Side effect of xarelto

Contents

Xarelto

Xarelto is the brand name for the prescription medication rivaroxaban, a blood thinner, or anticoagulant, that prevents blood clots from forming.

Xarelto is in a class of medications called factor Xa inhibitors, which means they affect the action of an enzyme, Factor X, that is involved in blood clotting.

Janssen Pharmaceuticals manufactures Xarelto; there is no generic form of rivaroxaban available in the United States.

Xarelto was first approved by the Food and Drug Administration (FDA) in 2011 to treat deep vein thrombosis (DVT) and prevent pulmonary embolism (PE) in people having hip or knee replacement surgery.

DVT is a condition that develops when a blood clot forms in a vein deep inside the body, usually in the lower leg or thigh. DVT may lead to PE, which is a blood clot in the lung.

Also in 2011, the FDA approved Xarelto for people diagnosed with a type of irregular heartbeat called nonvalvular atrial fibrillation (or afib) that is not related to a heart valve problem. Atrial fibrillation increases a person’s risk for blood clots and stroke.

In 2012, the FDA expanded the approved uses of Xarelto to include prevention of recurring DVT and PE. If you have one of those conditions you can continue taking the drug to prevent these dangerous blood clots from developing again.

Xarelto was tested in a Phase 3 clinical trial for people with recent acute coronary syndrome (ACS); they were given a twice-daily low dose of rivaroxaban as part of their treatment plan.

Results of the trial, published in the New England Journal of Medicine, suggested the drug could play an effective role. However, an FDA advisory committee repeatedly voted against expanding Xarelto’s uses.

In 2012 and 2014, the committee concluded that the risk for bleeding was too high to approve the drug for people with ACS.

Xarelto Warnings

If you get a cut or an injury while on Xarelto, the bleeding may take longer than usual to stop. You may also bruise or bleed more easily.

Call your doctor immediately if you have abnormal bleeding or bruising while on Xarelto because it could be a serious, even life-threatening, condition.

After you stop taking Xarelto, you’re at greater risk for stroke. You shouldn’t stop taking the drug without consulting your doctor.

If you receive an epidural, spinal anesthesia, or a spinal puncture while you’re taking Xarelto, you’re at increased risk for a blood clot around your spine that could lead to paralysis.

Read the complete FDA warning on Xarelto.

Xarelto has side effects and can interfere with some medications. If you have any of the medical conditions noted below, use this drug with caution:

  • Heart valve replacement
  • Bleeding disorders or bleeding problems
  • Liver disease
  • Kidney problems
  • Any other medical conditions

Always tell your doctor if you have allergies to any medications, and discuss all the risks and benefits of Xarelto before you begin treatment.

Finally, if you are taking Xarelto, be sure to talk to your doctor before you have surgery or medical or dental procedures, as it can cause excess bleeding.

Xarelto and Pregnancy

Tell your doctor if you are pregnant, may become pregnant, are breastfeeding, or plan to breastfeed.

It’s not clear whether Xarelto is safe to take during pregnancy, so pregnant women should take the drug only if the potential benefits outweigh the risks to the fetus.

It’s also unknown whether Xarelto passes into breast milk, so nursing women should not take Xarelto or should discontinue breastfeeding while on Xarelto treatment.

It’s not known whether Xarelto is safe or effective in children.

Rivaroxaban

It’s very important to take rivaroxaban as your doctor has told you.

It’s usual to take it once a day just after you have eaten a meal or snack.

It’s important to take rivaroxaban with some food to help your body absorb the whole dose. Try to take it at the same time every day.

People who are taking rivaroxaban to treat DVT or a pulmonary embolism may need to take it twice a day for the first few weeks. Your doctor will tell you if you need to do this.

If you have trouble swallowing pills, speak to your doctor or pharmacist.

You can crush rivaroxaban tablets and mix them with water or apple purée. Swallow this mixture, then eat some food straight away.

How much will I take?

Your dose of rivaroxaban depends on why you’re taking it:

  • For people with a heart condition called atrial fibrillation – the usual dose is 20mg a day. But your doctor might prescribe a lower dose if you have kidney disease and are at a higher risk of bleeding.
  • For people who have had a blood clot (DVT or pulmonary embolism) – the usual dose is 20mg a day. You might need to take a dose of 15mg twice a day for the first few weeks of taking rivaroxaban. If you have kidney disease and are at a higher risk of bleeding, your doctor may prescribe a lower dose.
  • For people who have had an operation to replace a hip or knee joint – the usual dose is 10mg a day.
  • For people who have had a heart attack or have a heart condition called unstable angina – the usual dose is 2.5mg twice a day.

If you’re unsure what dose you need to take, check with your doctor or pharmacist.

What if I forget to take it?

What you need to do depends on the dose you normally take:

  • If you normally take 10mg, 15mg or 20mg once a day – take a dose as soon as you remember, unless it’s nearly time for your next one. Take your next dose at the usual time and then carry on as normal. Never take more than 1 dose in a single day.
  • If you normally take 15mg twice a day – take a dose as soon as you remember. You can take 2 x 15mg tablets at the same time to get a total of 2 doses in 1 day. Never take more than 2 doses in 1 day.
  • If you normally take 2.5mg twice a day – take a dose as soon as you remember, unless it’s nearly time for your one. Do not take a double dose to make up for a missed one. Take your next dose at the usual time, and then carry on as normal.

It’s very important that you remember to take rivaroxaban every day.

If you forget doses often, it may help to set an alarm to remind you.

You could also ask your pharmacist for advice on other ways to help you remember to take your medicine.

If you’re worried, contact your doctor or pharmacist.

What if I take too much?

Ask your doctor or pharmacist for advice straight away, as overdose puts you at risk of bleeding.

How long will I take it for?

How long you need to take rivaroxaban will depend on why you’re taking it.

If you have had an operation to replace your knee or hip joint, you’ll probably take rivaroxaban for 2 to 5 weeks.

If you have had a blood clot (DVT or pulmonary embolism), you’ll normally take rivaroxaban for at least 3 months. Depending on what caused the blood clot, you might need to take it for longer.

If you have a heart problem like atrial fibrillation or have had a heart attack, you might need to take rivaroxaban long term or even for the rest of your life.

Anticoagulant alert card

Your doctor or pharmacist will give you an anticoagulant alert card.

Carry this with you all the time. It tells healthcare professionals that you’re taking an anticoagulant. This can be useful for them to know in case of a medical emergency.

If you need any medical or dental treatment, show your anticoagulant alert card to the nurse, doctor or dentist.

This includes before you have vaccinations and routine sessions with the dental hygienist.

Your doctor may advise you to stop taking rivaroxaban or reduce your dose for a short time.

Switching from warfarin to rivaroxaban

If you need to switch from warfarin to rivaroxaban, your doctor will advise you when to stop taking warfarin. This will probably be a few days before you start rivaroxaban.

Your doctor or anticoagulant clinic will do a blood test called the international normalised ratio (INR) to check how quickly your blood’s clotting.

This is to help decide exactly when you should start taking rivaroxaban.

Switching from rivaroxaban to warfarin

If you need to switch from rivaroxaban to warfarin, you may need to take both medicines together for a few days.

Your doctor or anticoagulant clinic will do a blood test called the international normalised ratio (INR) to check how quickly your blood’s clotting.

This is to help decide exactly when you should stop taking rivaroxaban.

Xarelto and Ibuprofen

Late response here…
I asked my doctor about this a couple of weeks ago because Tylenol wasn’t working on my neck pain. The general recommendation was against, but it wasn’t a strong “no” and he basically conceded that I could take it once in a while. In your situation I would have given them a quick call to double-check the info.
Last summer while on warfarin I was regularly going to a specialized anticoagulant lab with a nurse who was very studied on anticoagulation and had been to conferences etc. He had an actual algorithm to check what your dose should be based on weight, medications, current INR and other factors, as opposed to in my experience most cardiologists who just kinda randomly pick numbers based on your labs.
For the most part he made warfarin seem much less delicate than we are led to believe. You’re allowed to eat extra vegetables sometimes. You can drink sometimes. You can take ibuprofen sometimes. He explained that for the most part it’s not like you’re going to take a few ibuprofen pills and then hemorrhage that night. If you take a bunch of ibuprofen every day for a while and don’t have your warfarin dose adjusted then yes it could become an issue. Even say five drinks every once in a while is fine (from the bleeding standpoint), whereas just 1-2 every day consistently would be a problem if medication was not adjusted. It’s more the medium-term than the short-term.
All that being said, I know Xarelto does not work the same way and so it might be a different story. So this whole post may be irrelevant unless you take warfarin!

Americans’ use of supplements, prescriptions and over the counter (OTC) medications has been steadily increasing over the past couple of years. This increase can sometimes put patients at risk for complications and interactions. Believe it or not, a lot of over-the-counter medications can actually interact with your prescription medications (and affect how they work) without you even realizing it. Understanding how OTC medications, vitamins, supplements and prescriptions medications interact is important for your health and safety.

First off what is an OTC medication?

An over the counter medication, according to the Food and Drug Administration (FDA), is a medicine that you can buy without a prescription. These medications are considered safe and effective when you follow the directions on the label, or as directed by your health care professional.

The beauty of OTC medications is the convenience and ability, as a patient, to select a medication for your specific symptoms without a trip to the doctor. However, if you take any prescription medications, it is always recommended to check with your doctor or pharmacist before perusing the OTC aisles to ensure that it wont interact with any prescription medications.

What about vitamins, minerals, supplements?

Many people consider vitamins, minerals and supplements as “natural,” thinking that they won’t cause any problems or interactions. It may come as a surprise to some, but just like other OTC medications, vitamins, minerals and supplements can also interact with prescription medications.

It is important to understand the risks associated with the use of OTC medications, including those that give the illusion that they are natural or safe.

What are some common OTC and prescription drug interactions that I should know of?

  • Blood Thinners like Coumadin (warfarin), Pradaxa, Eliquis, Xarelto and Plavix can interact with the following and cause an increased risk of bleeding:
    • Vitamin E
    • Ginkgo biloba
    • Alka-Seltzer products
    • Supplement drinks containing vitamin K (like Ensure or Boost)
    • Nonsteroidal anti-inflammatories (NSAIDS) like ibuprofen (Motrin, Advil), (naproxen) Aleve, and aspirin.
  • Birth control like Loesterin Fe, Ortho-Tri Cyclen, Seasonale and Yaz can become less effective in combination with St. John’s Wart. In fact, mixing these two products could lead to possible pregnancy
  • SSRI Antidepressant Medications like Celexa, Lexapro and Prozac also interact with St. John’s Wort. Mixing these could increase your risk for serotonin syndrome, which can cause symptoms like diarrhea, seizures or even death.
  • MAOI antidepressants like Parnate, Nardil and Marplan interact with the following and can also increase your risk for serotonin syndrome.
    • Robitussin DM
    • Mucinex DM
    • Nyquil Cold & Flu
    • Coricidin HBP Products
  • Pain Medications like Norco, Vicodin, Percocet, Tylenol with Codeine and Ultracet don’t mix well with other products containing Tylenol, like Tylenol PM, Nyquil, Dayquil, and Mucinex. The maximum daily amount of Tylenol (acetaminophen) is now 3,000 mg per day, so mixing pain medications that contain acetaminophen with other Tylenol products can mean that you are taking more than the recommended amount of Tylenol without realizing it.

These are just a few of the common interactions between prescription and OTC medications! Remember, if you are concerned about any interactions between your medications, you can always check with your doctor or pharmacist.

  • CLINICAL PHARMACOLOGY

    Mechanism Of Action

    XARELTO is a selective inhibitor of FXa. It does not require a cofactor (such as Anti-thrombin III) for activity. Rivaroxaban inhibits free FXa and prothrombinase activity. Rivaroxaban has no direct effect on platelet aggregation, but indirectly inhibits platelet aggregation induced by thrombin. By inhibiting FXa, rivaroxaban decreases thrombin generation.

    Pharmacodynamics

    Dose-dependent inhibition of FXa activity was observed in humans. Neoplastin® prothrombin time (PT), activated partial thromboplastin time (aPTT) and HepTest® are also prolonged dose-dependently. Anti-factor Xa activity is also influenced by rivaroxaban.

    Specific Populations

    Renal Impairment

    The relationship between systemic exposure and pharmacodynamic activity of rivaroxaban was altered in subjects with renal impairment relative to healthy control subjects .

    Table 9: Percentage Increase in Rivaroxaban PK and PD Measures in Subjects with Renal Impairment Relative to Healthy Subjects from Clinical Pharmacology Studies

    Measure Parameter Creatinine Clearance (mL/min)
    50-79 30-49 15-29 ESRD (on dialysis)* ESRD (post-dialysis)*
    Exposure AUC 44 52 64 47 56
    FXa Inhibition AUEC 50 86 100 49 33
    PT Prolongation AUEC 33 116 144 112 158
    *Separate stand-alone study.
    PT = Prothrombin time; FXa = Coagulation factor Xa; AUC = Area under the plasma concentration-time curve; AUEC = Area under the effect-time curve

    Hepatic Impairment

    Anti-Factor Xa activity was similar in subjects with normal hepatic function and in mild hepatic impairment (Child-Pugh A class). There is no clear understanding of the impact of hepatic impairment beyond this degree on the coagulation cascade and its relationship to efficacy and safety.

    Pharmacokinetics

    Absorption

    The absolute bioavailability of rivaroxaban is dose-dependent. For the 2.5 mg and 10 mg dose, it is estimated to be 80% to 100% and is not affected by food. XARELTO 10 mg tablets can be taken with or without food. For the 20 mg dose in the fasted state, the absolute bioavailability is approximately 66%. Coadministration of XARELTO with food increases the bioavailability of the 20 mg dose (mean AUC and Cmax increasing by 39% and 76% respectively with food). XARELTO 15 mg and 20 mg tablets should be taken with food .

    The maximum concentrations (Cmax) of rivaroxaban appear 2 to 4 hours after tablet intake. The pharmacokinetics of rivaroxaban were not affected by drugs altering gastric pH. Coadministration of XARELTO (30 mg single dose) with the H2-receptor antagonist ranitidine (150 mg twice daily), the antacid aluminum hydroxide/magnesium hydroxide (10 mL) or XARELTO (20 mg single dose) with the PPI omeprazole (40 mg once daily) did not show an effect on the bioavailability and exposure of rivaroxaban (see Figure 4).

    Absorption of rivaroxaban is dependent on the site of drug release in the GI tract. A 29% and 56% decrease in AUC and Cmax compared to tablet was reported when rivaroxaban granulate is released in the proximal small intestine. Exposure is further reduced when drug is released in the distal small intestine, or ascending colon. Avoid administration of rivaroxaban distal to the stomach which can result in reduced absorption and related drug exposure.

    In a study with 44 healthy subjects, both mean AUC and Cmax values for 20 mg rivaroxaban administered orally as a crushed tablet mixed in applesauce were comparable to that after the whole tablet. However, for the crushed tablet suspended in water and administered via an NG tube followed by a liquid meal, only mean AUC was comparable to that after the whole tablet, and Cmax was 18% lower.

    Distribution

    Plasma protein binding of rivaroxaban in human plasma is approximately 92% to 95%, with albumin being the main binding component. The steady-state volume of distribution in healthy subjects is approximately 50 L.

    Metabolism

    Approximately 51% of an orally administered -rivaroxaban dose was recovered as inactive metabolites in urine (30%) and feces (21%). Oxidative degradation catalyzed by CYP3A4/5 and CYP2J2 and hydrolysis are the major sites of biotransformation. Unchanged rivaroxaban was the predominant moiety in plasma with no major or active circulating metabolites.

    Excretion

    In a Phase 1 study, following the administration of -rivaroxaban, approximately one-third (36%) was recovered as unchanged drug in the urine and 7% was recovered as unchanged drug in feces. Unchanged drug is excreted into urine, mainly via active tubular secretion and to a lesser extent via glomerular filtration (approximate 5:1 ratio). Rivaroxaban is a substrate of the efflux transporter proteins P-gp and ABCG2 (also abbreviated Bcrp). Rivaroxaban’s affinity for influx transporter proteins is unknown.

    Rivaroxaban is a low-clearance drug, with a systemic clearance of approximately 10 L/hr in healthy volunteers following intravenous administration. The terminal elimination half-life of rivaroxaban is 5 to 9 hours in healthy subjects aged 20 to 45 years.

    The effects of level of renal impairment, age, body weight, and level of hepatic impairment on the pharmacokinetics of rivaroxaban are summarized in Figure 3.

    Figure 3: Effect of Specific Populations on the Pharmacokinetics of Rivaroxaban

    Gender

    Gender did not influence the pharmacokinetics or pharmacodynamics of XARELTO.

    Race

    Healthy Japanese subjects were found to have 20 to 40% on average higher exposures compared to other ethnicities including Chinese. However, these differences in exposure are reduced when values are corrected for body weight.

    Elderly

    The terminal elimination half-life is 11 to 13 hours in the elderly subjects aged 60 to 76 years .

    The safety and pharmacokinetics of single-dose XARELTO (10 mg) were evaluated in a study in healthy subjects and in subjects with varying degrees of renal impairment (see Figure 3). Compared to healthy subjects with normal creatinine clearance, rivaroxaban exposure increased in subjects with renal impairment. Increases in pharmacodynamic effects were also observed .

    Hemodialysis in ESRD subjects: Systemic exposure to rivaroxaban administered as a single 15 mg dose in ESRD subjects dosed 3 hours after the completion of a 4-hour hemodialysis session (postdialysis) is 56% higher when compared to subjects with normal renal function (see Table 9). The systemic exposure to rivaroxaban administered 2 hours prior to a 4-hour hemodialysis session with a dialysate flow rate of 600 mL/min and a blood flow rate in the range of 320 to 400 mL/min is 47% higher compared to those with normal renal function. The extent of the increase is similar to the increase in patients with CrCl 15 to 50 mL/min taking XARELTO 15 mg. Hemodialysis had no significant impact on rivaroxaban exposure. Protein binding was similar (86% to 89%) in healthy controls and ESRD subjects in this study.

    The safety and pharmacokinetics of single-dose XARELTO (10 mg) were evaluated in a study in healthy subjects (n=16) and subjects with varying degrees of hepatic impairment (see Figure 3). No patients with severe hepatic impairment (Child-Pugh C) were studied. Compared to healthy subjects with normal liver function, significant increases in rivaroxaban exposure were observed in subjects with moderate hepatic impairment (Child-Pugh B) (see Figure 3). Increases in pharmacodynamic effects were also observed .

    Drug Interactions

    In vitro studies indicate that rivaroxaban neither inhibits the major cytochrome P450 enzymes CYP1A2, 2C8, 2C9, 2C19, 2D6, 2J2, and 3A nor induces CYP1A2, 2B6, 2C19, or 3A. In vitro data also indicates a low rivaroxaban inhibitory potential for P-gp and ABCG2 transporters.

    The effects of coadministered drugs on the pharmacokinetics of rivaroxaban exposure are summarized in Figure 4 .

    Figure 4: Effect of Coadministered Drugs on the Pharmacokinetics of Rivaroxaban

    Anticoagulants

    In a drug interaction study, single doses of enoxaparin (40 mg subcutaneous) and XARELTO (10 mg) given concomitantly resulted in an additive effect on anti-factor Xa activity. In another study, single doses of warfarin (15 mg) and XARELTO (5 mg) resulted in an additive effect on factor Xa inhibition and PT. Neither enoxaparin nor warfarin affected the pharmacokinetics of rivaroxaban (see Figure 4).

    NSAIDs/Aspirin

    In ROCKET AF, concomitant aspirin use (almost exclusively at a dose of 100 mg or less) during the double-blind phase was identified as an independent risk factor for major bleeding. NSAIDs are known to increase bleeding, and bleeding risk may be increased when NSAIDs are used concomitantly with XARELTO. Neither naproxen nor aspirin affected the pharmacokinetics of rivaroxaban (see Figure 4).

    Clopidogrel

    In two drug interaction studies where clopidogrel (300 mg loading dose followed by 75 mg daily maintenance dose) and XARELTO (15 mg single dose) were coadministered in healthy subjects, an increase in bleeding time to 45 minutes was observed in approximately 45% and 30% of subjects in these studies, respectively. The change in bleeding time was approximately twice the maximum increase seen with either drug alone. There was no change in the pharmacokinetics of either drug.

    Drug-Disease Interactions With Drugs That Inhibit Cytochrome P450 3A Enzymes And Drug Transport Systems

    In a pharmacokinetic trial, XARELTO was administered as a single dose in subjects with mild (CrCl = 50 to 79 mL/min) or moderate renal impairment (CrCl = 30 to 49 mL/min) receiving multiple doses of erythromycin (a combined P-gp and moderate CYP3A inhibitor). Compared to XARELTO administered alone in subjects with normal renal function (CrCl >80 mL/min), subjects with mild and moderate renal impairment concomitantly receiving erythromycin reported a 76% and 99% increase in AUCinf and a 56% and 64% increase in Cmax, respectively. Similar trends in pharmacodynamic effects were also observed.

    QT/QTc Prolongation

    In a thorough QT study in healthy men and women aged 50 years and older, no QTc prolonging effects were observed for XARELTO (15 mg and 45 mg, single-dose).

    Clinical Studies

    Stroke Prevention In Nonvalvular Atrial Fibrillation

    The evidence for the efficacy and safety of XARELTO was derived from Rivaroxaban Once-daily oral direct factor Xa inhibition Compared with vitamin K antagonist for the prevention of stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) , a multi-national, double-blind study comparing XARELTO (at a dose of 20 mg once daily with the evening meal in patients with CrCl >50 mL/min and 15 mg once daily with the evening meal in patients with CrCl 30 to 50 mL/min) to warfarin (titrated to INR 2.0 to 3.0) to reduce the risk of stroke and non-central nervous system (CNS) systemic embolism in patients with nonvalvular atrial fibrillation (AF). Patients had to have one or more of the following additional risk factors for stroke:

    • a prior stroke (ischemic or unknown type), transient ischemic attack (TIA) or non-CNS systemic embolism, or
    • 2 or more of the following risk factors:
      • age ≥75 years,
      • hypertension,
      • heart failure or left ventricular ejection fraction ≤35%, or
      • diabetes mellitus

    ROCKET AF was a non-inferiority study designed to demonstrate that XARELTO preserved more than 50% of warfarin’s effect on stroke and non-CNS systemic embolism as established by previous placebo-controlled studies of warfarin in atrial fibrillation.

    A total of 14264 patients were randomized and followed on study treatment for a median of 590 days. The mean age was 71 years and the mean CHADS2 score was 3.5. The population was 60% male, 83% Caucasian, 13% Asian and 1.3% Black. There was a history of stroke, TIA, or non-CNS systemic embolism in 55% of patients, and 38% of patients had not taken a vitamin K antagonist (VKA) within 6 weeks at time of screening. Concomitant diseases of patients in this study included hypertension 91%, diabetes 40%, congestive heart failure 63%, and prior myocardial infarction 17%. At baseline, 37% of patients were on aspirin (almost exclusively at a dose of 100 mg or less) and few patients were on clopidogrel. Patients were enrolled in Eastern Europe (39%); North America (19%); Asia, Australia, and New Zealand (15%); Western Europe (15%); and Latin America (13%). Patients randomized to warfarin had a mean percentage of time in the INR target range of 2.0 to 3.0 of 55%, lower during the first few months of the study.

    In ROCKET AF, XARELTO was demonstrated non-inferior to warfarin for the primary composite endpoint of time to first occurrence of stroke (any type) or non-CNS systemic embolism , but superiority to warfarin was not demonstrated. There is insufficient experience to determine how XARELTO and warfarin compare when warfarin therapy is well-controlled.

    Table 10 displays the overall results for the primary composite endpoint and its components.

    Table 10: Primary Composite Endpoint Results in ROCKET AF Study (Intent-to-Treat Population)

    Figure 5 is a plot of the time from randomization to the occurrence of the first primary endpoint event in the two treatment arms.

    Figure 5: Time to First Occurrence of Stroke (any type) or Non-CNS Systemic Embolism by Treatment Group (Intent-to-Treat Population)

    Figure 6 shows the risk of stroke or non-CNS systemic embolism across major subgroups.

    Figure 6: Risk of Stroke or Non-CNS Systemic Embolism by Baseline Characteristics in ROCKET AF* (Intent-to-Treat Population)

    * Data are shown for all randomized patients followed to site notification that the study would end. Note: The figure above presents effects in various subgroups all of which are baseline characteristics and all of which were pre-specified (diabetic status was not pre-specified in the subgroup, but was a criterion for the CHADS2 score). The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted.

    The efficacy of XARELTO was generally consistent across major subgroups.

    The protocol for ROCKET AF did not stipulate anticoagulation after study drug discontinuation, but warfarin patients who completed the study were generally maintained on warfarin. XARELTO patients were generally switched to warfarin without a period of coadministration of warfarin and XARELTO, so that they were not adequately anticoagulated after stopping XARELTO until attaining a therapeutic INR. During the 28 days following the end of the study, there were 22 strokes in the 4637 patients taking XARELTO vs. 6 in the 4691 patients taking warfarin.

    Few patients in ROCKET AF underwent electrical cardioversion for atrial fibrillation. The utility of XARELTO for preventing post-cardioversion stroke and systemic embolism is unknown.

    Treatment Of Deep Vein Thrombosis (DVT) And/Or Pulmonary Embolism (PE)

    EINSTEIN Deep Vein Thrombosis And EINSTEIN Pulmonary Embolism Studies

    XARELTO for the treatment of DVT and/or PE was studied in EINSTEIN DVT and EINSTEIN PE , multi-national, open-label, non-inferiority studies comparing XARELTO (at an initial dose of 15 mg twice daily with food for the first three weeks, followed by XARELTO 20 mg once daily with food) to enoxaparin 1 mg/kg twice daily for at least five days with VKA and then continued with VKA only after the target INR (2.0-3.0) was reached. Patients who required thrombectomy, insertion of a caval filter, or use of a fibrinolytic agent and patients with creatinine clearance <30 mL/min, significant liver disease, or active bleeding were excluded from the studies. The intended treatment duration was 3, 6, or 12 months based on investigator’s assessment prior to randomization.

    A total of 8281 (3449 in EINSTEIN DVT and 4832 in EINSTEIN PE) patients were randomized and followed on study treatment for a mean of 208 days in the XARELTO group and 204 days in the enoxaparin/VKA group. The mean age was approximately 57 years. The population was 55% male, 70% Caucasian, 9% Asian and about 3% Black. About 73% and 92% of XARELTO-treated patients in the EINSTEIN DVT and EINSTEIN PE studies, respectively, received initial parenteral anticoagulant treatment for a median duration of 2 days. Enoxaparin/VKA-treated patients in the EINSTEIN DVT and EINSTEIN PE studies received initial parenteral anticoagulant treatment for a median duration of 8 days. Aspirin was taken as on treatment concomitant antithrombotic medication by approximately 12% of patients in both treatment groups. Patients randomized to VKA had an unadjusted mean percentage of time in the INR target range of 2.0 to 3.0 of 58% in EINSTEIN DVT study and 60% in EINSTEIN PE study, with the lower values occurring during the first month of the study.

    In the EINSTEIN DVT and EINSTEIN PE studies, XARELTO was demonstrated to be non-inferior to enoxaparin/VKA for the primary composite endpoint of time to first occurrence of recurrent DVT or non-fatal or fatal PE . In each study the conclusion of non-inferiority was based on the upper limit of the 95% confidence interval for the hazard ratio being less than 2.0.

    Table 11 displays the overall results for the primary composite endpoint and its components for EINSTEIN DVT and EINSTEIN PE studies.

    Table 11: Primary Composite Endpoint Results* in EINSTEIN DVT and EINSTEIN PE Studies – Intent-to-Treat Population

    Figures 7 and 8 are plots of the time from randomization to the occurrence of the first primary efficacy endpoint event in the two treatment groups in EINSTEIN DVT and EINSTEIN PE studies, respectively.

    Figure 7: Time to First Occurrence of the Composite of Recurrent DVT or Non-fatal or Fatal PE by Treatment Group (Intent-to-Treat Population) – EINSTEIN DVT Study

    Figure 8: Time to First Occurrence of the Composite of Recurrent DVT or Non-fatal or Fatal PE by Treatment Group (Intent-to-Treat Population) – EINSTEIN PE Study

    Reduction In The Risk Of Recurrence Of DVT And/Or PE

    EINSTEIN CHOICE Study

    XARELTO for reduction in the risk of recurrence of DVT and of PE was evaluated in the EINSTEIN CHOICE study , a multi-national, double-blind, superiority study comparing XARELTO (10 or 20 mg once daily with food) to 100 mg acetylsalicylic acid (aspirin) once daily in patients who had completed 6 to 12 months of anticoagulant treatment for DVT and/or PE following the acute event. The intended treatment duration in the study was up to 12 months. Patients with an indication for continued therapeutic-dose anticoagulation were excluded.

    Because the benefit-risk assessment favored the 10 mg dose versus aspirin compared to the 20 mg dose versus aspirin, only the data concerning the 10 mg dose is discussed below.

    In the EINSTEIN CHOICE study, XARELTO 10 mg was demonstrated to be superior to aspirin 100 mg for the primary composite endpoint of time to first occurrence of recurrent DVT or nonfatal or fatal PE.

    Table 12 displays the overall results for the primary composite endpoint and its components.

    Table 12: Primary Composite Endpoint and its Components Results* in EINSTEIN CHOICE Study – Full Analysis Set

    Figure 9 is a plot of the time from randomization to the occurrence of the first primary efficacy endpoint event in the two treatment groups.

    Figure 9: Time to First Occurrence of the Composite of Recurrent DVT or Non-fatal or Fatal PE by Treatment Group (Full Analysis Set) – EINSTEIN CHOICE Study

    Prophylaxis Of Deep Vein Thrombosis Following Hip Or Knee Replacement Surgery

    XARELTO was studied in 9011 patients (4487 XARELTO-treated, 4524 enoxaparin-treated patients) in the REgulation of Coagulation in ORthopedic Surgery to Prevent DVT and PE, Controlled, Double-blind, Randomized Study of BAY 59-7939 in the Extended Prevention of VTE in Patients Undergoing Elective Total Hip or Knee Replacement (RECORD 1, 2, and 3) studies.

    The two randomized, double-blind, clinical studies (RECORD 1 and 2) in patients undergoing elective total hip replacement surgery compared XARELTO 10 mg once daily starting at least 6 to 8 hours (about 90% of patients dosed 6 to 10 hours) after wound closure versus enoxaparin 40 mg once daily started 12 hours preoperatively. In RECORD 1 and 2, a total of 6727 patients were randomized and 6579 received study drug. The mean age was 63 ± 12.2 (range 18 to 93) years with 49% of patients ≥65 years and 55% of patients were female. More than 82% of patients were White, 7% were Asian, and less than 2% were Black. The studies excluded patients undergoing staged bilateral total hip replacement, patients with severe renal impairment defined as an estimated creatinine clearance <30 mL/min, or patients with significant liver disease (hepatitis or cirrhosis). In RECORD 1, the mean exposure duration (± SD) to active XARELTO and enoxaparin was 33.3 ± 7.0 and 33.6 ± 8.3 days, respectively. In RECORD 2, the mean exposure duration to active XARELTO and enoxaparin was 33.5 ± 6.9 and 12.4 ± 2.9 days, respectively. After Day 13, oral placebo was continued in the enoxaparin group for the remainder of the double-blind study duration. The efficacy data for RECORD 1 and 2 are provided in Table 13.

    Table 13: Summary of Key Efficacy Analysis Results for Patients Undergoing Total Hip Replacement Surgery -Modified Intent-to-Treat Population

    One randomized, double-blind, clinical study (RECORD 3) in patients undergoing elective total knee replacement surgery compared XARELTO 10 mg once daily started at least 6 to 8 hours (about 90% of patients dosed 6 to 10 hours) after wound closure versus enoxaparin. In RECORD 3, the enoxaparin regimen was 40 mg once daily started 12 hours preoperatively. The mean age (± SD) of patients in the study was 68 ± 9.0 (range 28 to 91) years with 66% of patients ≥65 years. Sixty-eight percent (68%) of patients were female. Eighty-one percent (81%) of patients were White, less than 7% were Asian, and less than 2% were Black. The study excluded patients with severe renal impairment defined as an estimated creatinine clearance <30 mL/min or patients with significant liver disease (hepatitis or cirrhosis). The mean exposure duration (± SD) to active XARELTO and enoxaparin was 11.9 ± 2.3 and 12.5 ± 3.0 days, respectively. The efficacy data are provided in Table 14.

    Table 14: Summary of Key Efficacy Analysis Results for Patients Undergoing Total Knee Replacement Surgery -Modified Intent-to-Treat Population

    Reduction Of Risk Of Major Cardiovascular Events In Patients With Chronic CAD Or PAD

    The evidence for the efficacy and safety of XARELTO for the reduction in the risk of stroke, myocardial infarction, or cardiovascular death in patients with coronary artery disease (CAD) or peripheral artery disease (PAD) was derived from the double-blind Cardiovascular OutcoMes for People using Anticoagulation StrategieS trial (COMPASS) . A total of 27,395 patients were evenly randomized to rivaroxaban 2.5 mg orally twice daily plus aspirin 100 mg once daily, rivaroxaban 5 mg orally twice daily alone, or aspirin 100 mg once daily alone. Because the 5 mg dose alone was not superior to aspirin alone, only the data concerning the 2.5 mg dose plus aspirin are discussed below.

    Patients with established CAD or PAD were eligible. Patients with CAD who were younger than 65 years of age were also required to have documentation of atherosclerosis involving at least two vascular beds or to have at least two additional cardiovascular risk factors (current smoking, diabetes mellitus, an estimated glomerular filtration rate <60 mL per minute, heart failure, or non-lacunar ischemic stroke ≥1 month earlier). Patients with PAD were either symptomatic with ankle brachial index <0.90 or had asymptomatic carotid artery stenosis ≥50%, a previous carotid revascularization procedure, or established ischemic disease of one or both lower extremities. Patients were excluded for use of dual antiplatelet, other non-aspirin antiplatelet, or oral anticoagulant therapies, ischemic, non-lacunar stroke within 1 month, hemorrhagic or lacunar stroke at any time, or eGFR <15 mL/min. .

    The mean age was 68 years and 21% of the subject population were ≥75 years. Of the included patients, 91% had CAD, 27% had PAD, and 18% had both CAD and PAD. Of the patients with CAD, 69% had prior MI, 60% had prior percutaneous transluminal coronary angioplasty (PTCA)/atherectomy/ percutaneous coronary intervention (PCI), and 26% had history of coronary artery bypass grafting (CABG) prior to study. Of the patients with PAD, 49% had intermittent claudication, 27% had peripheral artery bypass surgery or peripheral percutaneous transluminal angioplasty, 26% had asymptomatic carotid artery stenosis > 50%, and 4% had limb or foot amputation for arterial vascular disease.

    The mean duration of follow-up was 23 months. Relative to aspirin alone, XARELTO plus aspirin reduced the rate of the primary composite outcome of stroke, myocardial infarction or cardiovascular death. The benefit was observed early with a constant treatment effect over the entire treatment period (see Table 15 and Figure 11).

    A benefit-risk analysis of the data from COMPASS was performed by comparing the number of CV events (CV deaths, myocardial infarctions and non-hemorrhagic strokes) prevented to the number of fatal or life-threatening bleeding events (fatal bleeds + symptomatic non-fatal bleeds into a critical organ) in the XARELTO plus aspirin group versus the aspirin group. Compared to aspirin alone, during 10,000 patient-years of treatment, XARELTO plus aspirin would be expected to result in 70 fewer CV events and 12 additional life-threatening bleeds, indicating a favorable balance of benefits and risks.

    The results in patients with PAD, CAD, and both CAD and PAD were consistent with the overall efficacy and safety results (see Figure 10).

    Figure 10 shows the risk of primary efficacy outcome across major subgroups.

    Figure 10: Risk of Primary Efficacy Outcome by Baseline Characteristics in COMPASS (Intent-to-Treat Population)

    Table 15: Efficacy results from COMPASS study

    Figure 11: Time to first occurrence of primary efficacy outcome (stroke, myocardial infarction, cardiovascular death) in COMPASS

    How does this medication work? What will it do for me?

    Rivaroxaban belongs to the family of medications called anticoagulants. Anticoagulants prevent harmful blood clots from forming in the blood vessels by reducing the ability of the blood to clot. Rivaroxaban is used to prevent blood clots for people who have had total hip replacement or knee replacement surgery. It is used to treat blood clots for people who have had a deep vein thrombosis (DVT; a blood clot in the major arteries, particularly the leg) or pulmonary embolism (blood clot in the lung), and to prevent these clots from happening again.

    Rivaroxaban is also used to prevent stroke or blood clots in people with atrial fibrillation.

    This medication may be available under multiple brand names and/or in several different forms. Any specific brand name of this medication may not be available in all of the forms or approved for all of the conditions discussed here. As well, some forms of this medication may not be used for all of the conditions discussed here.

    Your doctor may have suggested this medication for conditions other than those listed in these drug information articles. If you have not discussed this with your doctor or are not sure why you are taking this medication, speak to your doctor. Do not stop taking this medication without consulting your doctor.

    Do not give this medication to anyone else, even if they have the same symptoms as you do. It can be harmful for people to take this medication if their doctor has not prescribed it.

    What form(s) does this medication come in?

    10 mg
    Each round, biconvex, light red, film-coated tablet, marked with the Bayer Cross on one side and “10” and a triangle on the other side, contains rivaroxaban 10 mg. Nonmedicinal ingredients: croscarmellose sodium, hypromellose 5 cP, lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate, ferric oxide red, hypromellose 15 cP, polyethylene glycol, and titanium dioxide.

    15 mg
    Each round, biconvex, red, film-coated tablet, marked with the Bayer Cross on one side and “15” and a triangle on the other side contains rivaroxaban 15 mg. Nonmedicinal ingredients: croscarmellose sodium, hypromellose 5 cP, lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate, ferric oxide red, hypromellose 15 cP, polyethylene glycol, and titanium dioxide.

    20 mg
    Each round, biconvex, brown-red, film-coated tablet, marked with the Bayer Cross on one side and “20” and a triangle on the other side contains rivaroxaban 20 mg. Nonmedicinal ingredients: croscarmellose sodium, hypromellose 5 cP, lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate, ferric oxide red, hypromellose 15 cP, polyethylene glycol, and titanium dioxide.

    How should I use this medication?

    For knee replacement surgery or hip replacement surgery, the usual dose of rivaroxaban is 10 mg taken by mouth, once daily with or without food. This medication is generally started within 6 to 10 hours after the surgery. For hip replacement surgery, the treatment should continue for 35 days. For knee replacement surgery, the treatment should continue for 14 days.

    To treat or prevent blood clots in the lungs or veins of your legs, the recommended starting dose is 15 mg taken two times a day, with food, for 3 weeks. After 3 weeks, the recommended dose is 20 mg taken once a day. The treatments should continue until your physician decides otherwise.

    For stroke and clot prevention in people with atrial fibrillation, the usual dose is 20 mg taken by mouth, once daily with food.

    If you are taking 15 mg or 20 mg at a time, it is suggested that you take this medication with or immediately after food. Many things can affect the dose of medication that a person needs, such as body weight, other medical conditions, and other medications. If your doctor has recommended a dose different from the ones listed here, do not change the way that you are taking the medication without consulting your doctor.

    It is important to take this medication exactly as prescribed by your doctor. If you miss a dose, of rivaroxaban and you are taking the medication once daily, take it as soon as possible and continue with your regular schedule. If you are taking rivaroxaban 15 mg two times a day, take the dose as soon as you remember and continue with your normal schedule. If it is time for your next dose already take 2 tablets (30 mg total) at once, then continue with your normal dosing schedule. If you are not sure what to do after missing a dose, contact your doctor or pharmacist for advice.

    Store this medication at room temperature and keep it out of the reach of children.

    Do not dispose of medications in wastewater (e.g. down the sink or in the toilet) or in household garbage. Ask your pharmacist how to dispose of medications that are no longer needed or have expired.

    Who should NOT take this medication?

    Do not take rivaroxaban if you:

    • are allergic to rivaroxaban or any ingredients of the medication
    • are bleeding actively or have a high risk of bleeds
    • are pregnant or breast-feeding
    • are taking certain medications such as ketoconazole, itraconazole, voriconazole, posaconazole, or ritonavir
    • are taking other anticoagulants (blood thinners, e.g., warfarin, heparin, low molecular weight heparin, apixaban)
    • have a body lesion at risk of bleeding, including bleeding in the brain within the last 6 months, or bleeding in your stomach or gut
    • have liver disease associated with an increased risk of bleeding

    What side effects are possible with this medication?

    Many medications can cause side effects. A side effect is an unwanted response to a medication when it is taken in normal doses. Side effects can be mild or severe, temporary or permanent.

    The side effects listed below are not experienced by everyone who takes this medication. If you are concerned about side effects, discuss the risks and benefits of this medication with your doctor.

    The following side effects have been reported by at least 1% of people taking this medication. Many of these side effects can be managed, and some may go away on their own over time.

    Contact your doctor if you experience these side effects and they are severe or bothersome. Your pharmacist may be able to advise you on managing side effects.

    • bleeding
    • bruising
    • constipation
    • decreased energy
    • diarrhea
    • fluid buildup in legs, ankles
    • headache
    • increased menstrual bleeding
    • nausea
    • stomach ache
    • vomiting

    Although most of these side effects listed below don’t happen very often, they could lead to serious problems if you do not seek medical attention.

    Check with your doctor as soon as possible if any of the following side effects occur:

    • bleeding or oozing from the surgical wound
    • confusion
    • decreased urine production
    • fast heartbeat
    • itchy skin or skin rash
    • signs of anemia (low red blood cells; e.g., dizziness, pale skin, unusual tiredness or weakness, shortness of breath)
    • signs of bleeding (e.g., bloody nose that lasts for more than 5 minutes, blood in urine, coughing blood, cuts that don’t stop bleeding, gums that bleed for longer than 5 minutes when brushing teeth, bleeding into the rectum or from hemorrhoids, excessive menstrual bleeding)
    • signs of infection (symptoms may include fever or chills, severe diarrhea, shortness of breath, prolonged dizziness, headache, stiff neck, weight loss, or listlessness)
    • signs of liver problems (e.g., nausea, vomiting, diarrhea, loss of appetite, weight loss, yellowing of the skin or whites of the eyes, dark urine, pale stools)
    • signs of low blood pressure (e.g., dizziness, lightheadedness, fainting)
    • stiff, sore, hot, or painful joints
    • symptoms of unidentified bleeding (e.g., weakness, paleness, dizziness, headache, unexplained swelling)
    • unexpected bruising or bleeding after surgery

    Stop taking the medication and seek immediate medical attention if any of the following occur:

    • signs of bleeding in the stomach (e.g., bloody, black, or tarry stools, spitting up of blood, vomiting blood or material that looks like coffee grounds)
    • signs of a serious allergic reaction (i.e., hives, difficulty breathing, or swelling of the face and throat)
    • signs of severe skin reactions (e.g., blistering, peeling, a rash covering a large area of the body, a rash that spreads quickly, or a rash combined with fever or discomfort)

    Some people may experience side effects other than those listed. Check with your doctor if you notice any symptom that worries you while you are taking this medication.

    Are there any other precautions or warnings for this medication?

    HEALTH CANADA ADVISORY

    December 20, 2018

    Health Canada has issued new restrictions concerning the use of Xarelto (rivaroxaban). To read the full Health Canada Advisory, visit Health Canada’s web site at healthycanadians.gc.ca.

    Before you begin using a medication, be sure to inform your doctor of any medical conditions or allergies you may have, any medications you are taking, whether you are pregnant or breast-feeding, and any other significant facts about your health. These factors may affect how you should use this medication.

    Increased bleeding risk: If you have conditions that are associated with an increased risk of bleeding (e.g., bleeding problems; uncontrolled very high blood pressure; a problem with the blood vessels in the back of the eye called retinopathy; current or past ulcer of the stomach or intestines; or recent stroke, recent surgery of the brain, spinal column, or eye), discuss with your doctor how this medication may affect your medical condition, how your medical condition may affect the dosing and effectiveness of this medication, and whether any special monitoring is needed.

    Kidney disease: If you have kidney disease, discuss with your doctor how this medication may affect your medical condition, how your medical condition may affect the dosing and effectiveness of this medication, and whether any special monitoring is needed.

    Lactose: This medication contains lactose. People with certain rare problems associated with lactose or galactose intolerance (e.g., Lapp lactase deficiency, glucose-galactose malabsorption) should not take this medication.

    Liver disease: If you have liver disease or decreased liver function, discuss with your doctor how this medication may affect your medical condition, how your medical condition may affect the dosing and effectiveness of this medication, and whether any special monitoring is needed.

    If you experience symptoms of liver problems such as fatigue, feeling unwell, loss of appetite, nausea, yellowing of the skin or whites of the eyes, dark urine, pale stools, abdominal pain or swelling, and itchy skin, contact your doctor immediately.

    Spinal or epidural injection or catheters: If you have a spinal or epidural catheter, discuss with your doctor how this medication may affect your medical condition, how your medical condition may affect the dosing and effectiveness of this medication, and whether any special monitoring is needed.

    Surgery: Inform all health care professionals involved in your care that you are taking rivaroxaban. Rivaroxaban may need to be stopped temporarily before dental or surgical procedures to reduce your risk of bleeding heavily during or after the procedure.

    Pregnancy: This medication should not be used during pregnancy. If you become pregnant while taking this medication, contact your doctor immediately.

    Breast-feeding: Rivaroxaban may pass into breast milk. If you are a breast-feeding mother and are taking this medication, it may affect your baby. This medication is not recommended to be taken while breast-feeding.

    Children: The safety and effectiveness of using this medication have not been established for children less than 18 years of age.

    Seniors: The side effects of this medication may be more noticeable in seniors. People who are over 65 years old should discuss with their doctor how this medication may affect them and whether any special monitoring is needed.

    What other drugs could interact with this medication?

    There may be an interaction between rivaroxaban and any of the following:

    • abciximab
    • acetylsalicylic acid (ASA)
    • alteplase
    • amiodarone
    • anagrelide
    • apixaban
    • argatroban
    • atorvastatin
    • azole antifungal medications (e.g., ketoconazole, itraconazole, voriconazole)
    • barbiturates (e.g., pentobarbital, phenobarbital)
    • boceprevir
    • bosentan
    • carbamazepine
    • carvedilol
    • clopidogrel
    • cobicistat
    • conivaptan
    • corticosteroids (e.g., dexamethasone, hydrocortisone, methylprednisone, prednisone)
    • cyclosporine
    • dabigatran
    • dabrafenib
    • dasatinib
    • deferasirox
    • diltiazem
    • dipyridamole
    • doxorubicin
    • dronedarone
    • enzalutamide
    • estrogens
    • fondaparinux
    • garlic
    • ginger
    • ginkgo biloba
    • ginseng
    • grapefruit juice
    • heparin and low-molecular weight heparins (e.g., enoxaparin, dalteparin)
    • HIV non-nucleoside reverse transcriptase inhibitors (NNRTIs; e.g., delaviridine, efavirenz)
    • HIV protease inhibitors (e.g., darunavir, indinavir, ritonavir)
    • imatinib
    • lapatinib
    • ledipasvir
    • macrolides (e.g., erythromycin, clarithromycin)
    • mefloquine
    • nefazodone
    • nicardipine
    • nilotinib
    • nonsteroidal anti-inflammatory medications (NSAIDs; e.g., diclofenac, ibuprofen, naproxen)
    • oxcarbazepine
    • omega-3-fatty acids
    • phenytoin
    • prasugrel
    • prazosin
    • primidone
    • progesterone
    • propranolol
    • quinidine
    • quinine
    • red clover
    • rifabutin
    • rifampin
    • rifampicin
    • SSRIs (e.g., citalopram, escitalopram, fluoxetine, paroxetine)
    • St. John’s wort
    • sunitinib
    • tacrolimus
    • tamoxifen
    • telaprevirt
    • trazodone
    • ticagrelor
    • ticlopidine
    • tirofiban
    • tocilizumab
    • ulipristal
    • vandetanib
    • vemurafenib
    • verapamil
    • vinblastine
    • vitamin E
    • warfarin

    If you are taking any of these medications, speak with your doctor or pharmacist. Depending on your specific circumstances, your doctor may want you to:

    • stop taking one of the medications,
    • change one of the medications to another,
    • change how you are taking one or both of the medications, or
    • leave everything as is.

    An interaction between two medications does not always mean that you must stop taking one of them. Speak to your doctor about how any drug interactions are being managed or should be managed.

    Medications other than those listed above may interact with this medication. Tell your doctor or prescriber about all prescription, over-the-counter (non-prescription), and herbal medications you are taking. Also tell them about any supplements you take. Since caffeine, alcohol, the nicotine from cigarettes, or street drugs can affect the action of many medications, you should let your prescriber know if you use them.

    All material copyright MediResource Inc. 1996 – 2020. Terms and conditions of use. The contents herein are for informational purposes only. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Source: www.medbroadcast.com/drug/getdrug/Xarelto

    What is Rivaroxaban and How is it Abused?

    Rivaroxaban, known by the brand name Xarelto, is a novel oral anticoagulant (NOAC) medication prescribed as a blood thinner. It is FDA approved to treat and prevent deep vein thrombosis (DVT) in people who have had knee or hip replacements as well as to minimize the risk for stroke in those who struggle with nonvalvular atrial fibrillation and pulmonary embolism (PE). Xarelto is a selective inhibitor of FXa, which helps to keep blood from clotting in people with specific risk factors for this.

    It is a useful and beneficial medication when it is used properly under the direct supervision and indication of a healthcare professional. Prescription medications such as Xarelto are often misused, however, taken in a manner that is outside of the bounds of a legitimate and necessary prescription. The National Survey on Drug Use and Health (NSDUH) reports that in the month leading up to the 2016 survey over 6 million Americans misused a psychotherapeutic medication.

    Misuse of Xarelto may be intentional or even accidental when the person taking the drug isn’t following the exact prescribing information. An article published in the journal Therapie reports that over 16 percent of people admitted to an emergency department (ED) for an adverse reaction to a NOAC medication during the study period were not using the drug properly. Misuse or abuse of Xarelto can be deadly as the drug can have very serious side effects.

    What are the Risks of Use and Abuse?

    Xarelto thins the blood and therefore carries a real risk for excessive bleeding. It is listed as a “high-alert” drug by the Institute for Safe Medication Practices (ISMP), as published by Meds News. The drug can increase the risk for internal bleeding both in the brain and in the gastrointestinal system as well as the potential for spinal epidural hematoma, which can lead to permanent paralysis.

    Part of the danger of Xarelto lies in the fact that there is no specific antidote to completely reverse the effects of the drug. Internal bleeding or hemorrhaging can cause lasting damage or even lead to death.

    According to the Quarterwatch Report published by ISMP in July 2017, there were over 1 million reports of adverse drug events involving anticoagulant medications in 2016, placing these drugs at the top of the list for drug safety problems. As reported by Consumer Safety, nearly half of all negative reactions to an anticoagulant, such as Xarelto, require a hospital stay.

    According to the prescription guide, stopping Xarelto use suddenly can be hazardous and increase the risk for stroke and blood clot formation, which can lead to a lack of oxygen to the brain. Mixing Xarelto with other medications or alcohol can increase the odds for a negative reaction as well.

    The maker of Xarelto, Janssen Pharmaceuticals, warns that it should not be mixed with the following medications due to an increased risk for potentially life-threatening bleeding:

    • Nonsteroidal anti-inflammatory drugs (NSAIDs)
    • Aspirin or products that contain aspirin
    • Selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs)
    • Additional medications designed to treat blood clots
    • Warfarin sodium (Jantoven, Coumadin)
    • Medications containing heparin
    • Clopidogrel (Plavix)

    In studied treatment groups, between 60 percent and 80 percent of individuals taking rivaroxaban had a minimum of one adverse reaction requiring emergency treatment, the U.S. National Library of Medicine’s (NLM) PubMed Health reports. Common side effects of Xarelto, other than bleeding, include headache, cough, chest pain, bruising, pain in extremities, nosebleeds, cough, and respiratory infections. Even taking the drug exactly as prescribed can have risks, and when the drug is abused, these potential hazards increase exponentially.

    Overdose on Xarelto is possible and can be fatal, as again, there is no exact antidote for the drug. As reported in Medicine, the main risk factor during a rivaroxaban overdose is excessive bleeding that can be irreversible and fatal.

    Rivaroxaban does have a “ceiling effect,” however, which means that after about 50 mg of the drug is ingested, additional amounts will not have the same FXa inhibitory effects on the blood. Taking more than the prescribed amount of Xarelto, taking it in a way other than as prescribed (e.g., crushing or chewing the tablets), or mixing it with other drugs or alcohol raises the odds for a possible overdose, which can become life-threatening.

    What are Available Addiction Treatment Options?

    Prescriptions for anticoagulant medications filled in a five-year period (between 2009 and 2014) for those experiencing incident atrial fibrillation (AF) were studied, and the Journal of the American Heart Association (JAHA) publishes that the mean age of those prescribed the drug was over 65 and over half were male. The elderly population comprises about one-third of all prescription medication use in the United States, which can put this demographic at a higher risk for drug abuse and misuse, the National Council on Alcoholism and Drug Dependence (NCADD) warns. This population group may be more isolated than other ages, and prescription drug abuse is often misdiagnosed, ignored, over overlooked.

    Many times, seniors are often taking multiple medications and may not intentionally be abusing Xarelto. Any use of Xarelto without a prescription, or use that varies from the prescribing instructions, is considered abuse. Taking too much at a time, taking it in between doses, taking Xarelto after the prescription has run out, or altering the drug to snort, smoke, or inject it are all methods of drug abuse.

    Prolonged use of a drug like Xarelto may lead to a lack of control over its use, which can become addiction. When a person takes Xarelto for a length of time, the brain can become accustomed to the way it interacts with its chemical balance. Stopping Xarelto suddenly can lead to withdrawal symptoms, the most serious of which can be stroke caused by blood clotting. Other possible withdrawal symptoms from Xarelto include backache, dizziness, headache, weakness in the legs, stomach upset, breathing difficulties, a lightheaded feeling, heart palpitations, fatigue, sleep issues, high blood pressure, dry mouth, potential emotional disturbances, and possible nerve damage.

    Xarelto shouldn’t be stopped “cold turkey,” and usually, it shouldn’t be stopped without the introduction of a different anticoagulant. Initial treatment for Xarelto abuse and addiction is a detox program that can carefully wean the medication out of the body in a controlled manner. This generally takes place via a set tapering schedule under the watchful eyes of trained medical professionals.

    Medical detox will often involve the use of additional medications to help mitigate potential adverse reactions and withdrawal symptoms. During medical detox, the individual can be constantly monitored, helping to keep vital signs stable while the drug safely processes out of the body.

    After detox, an addiction treatment program can offer continued support, education, and encouragement. Behavioral therapies, support groups, relapse prevention training, alternative treatment methods, medication management, and more can all be offered as part of a comprehensive addiction treatment program.

    Treatment programs are designed for each individual and cater to specific needs and circumstances. There are specialty programs for different demographics, such as gender-specific or programs for the elderly, which can help a person to feel connected and supported moving forward. While some of the physical damage from Xarelto abuse may not be entirely reversible, most of the side effects of addiction and abuse can be managed and improved through a complete addiction treatment program in a specialized facility.

    WHAT IS THE MOST IMPORTANT INFORMATION I SHOULD KNOW ABOUT XARELTO®?

    XARELTO® may cause serious side effects, including:

    • Increased risk of blood clots if you stop taking XARELTO®. People with atrial fibrillation (an irregular heart beat) that is not caused by a heart valve problem (nonvalvular) are at an increased risk of forming a blood clot in the heart, which can travel to the brain, causing a stroke, or to other parts of the body. XARELTO® lowers your chance of having a stroke by helping to prevent clots from forming. If you stop taking XARELTO®, you may have increased risk of forming a clot in your blood.

      Do not stop taking XARELTO® without talking to the doctor who prescribes it for you. Stopping XARELTO® increases your risk of having a stroke. If you have to stop taking XARELTO®, your doctor may prescribe another blood thinner medicine to prevent a blood clot from forming.

    • Increased risk of bleeding. XARELTO® can cause bleeding which can be serious, and may lead to death. This is because XARELTO® is a blood thinner medicine (anticoagulant) that lowers blood clotting. During treatment with XARELTO® you are likely to bruise more easily, and it may take longer for bleeding to stop. You may be at higher risk of bleeding if you take XARELTO® and have certain other medical problems.

      You may have a higher risk of bleeding if you take XARELTO® and take other medicines that increase your risk of bleeding, including:

      • Aspirin or aspirin-containing products
      • Long-term (chronic) use of non-steroidal anti-inflammatory drugs (NSAIDs)
      • Warfarin sodium (Coumadin®, Jantoven®)
      • Any medicine that contains heparin
      • Clopidogrel (Plavix®)
      • Selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs)
      • Other medicines to prevent or treat blood clots

      Tell your doctor if you take any of these medicines. Ask your doctor or pharmacist if you are not sure if your medicine is one listed above. ​

      Call your doctor or get medical help right away if you develop any of these signs or symptoms of bleeding:

      • Unexpected bleeding or bleeding that lasts a long time, such as:
        • Nosebleeds that happen often
        • Unusual bleeding from gums
        • Menstrual bleeding that is heavier than normal, or vaginal bleeding
      • Bleeding that is severe or you cannot control
      • Red, pink, or brown urine
      • Bright red or black stools (looks like tar)
      • Cough up blood or blood clots
      • Vomit blood or your vomit looks like “coffee grounds”
      • Headaches, feeling dizzy or weak
      • Pain, swelling, or new drainage at wound sites
    • Spinal or epidural blood clots (hematoma). People who take a blood thinner medicine (anticoagulant) like XARELTO®, and have medicine injected into their spinal and epidural area, or have a spinal puncture, have a risk of forming a blood clot that can cause long-term or permanent loss of the ability to move (paralysis). Your risk of developing a spinal or epidural blood clot is higher if:
      • A thin tube called an epidural catheter is placed in your back to give you certain medicine
      • You take NSAIDs or a medicine to prevent blood from clotting
      • You have a history of difficult or repeated epidural or spinal punctures
      • You have a history of problems with your spine or have had surgery on your spine

      If you take XARELTO® and receive spinal anesthesia or have a spinal puncture, your doctor should watch you closely for symptoms of spinal or epidural blood clots. Tell your doctor right away if you have back pain, tingling, numbness, muscle weakness (especially in your legs and feet), or loss of control of the bowels or bladder (incontinence).

    XARELTO® is not for use in people with artificial heart valves.

    XARELTO® is not for use in people with antiphospholipid syndrome (APS), especially with positive triple antibody testing.

    ​​Do not take XARELTO® if you:

    • Currently have certain types of abnormal bleeding. Talk to your doctor before taking XARELTO® if you currently have unusual bleeding.
    • Are allergic to rivaroxaban or any of the ingredients of XARELTO®.

    ​​Before taking XARELTO®, tell your doctor about all your medical conditions, including if you:

    • Have ever had bleeding problems
    • Have liver or kidney problems
    • Have antiphospholipid syndrome (APS)
    • Are pregnant or plan to become pregnant. It is not known if XARELTO® will harm your unborn baby.
      • Tell your doctor right away if you become pregnant during treatment with XARELTO®. Taking XARELTO® while you are pregnant may increase the risk of bleeding in you or in your unborn baby.
      • If you take XARELTO® during pregnancy, tell your doctor right away if you have any signs or symptoms of bleeding or blood loss. See “What is the most important information I should know about XARELTO®?” for signs and symptoms of bleeding.
    • Are breastfeeding or plan to breastfeed. XARELTO® may pass into your breast milk. Talk to your doctor about the best way to feed your baby during treatment with XARELTO®.

    Tell all of your doctors and dentists that you are taking XARELTO®. They should talk to the doctor who prescribed XARELTO® for you before you have any surgery, medical or dental procedure.

    Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

    Some of your other medicines may affect the way XARELTO® works, causing side effects. Certain medicines may increase your risk of bleeding. See “What is the most important information I should know about XARELTO®?”

    HOW SHOULD I TAKE XARELTO®?

    • Take XARELTO® exactly as prescribed by your doctor.
    • Do not change your dose or stop taking XARELTO® unless your doctor tells you to. Your doctor may change your dose if needed.
    • Your doctor will decide how long you should take XARELTO®.
    • XARELTO® may need to be stopped for one or more days before any surgery or medical or dental procedure. Your doctor will tell you when to stop taking XARELTO® and when to start taking XARELTO® again after your surgery or procedure.
    • If you need to stop taking XARELTO® for any reason, talk to the doctor who prescribed XARELTO® to you to find out when you should stop taking it. Do not stop taking XARELTO® without first talking to the doctor who prescribes it to you.
    • If you have difficulty swallowing XARELTO® tablets whole, talk to your doctor about other ways to take XARELTO®.
    • Do not run out of XARELTO®. Refill your prescription of XARELTO® before you run out. When leaving the hospital following a hip or knee replacement, be sure that you will have XARELTO® available to avoid missing any doses.
    • If you take too much XARELTO®, go to the nearest hospital emergency room or call your doctor right away.

    If you take XARELTO® for:​

      • Atrial Fibrillation that is not caused by a heart valve problem:
        • Take XARELTO® 1 time a day with your evening meal.
        • If you miss a dose of XARELTO®, take it as soon as you remember on the same day. Take your next dose at your regularly scheduled time.
      • Blood clots in the veins of your legs or lungs:
        • Take XARELTO® 1 or 2 times a day as prescribed by your doctor.
        • For the 10-mg dose, XARELTO® may be taken with or without food.
        • For the 15-mg and 20-mg doses, take XARELTO® with food at the same time each day.
        • If you miss a dose:
          • If you take the 15-mg dose of XARELTO® 2 times a day (a total of 30 mg of XARELTO® in 1 day): Take XARELTO® as soon as you remember on the same day. You may take 2 doses at the same time to make up for the missed dose. Take your next dose at your regularly scheduled time.
          • If you take XARELTO® 1 time a day: Take XARELTO® as soon as you remember on the same day. Take your next dose at your regularly scheduled time.​
      • Hip or knee replacement surgery:
        • Take XARELTO® 1 time a day with or without food.
        • If you miss a dose of XARELTO®, take it as soon as you remember on the same day. Take your next dose at your regularly scheduled time.
      • Blood clots in people hospitalized for an acute illness:
        • Take XARELTO® 1 time a day, with or without food, while you are in the hospital and after you are discharged as prescribed by your doctor.
        • If you miss a dose of XARELTO®, take it as soon as you remember on the same day. Take your next dose at your regularly scheduled time.
      • Reducing the risk of serious heart problems, heart attack and stroke in coronary artery disease or peripheral artery disease:
        • Take XARELTO® 2 times a day with or without food.
        • If you miss a dose of XARELTO®, take your next dose at your regularly scheduled time.

    WHAT ARE THE POSSIBLE SIDE EFFECTS OF XARELTO®?

    XARELTO® may cause serious side effects:

    • See “What is the most important information I should know about XARELTO®?”

    The most common side effect of XARELTO® was bleeding.

    Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Janssen Pharmaceuticals, Inc., at 1-800-JANSSEN (1-800-526-7736).

    Please see full Prescribing Information, including Boxed Warnings, and Medication Guide for XARELTO®.

    Trademarks are those of their respective owners.

    cp-53637v5

    SIDE EFFECTS

    The following adverse reactions are also discussed in other sections of the labeling:

    • Increased risk of stroke after discontinuation in nonvalvular atrial fibrillation
    • Bleeding risk
    • Spinal/epidural hematoma

    Clinical Trials Experience

    Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

    During clinical development for the approved indications, 27,694 patients were exposed to XARELTO. These included 7111 patients who received XARELTO 15 mg or 20 mg orally once daily for a mean of 19 months (5558 for 12 months and 2512 for 24 months) to reduce the risk of stroke and systemic embolism in nonvalvular atrial fibrillation (ROCKET AF); 6962 patients who received XARELTO 15 mg orally twice daily for three weeks followed by 20 mg orally once daily to treat DVT or PE (EINSTEIN DVT, EINSTEIN PE), 10 mg or 20 mg orally once daily (EINSTEIN Extension, EINSTEIN CHOICE) to reduce the risk of recurrence of DVT and/or PE; 4487 patients who received XARELTO 10 mg orally once daily for prophylaxis of DVT following hip or knee replacement surgery (RECORD 1-3); and 9134 patients who received XARELTO 2.5 mg orally twice daily, in combination with aspirin 100 mg once daily, for the reduction in risk of major cardiovascular events in patients with chronic CAD or PAD (COMPASS).

    Hemorrhage

    The most common adverse reactions with XARELTO were bleeding complications .

    Nonvalvular Atrial Fibrillation

    In the ROCKET AF trial, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 4.3% for XARELTO vs. 3.1% for warfarin. The incidence of discontinuations for non-bleeding adverse events was similar in both treatment groups.

    Table 2 shows the number of patients experiencing various types of bleeding events in the ROCKET AF trial.

    Table 2: Bleeding Events in ROCKET AF*-On Treatment Plus 2 Days

    Figure 1 shows the risk of major bleeding events across major subgroups.

    Figure 1: Risk of Major Bleeding Events by Baseline Characteristics in ROCKET AF – On Treatment Plus 2 Days

    Note: The figure above presents effects in various subgroups all of which are baseline characteristics and all of which were pre-specified (diabetic status was not pre-specified in the subgroup, but was a criterion for the CHADS2 score). The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted.

    EINSTEIN DVT and EINSTEIN PE Studies

    In the pooled analysis of the EINSTEIN DVT and EINSTEIN PE clinical studies, the most frequent adverse reactions leading to permanent drug discontinuation were bleeding events, with XARELTO vs. enoxaparin/Vitamin K antagonist (VKA) incidence rates of 1.7% vs. 1.5%, respectively. The mean duration of treatment was 208 days for XARELTO-treated patients and 204 days for enoxaparin/VKA-treated patients.

    Table 3 shows the number of patients experiencing major bleeding events in the pooled analysis of the EINSTEIN DVT and EINSTEIN PE studies.

    Table 3: Bleeding Events* in the Pooled Analysis of EINSTEIN DVT and EINSTEIN PE Studies

    In the EINSTEIN CHOICE clinical study, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 1% for XARELTO 10 mg, 2% for XARELTO 20 mg, and 1% for acetylsalicylic acid (aspirin) 100 mg. The mean duration of treatment was 293 days for XARELTO 10 mg-treated patients and 286 days for aspirin 100 mg-treated patients.

    Table 4 shows the number of patients experiencing bleeding events in the EINSTEIN CHOICE study.

    Table 4: Bleeding Events* in EINSTEIN CHOICE

    Parameter XARELTO† 10 mg
    N=1127
    n (%)
    Acetylsalicylic Acid (aspirin)† 100 mg
    N=1131
    n (%)
    Major bleeding event 5 (0.4) 3 (0.3)
    Fatal bleeding 0 1 (<0.1)
    Non-fatal critical organ bleeding 2 (0.2) 1 (<0.1)
    Non-fatal non-critical organ bleeding§ 3 (0.3) 1 (<0.1)
    Clinically relevant non-major (CRNM) bleeding¶ 22 (2.0) 20 (1.8)
    Any bleeding 151 (13.4) 138 (12.2)
    * Bleeding event occurred after the first dose and up to 2 days after the last dose of study drug. Although a patient may have had 2 or more events, the patient is counted only once in a category.
    † Treatment schedule: XARELTO 10 mg once daily or aspirin 100 mg once daily.
    § Major bleeding which is not fatal or in a critical organ, but resulting in a decrease in Hb ≥ 2 g/dL and/or transfusion of ≥ 2 units of whole blood or packed red blood cells.
    ¶ Bleeding which was clinically overt, did not meet the criteria for major bleeding, but was associated with medical intervention, unscheduled contact with a physician, temporary cessation of treatment, discomfort for the patient, or impairment of activities of daily life.

    In the EINSTEIN CHOICE study, there was an increased incidence of bleeding, including major and CRNM bleeding in the XARELTO 20 mg group compared to the XARELTO 10 mg or aspirin 100 mg groups.

    In the RECORD clinical trials, the overall incidence rate of adverse reactions leading to permanent treatment discontinuation was 3.7% with XARELTO.

    The rates of major bleeding events and any bleeding events observed in patients in the RECORD clinical trials are shown in Table 5.

    Table 5: Bleeding Events* in Patients Undergoing Hip or Knee Replacement Surgeries (RECORD 1-3)

    Following XARELTO treatment, the majority of major bleeding complications (≥60%) occurred during the first week after surgery.

    In the COMPASS trial, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 2.7% for XARELTO 2.5 mg twice daily in combination with aspirin 100 mg once daily vs. 1.2% for aspirin 100 mg once daily.

    Table 6 shows the number of patients experiencing various types of major bleeding events in the COMPASS trial.

    Table 6: Major Bleeding Events* in COMPASS -On Treatment Plus 2 days

    Figure 2 shows the risk of modified ISTH major bleeding events across major subgroups.

    Figure 2: Risk of Modified ISTH Major Bleeding Events by Baseline Characteristics in COMPASS – On Treatment Plus 2 Days

    Other Adverse Reactions

    Non-hemorrhagic adverse reactions reported in ≥1% of XARELTO-treated patients in the EINSTEIN DVT and EINSTEIN PE studies are shown in Table 7.

    Table 7: Other Adverse Reactions* Reported by ≥1% of XARELTO-Treated Patients in EINSTEIN DVT and EINSTEIN PE Studies

    Non-hemorrhagic adverse reactions reported in ≥1% of XARELTO-treated patients in RECORD 1-3 studies are shown in Table 8.

    Table 8: Other Adverse Drug Reactions* Reported by ≥1% of XARELTO-Treated Patients in RECORD 1-3 Studies

    Body System Adverse Reaction XARELTO 10 mg
    N=4487
    n (%)
    Enoxaparin†
    N=4524
    n (%)
    Injury, poisoning and procedural complications
    Wound secretion 125 (2.8) 89 (2.0)
    Musculoskeletal and connective tissue disorders
    Pain in extremity 74 (1.7) 55 (1.2)
    Muscle spasm 52 (1.2) 32 (0.7)
    Nervous system disorders
    Syncope 55 (1.2) 32 (0.7)
    Skin and subcutaneous tissue disorders
    Pruritus 96 (2.1) 79 (1.8)
    Blister 63 (1.4) 40 (0.9)
    * Adverse reaction occurring any time following the first dose of double-blind medication, which may have been prior to administration of active drug, until two days after the last dose of double-blind study medication
    † Includes the placebo-controlled period of RECORD 2, enoxaparin dosing was 40 mg once daily (RECORD 1-3)

    Other Clinical Trial Experience

    In an investigational study of acute medically ill patients being treated with XARELTO 10 mg tablets, cases of pulmonary hemorrhage and pulmonary hemorrhage with bronchiectasis were observed.

    Postmarketing Experience

    The following adverse reactions have been identified during post-approval use of XARELTO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

    Blood and lymphatic system disorders: agranulocytosis, thrombocytopenia

    Gastrointestinal disorders: retroperitoneal hemorrhage

    Hepatobiliary disorders: jaundice, cholestasis, hepatitis (including hepatocellular injury)

    Immune system disorders: hypersensitivity, anaphylactic reaction, anaphylactic shock, angioedema

    Nervous system disorders: cerebral hemorrhage, subdural hematoma, epidural hematoma, hemiparesis

    Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome

    Read the entire FDA prescribing information for Xarelto (Rivaroxaban Film-Coated Oral Tablets)

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