of rivaroxaban.[5][21] A small retrospective cohort study reported that the use of moderate CYP3A4 and P-glycoprotein inhibitors such as amiodarone or verapamil, increased the risk of bleeding when administered with rivaroxaban.[22] Although this increase was not statistically significant, there was a trend showing increased bleeding in the rivaroxaban with moderate CYP3A4 and P-glycoprotein inhibitors group.[22] Therefore, it is important to monitor for bleeding when concurrently on rivaroxaban and moderate CYP3A4 and P-glycoprotein inhibitors.[22]
As of 2015[update], post-marketing assessments showed liver toxicity, and further studies are needed to quantify this risk.[26][27] In 2015, rivaroxaban accounted for the highest number of reported cases of serious injury among regularly monitored medications to the FDA's Adverse Events Reporting System (AERS).[28]
Rivaroxaban inhibits both free and bound Factor Xa in the prothrombinase complex.[33] It is a selective direct factor Xa inhibitor with an onset of action of 2.5 to 4 hours.[34] Inhibition of Factor Xa interrupts the intrinsic and extrinsic pathway of the blood coagulation cascade, inhibiting both thrombin formation and development of thrombi. Rivaroxaban does not inhibit thrombin (activated Factor II), and no effects on platelets have been demonstrated.[4] It allows predictable anticoagulation and dose adjustments and routine coagulation monitoring;[4] dietary restrictions are not needed.[35]
Rivaroxaban has predictable pharmacokinetics across a wide spectrum of patients (age, gender, weight, race) and has a flat dose response across an eightfold dose range (5–40 mg).[37] The oral bioavailability is dose-dependent.[5] Doses of rivaroxaban under 10 mg can be taken with or without food, as it displayed high bioavailability independent of whether food was consumed or not.[38] If rivaroxaban is given at oral doses of 15 mg or 20 mg, it needs to be taken with food to aid in drug absorption and achieve appropriate bioavailability (≥ 80%).[38]
Chemistry
Chemical structures of linezolid (top) and rivaroxaban (bottom). The shared structure is shown in blue.
Rivaroxaban bears a striking structural similarity to the antibiotic linezolid: both drugs share the same oxazolidinone-derived core structure.[39] Accordingly, rivaroxaban was studied for any possible antimicrobial effects and for the possibility of mitochondrial toxicity, which is a known complication of long-term linezolid use.[40] Studies found that neither rivaroxaban nor its metabolites have any antibiotic effect against Gram-positive bacteria.[citation needed] As for mitochondrial toxicity, in vitro studies published before 2008 found the risk to be low.[39]
Using rivaroxaban rather than warfarin costs 70 times more, according to Express Scripts Holding Co, the largest U.S. pharmacy benefits manager.[35] As of 2016, Bayer claimed that the drug was licensed in 130 countries and that more than 23 million patients had been treated.[43]
In the same month, the European Commission also granted marketing authorization of rivaroxaban to prevent venous thromboembolism in adults undergoing elective hip and knee replacement.[45][6]
In November 2011, the US FDA approved rivaroxaban for stroke prevention in people with non-valvular atrial fibrillation.[47]
Legal action
On March 25, 2019, over 25,000 lawsuits over rivaroxaban in the US were settled for $775 million to get paid out to those affected. Plaintiffs accused the drugmakers of not warning about the bleeding risks, claiming their injuries could have been prevented had doctors and patients been provided adequate information.[48]
Research
Researchers at the Duke Clinical Research Institute have been accused of withholding clinical data used to evaluate rivaroxaban.[49] Duke tested rivaroxaban in a clinical trial known as the ROCKET AF trial.[50] The clinical trial, published 2011 in the New England Journal of Medicine[51] and headed by Robert Califf, then Commissioner of the FDA,[52] found rivaroxaban to be more effective than warfarin in reducing the likelihood of ischemic strokes in patients with atrial fibrillation.[51] The validity of the study was called into question in 2014, when pharmaceutical sponsors Bayer and Johnson & Johnson revealed that the INRatio blood monitoring devices used were not functioning properly,[49][50] A subsequent analysis by the Duke team published in February 2016 found that this had no significant effect on efficacy and safety in the trial.[53]
Under-representation of racial minorities in clinical trials has been noted.[citation needed]
^World Health Organization (2021). World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization. hdl:10665/345533. WHO/MHP/HPS/EML/2021.02.
^ abcHanigan S, Das J, Pogue K, Barnes GD, Dorsch MP (May 2020). "The real world use of combined P-glycoprotein and moderate CYP3A4 inhibitors with rivaroxaban or apixaban increases bleeding". Journal of Thrombosis and Thrombolysis. 49 (4): 636–643. doi:10.1007/s11239-020-02037-3. PMID31925665.
^Mo Y, Yam FK (February 2015). "Recent advances in the development of specific antidotes for target-specific oral anticoagulants". Pharmacotherapy. 35 (2): 198–207. doi:10.1002/phar.1532. PMID25644580. S2CID22593448.
^ abStampfuss J, Kubitza D, Becka M, Mueck W (July 2013). "The effect of food on the absorption and pharmacokinetics of rivaroxaban". International Journal of Clinical Pharmacology and Therapeutics. 51 (7): 549–561. doi:10.5414/CP201812. PMID23458226.
