RIVAZEST Tablets (Rivaroxaban)

Table of Content

For the use of a Registered Medical Practitioner or a Hospital or a Laboratory only

WARNING:

(A) Premature Discontinuation of RIVAZEST Increases the Risk of Thrombotic Events, (B) Spinal/Epidural Hematoma

  1. Premature discontinuation of RIVAZEST increases the risk of thrombotic events- Premature discontinuation of any oral anticoagulant, including RIVAZEST, increases the risk of thrombotic events. If anticoagulation with RIVAZEST is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant.
  2.  Spinal/epidural hematoma- Epidural or spinal hematomas have occurred in patients treated with RIVAZEST who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include:
  • use of indwelling epidural catheters
  • concomitant use of other drugs that affect hemostasis, such as non- steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants
  • a history of traumatic or repeated epidural or spinal punctures
  • a history of spinal deformity or spinal surgery
  • optimal timing between the administration of RIVAZEST and neuraxial procedures is not known

Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary. Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis.

Quantitative and Qualitative Composition

Each film-coated tablet contains 2.5 mg rivaroxaban

Each film-coated tablet contains 10 mg rivaroxaban

Each film-coated tablet contains 15 mg rivaroxaban

Each film-coated tablet contains 20 mg rivaroxaban

Dosage Form & Strength

2.5 mg tablets, 10 mg tablets, 15 mg tablets, 20 mg tablets

Clinical Particulars

Therapeutic Indication

Reduction of Risk of Stroke and Systemic Embolism in valvular Atrial Fibrillation; Treatment of Deep Vein Thrombosis; Treatment of Pulmonary Embolism; Reduction in the Risk of Recurrence of Deep Vein Thrombosis and/or Pulmonary Embolism; Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery; Reduction of Risk of Major Cardiovascular Events in Patients with Chronic Coronary Artery Disease (CAD) or Peripheral Artery Disease (PAD)

Dosage and Administration

Table 1: Recommended dosage

Indication

Renal Considerations*

Dosage

Food/ Timing†

Reduction in Risk of Stroke in Nonvalvular Atrial Fibrillation

CrCl >50 mL/min

20 mg once daily

Take with evening meal

CrCl ≤50 mL/min§

15 mg once daily

Take with evening meal

Treatment of DVT and/or PE

 

CrCl ≥15 mL/min§

15 mg twice daily

after 21 days, transition to

20 mg once daily

Take with food, at the same time each day

CrCl <15 mL/min

Avoid Use

Reduction in the Risk of Recurrence of DVT and/or PE in patients at continued risk for DVT and/or PE

 

CrCl ≥15 mL/min§

10 mg once daily, after at least 6 months of standard anticoagulant treatment

Take with or without food

CrCl <15 mL/min

Avoid Use

Prophylaxis of DVT Following:

 

- Hip Replacement Surgery‡

 

CrCl ≥15 mL/min§

10 mg once daily for 35 days, 6-10 hours after surgery once hemostasis has been established

Take with or without food

CrCl <15 mL/min

Avoid Use

- Knee Replacement Surgery‡

CrCl ≥15 mL/min§

10 mg once daily for 12 days, 6-10 hours after surgery once hemostasis has been established

Take with or without food

CrCl <15 mL/min

Avoid Use

Reduction of Risk of Major Cardiovascular

Events (CV Death, MI, and Stroke) in Chronic CAD

or PAD

No dose adjustment needed based on CrCl

2.5 mg twice daily, plus aspirin (75-100 mg) once daily

Take with or without food

*Calculate CrCl based on actual weight. See Warnings and Precautions and Use in Specific Populations

†  See Clinical Pharmacology

See Dosage and Administration

§  Patients with CrCl <30 mL/min were not studied, but administration of rivaroxaban is expected to result in serum concentrations of rivaroxaban similar to those in patients with moderate renal impairment (CrCl 30 to <50 mL/min)

Switching to and from Rivaroxaban

Switching from Warfarin to Rivaroxaban - When switching patients from warfarin to rivaroxaban, discontinue warfarin and start rivaroxaban as soon as the International Normalized Ratio (INR) is below 3.0 to avoid periods of inadequate anticoagulation.

Switching from Rivaroxaban to Warfarin - No clinical trial data are available to guide converting patients from rivaroxaban to warfarin. Rivaroxaban affects INR, so INR measurements made during coadministration with warfarin may not be useful for determining the appropriate dose of warfarin. One approach is to discontinue rivaroxaban and begin both a parenteral anticoagulant and warfarin at the time the next dose of rivaroxaban would have been taken.

Switching from Rivaroxaban to Anticoagulants other than Warfarin - For patients currently taking rivaroxaban and transitioning to an anticoagulant with rapid onset, discontinue rivaroxaban and give the first dose of the other anticoagulant (oral or parenteral) at the time that the next rivaroxaban dose would have been taken.

Switching from Anticoagulants other than Warfarin to Rivaroxaban - For patients currently receiving an anticoagulant other than warfarin, start rivaroxaban 0 to 2 hours prior to the next scheduled evening administration of the drug (e.g., low molecular weight heparin or non-warfarin oral anticoagulant) and omit administration of the other anticoagulant. For unfractionated heparin being administered by continuous infusion, stop the infusion and start rivaroxaban at the same time.

Discontinuation for Surgery and other Interventions- If anticoagulation must be discontinued to reduce the risk of bleeding with surgical or other procedures, rivaroxaban should be stopped at least 24 hours before the procedure to reduce the risk of bleeding. In deciding whether a procedure should be delaye until 24 hours after the last dose of rivaroxaban, the increased risk of bleeding should be weighed against the urgency of intervention. Rivaroxaban should be restarted after the surgical or other procedures as soon as adequate hemostasis has been established, noting that the time to onset of therapeutic effect is short . If oral medication cannot be taken during or after surgical intervention, consider administering a parenteral anticoagulant.

Missed Dose

  • For patients receiving 2.5 mg twice daily: if a dose is missed, the patient should take a single 2.5 mg rivaroxaban dose as recommended at the next scheduled time.
  • For patients receiving 15 mg twice daily: The patient should take rivaroxaban immediately to ensure intake of 30 mg rivaroxaban per day. Two 15 mg tablets may be taken at once.
  • For patients receiving 20 mg, 15 mg or 10 mg once daily: The patient should take the missed rivaroxaban dose immediately. The dose should not be doubled within the same day to make up for a missed dose.

Contraindication

Rivaroxaban is contraindicated in patients with active pathological bleeding & severe hypersensitivity reaction to rivaroxaban (e.g., anaphylactic reactions)

Warnings & Precautions

 Increased Risk of Thrombotic Events after Premature Discontinuation - Premature discontinuation of any oral anticoagulant, including rivaroxaban, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from rivaroxaban to warfarin in clinical trials in atrial fibrillation patients. If rivaroxaban is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant.

Risk of Bleeding- Rivaroxaban increases the risk of bleeding and can cause serious or fatal bleeding. In deciding whether to prescribe rivaroxaban to patients at increased risk of bleeding, the risk of thrombotic events should be weighed against the risk of bleeding. Promptly evaluate any signs or symptoms of blood loss and consider the need for blood replacement. Discontinue rivaroxaban in patients with active pathological hemorrhage. The terminal elimination half-life of rivaroxaban is 5 to 9 hours in healthy subjects aged 20 to 45 years. Concomitant use of other drugs that impair hemostasis increases the risk of bleeding. These include aspirin, P2Y12 platelet inhibitors, dual antiplatelet therapy, other antithrombotic agents, fibrinolytic therapy, non-steroidal anti- inflammatory drugs (NSAIDs), selective serotonin reuptake inhibitors, and serotonin norepinephrine reuptake inhibitors. Concomitant use of drugs that are known combined P-gp and strong CYP3A inhibitors increases rivaroxaban exposure and may increase bleeding risk.

Risk of Hemorrhage in Acutely Ill Medical Patients at High Risk of Bleeding- Acutely ill medical patients with the following conditions are at increased risk of bleeding with the use of rivaroxaban for primary VTE prophylaxis: history of bronchiectasis, pulmonary cavitation, or pulmonary hemorrhage, active cancer (i.e. undergoing acute, in-hospital cancer treatment), active gastroduodenal ulcer in the three months prior to treatment, history of bleeding in the three months prior to treatment, or dual antiplatelet therapy. rivaroxaban is not for use for primary VTE prophylaxis in these hospitalized, acutely ill medical patients at high risk of bleeding.

Reversal of Anticoagulant Effect- An agent to reverse the anti-factor Xa activity of rivaroxaban is available. Because of high plasma protein binding, rivaroxaban is not dialyzable . Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban. Use of procoagulant reversal agents, such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate or recombinant factor VIIa, may be considered but has not been evaluated in clinical efficacy and safety studies. Monitoring for the anticoagulation effect of rivaroxaban using a clotting test (PT, INR or aPTT) or anti-factor Xa (FXa) activity is not recommended.

Spinal/Epidural Anesthesia or Puncture- When neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture is employed, patients treated with anticoagulant agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis .To reduce the potential risk of bleeding associated with the concurrent use of rivaroxaban and epidural or spinal anesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of rivaroxaban. Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of rivaroxaban is low; however, the exact timing to reach a sufficiently low anticoagulant effect in each patient is not known.

An indwelling epidural or intrathecal catheter should not be removed before at least 2 half-lives have elapsed (i.e., 18 hours in young patients aged 20 to 45 years and 26 hours in elderly patients aged 60 to 76 years), after the last administration of rivaroxaban . The next rivaroxaban dose should not be administered earlier than 6 hours after the removal of the catheter. If traumatic puncture occurs, delay the administration of rivaroxaban for 24 hours. Should the physician decide to administer anticoagulation in the context of epidural or spinal anesthesia/analgesia or lumbar puncture, monitor frequently to detect any signs or symptoms of neurological impairment, such as midline back pain, sensory and motor deficits (numbness, tingling, or weakness in lower limbs), bowel and/or bladder dysfunction. Instruct patients to immediately report if they experience any of the above signs or symptoms. If signs or symptoms of spinal hematoma are suspected, initiate urgent diagnosis and treatment including consideration for spinal cord decompression even though such treatment may not prevent or reverse neurological sequelae.

Use in Patients with Renal Impairment

Nonvalvular Atrial Fibrillation- Periodically assess renal function as clinically indicated (i.e., more frequently in situations in which renal function may decline) and adjust therapy accordingly. Consider dose adjustment or discontinuation of rivaroxaban in patients who develop acute renal failure while on rivaroxaban.

Treatment of Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), and Reduction in the Risk of Recurrence of DVT and of PE- In patients with CrCl <30 mL/min, rivaroxaban exposure and pharmacodynamic effects are increased compared to patients with normal renal function. There are limited clinical data in patients with CrCl 15 to <30 mL/min; therefore, observe closely and promptly evaluate any signs or symptoms of blood loss in these patients. There are no clinical data in patients with CrCl <15 mL/min (including patients on dialysis); therefore, avoid the use of rivaroxaban in these patients. Discontinue rivaroxaban in patients who develop acute renal failure while on treatment.

Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery- In patients with CrCl <30 mL/min, rivaroxaban exposure and pharmacodynamic effects are increased compared to patients with normal renal function. There are limited clinical data in patients with CrCl 15 to <30 mL/min; therefore, observe closely and promptly evaluate any signs or symptoms of blood loss in these patients. There are no clinical data in patients with CrCl <15 mL/min (including patients on dialysis); therefore, avoid the use of rivaroxaban in these patients. Discontinue rivaroxaban in patients who develop acute renal failure while on treatment.

Prophylaxis of Venous Thromboembolism in Acutely Ill Medical Patients at Risk for Thromboembolic Complications Not at High Risk of Bleeding - In patients with CrCl <30 mL/min, rivaroxaban exposure and pharmacodynamic effects are increased compared to patients with normal renal function. There are limited clinical data in patients with CrCl 15 to <30 mL/min; therefore, observe closely and promptly evaluate any signs or symptoms of blood loss in these patients. There are no clinical data in patients with CrCl <15 mL/min (including patients on dialysis); therefore, avoid the use of rivaroxaban in these patients. Discontinue rivaroxaban in patients who develop acute renal failure while on treatment.

Use in Patients with Hepatic Impairment- No clinical data are available for patients with severe hepatic impairment. Avoid use of rivaroxaban in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy since drug exposure and bleeding risk may be increased.

Use with P-gp and Strong CYP3A Inhibitors or Inducers- Avoid concomitant use of rivaroxaban with known combined P-gp and strong CYP3A inhibitors. Avoid concomitant use of rivaroxaban with drugs that are known combined P-gp and strong CYP3A inducers.

Risk of Pregnancy-Related Hemorrhage- In pregnant women, rivaroxaban should be used only if the potential benefit justifies the potential risk to the mother and fetus. rivaroxaban dosing in pregnancy has not been studied. The anticoagulant effect of rivaroxaban cannot be monitored with standard laboratory testing. Promptly evaluate any signs or symptoms suggesting blood loss (e.g., a drop in hemoglobin and/or hematocrit, hypotension, or fetal distress).

Patients with Prosthetic Heart Valves- On the basis of the GALILEO study, use of rivaroxaban is not recommended in patients who have had transcatheter aortic valve replacement (TAVR) because patients randomized to rivaroxaban experienced higher rates of death and bleeding compared to those randomized to an anti-platelet regimen. The safety and efficacy of rivaroxaban have not been studied in patients with other prosthetic heart valves or other valve procedures. Use of rivaroxaban is not recommended in patients with prosthetic heart valves.

Acute PE in Hemodynamically Unstable Patients or Patients Who Require Thrombolysis or Pulmonary Embolectomy- Initiation of rivaroxaban is not recommended acutely as an alternative to unfractionated heparin in patients with pulmonary embolism who present with hemodynamic instability or who may receive thrombolysis or pulmonary embolectomy.

Increased Risk of Thrombosis in Patients with Triple Positive Antiphospholipid Syndrome- Direct-acting oral anticoagulants (DOACs), including rivaroxaban, are not recommended for use in patients with triple-positive antiphospholipid syndrome (APS). For patients with APS (especially those who are triple positive ), treatment with DOACs has been associated with increased rates of recurrent thrombotic events compared with vitamin K antagonist therapy.

Use in Specific Populations

Pregnancy

Risk Summary

The limited available data on rivaroxaban in pregnant women are insufficient to inform a drug-associated risk of adverse developmental outcomes. Use rivaroxaban with caution in pregnant patients because of the potential for pregnancy related hemorrhage and/or emergent delivery. The anticoagulant effect of rivaroxaban cannot be reliably monitored with standard laboratory testing. Consider the benefits and risks of rivaroxaban for the mother and possible risks to the fetus when prescribing rivaroxaban to a pregnant woman.

Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk

Pregnancy is a risk factor for venous thromboembolism and that risk is increased in women with inherited or acquired thrombophilias. Pregnant women with thromboembolic disease have an increased risk of maternal complications including pre-eclampsia. Maternal thromboembolic disease increases the risk for intrauterine growth restriction, placental abruption and early and late pregnancy loss.

Fetal/Neonatal adverse Reactions

Based on the pharmacologic activity of Factor Xa inhibitors and the potential to cross the placenta, bleeding may occur at any site in the fetus and/or neonate.

Labor or delivery

All patients receiving anticoagulants, including pregnant women, are at risk for bleeding and this risk may be increased during labor or delivery . The risk of bleeding should be balanced with the risk of thrombotic events when considering the use of rivaroxaban in this setting.

Data

Human Data

There are no adequate or well-controlled studies of rivaroxaban in pregnant women, and dosing for pregnant women has not been established. Post-marketing experience is currently insufficient to determine a rivaroxaban-associated risk for major birth defects or miscarriage. In an in vitro placenta perfusion model, unbound rivaroxaban was rapidly transferred across the human placenta.

Lactation

Risk Summary

Rivaroxaban has been detected in human milk. There are insufficient data to determine the effects of rivaroxaban on the breastfed child or on milk production. Rivaroxaban and/or its metabolites were present in the milk of rats. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for rivaroxaban and any potential adverse effects on the breastfed infant from rivaroxaban or from the underlying maternal condition.

Females and Males of Reproductive Potential: Females of reproductive potential requiring anticoagulation should discuss pregnancy planning with their physician

Pediatric Use- Safety and effectiveness in pediatric patients have not been established.

Geriatric Use- Of the total number of patients in the RECORD 1-3 clinical studies evaluating rivaroxaban, about 54% were 65 years and over, while about 15% were >75 years. In ROCKET AF, approximately 77% were 65 years and over and about 38% were >75 years. In the EINSTEIN DVT, PE and Extension clinical studies approximately 37% were 65 years and over and about 16% were >75 years. In EINSTEIN CHOICE, approximately 39% were 65 years and over and about 12% were >75 years. In the MAGELLAN study, approximately 67% were 65 years and over and about 37% were >75 years. In the COMPASS study, approximately 76% were 65 years and over and about 17% were >75 years. In clinical trials the efficacy of rivaroxaban in the elderly (65 years or older) was similar to that seen in patients younger than 65 years. Both thrombotic and bleeding event rates were higher in these older patients.

Renal Impairment: In pharmacokinetic studies, compared to healthy subjects with normal creatinine clearance, rivaroxaban exposure increased by approximately 44 to 64% in subjects with renal impairment. Increases in pharmacodynamic effects were also observed.

Undesirable Effects

The following clinically significant 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

Due to the pharmacological mode of action, the use of RIVAZEST may be associated with an increased risk of occult or overt bleeding from any tissue or organ which may result in post haemorrhagic anaemia. The signs, symptoms, and severity (including fatal outcome) will vary according to the location and degree or extent of the bleeding and/or anaemia. In the clinical studies mucosal bleedings (i.e. epistaxis, gingival, gastrointestinal, genito urinary including abnormal vaginal or increased menstrual bleeding) and anaemia were seen more frequently during long term rivaroxaban treatment compared with VKA treatment. Thus, in addition to adequate clinical surveillance, laboratory testing of haemoglobin/haematocrit could be of value to detect occult bleeding and quantify the clinical relevance of overt bleeding, as judged to be appropriate. The risk of bleedings may be increased in certain patient groups, e.g. those patients with uncontrolled severe arterial hypertension and/or on concomitant treatment affecting haemostasis. Menstrual bleeding may be intensified and/or prolonged. Haemorrhagic complications may present as weakness, paleness, dizziness, headache or unexplained swelling, dyspnoea and unexplained shock. In some cases as a consequence of anaemia, symptoms of cardiac ischaemia like chest pain or angina pectoris have been observed.

Known complications secondary to severe bleeding such as compartment syndrome and renal failure due to hypoperfusion have been reported for RIVAZEST. Therefore, the possibility of haemorrhage is to be considered in evaluating the condition in any anticoagulated patient.

If you experience any side-effects, talk to your doctor or pharmacist or write to drugsafety@cipla.com. You can also report side effects directly via the national pharmacovigilance program of India by calling on 1800 180 3024.

By reporting side-effects, you can help provide more information on the safety of this product.

Overdosage

Overdose of rivaroxaban may lead to hemorrhage. Discontinue rivaroxaban and initiate appropriate therapy if bleeding complications associated with overdosage occur. Rivaroxaban systemic exposure is not further increased at single doses >50 mg due to limited absorption. The use of activated charcoal to reduce absorption in case of rivaroxaban overdose may be considered. Due to the high plasma protein binding, rivaroxaban is not dialyzable . Partial reversal of laboratory anticoagulation parameters may be achieved with use of plasma products. An agent to reverse the anti-factor Xa activity of rivaroxaban is available.

Pharmacological Properties

Mechanism of Action

Rivaroxaban 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 2: 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. Rivaroxaban 2.5 mg and 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 rivaroxaban with food increases the bioavailability of the 20 mg dose (mean AUC and Cmax increasing by 39% and 76% respectively with food). Rivaroxaban 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 rivaroxaban (30 mg single dose) with the H2-receptor antagonist ranitidine (150 mg twice daily), the antacid aluminum hydroxide/magnesium hydroxide (10 mL) or rivaroxaban (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 2). Absorption of rivaroxaban is dependent on the site of drug release in the GI tract. Avoid administration of rivaroxaban distal to the stomach which can result in reduced absorption and related drug exposure.

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.

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.

Specific Populations

The effects of level of renal impairment, age, body weight, and level of hepatic impairment on the pharmacokinetics of rivaroxaban are summarized in Figure 1.

Figure 1: Effect of specific populations on the pharmacokinetics of rivaroxaban

Gender- Gender did not influence the pharmacokinetics or pharmacodynamics of rivaroxaban.

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.

Renal Impairment- The safety and pharmacokinetics of single-dose rivaroxaban (10 mg) were evaluated in a study in healthy subjects and in subjects with varying degrees of renal impairment (see Figure 1). 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 (post-dialysis) is 56% higher when compared to subjects with normal renal function (see Table 2). 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 rivaroxaban 15 mg.

Hepatic Impairment- The safety and pharmacokinetics of single-dose rivaroxaban (10 mg) were evaluated in a study in healthy subjects (n=16) and subjects with varying degrees of hepatic impairment (see Figure 1). 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 1). 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 2 .

Figure 2: Effect of Coadministered Drugs on the Pharmacokinetics Of Rivaroxaban

Anticoagulants

In a drug interaction study, single doses of enoxaparin (40 mg subcutaneous) and rivaroxaban (10 mg) given concomitantly resulted in an additive effect on anti-factor Xa activity. In another study, single doses of warfarin (15 mg) and rivaroxaban (5 mg) resulted in an additive effect on factor Xa inhibition and PT. Neither enoxaparin nor warfarin affected the pharmacokinetics of rivaroxaban (see Figure 2).

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 rivaroxaban. Neither naproxen nor aspirin affected the pharmacokinetics of rivaroxaban (see Figure 2).

Clopidogrel

In two drug interaction studies where clopidogrel (300 mg loading dose followed by 75 mg daily maintenance dose) and rivaroxaban (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, rivaroxaban 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 rivaroxaban 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.

Non-Clinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Rivaroxaban was not carcinogenic when administered by oral gavage to mice or rats for up to 2 years. The systemic exposures (AUCs) of unbound rivaroxaban in male and female mice at the highest dose tested (60 mg/kg/day) were 1-and 2-times, respectively, the human exposure of unbound drug at the human dose of 20 mg/day. Systemic exposures of unbound drug in male and female rats at the highest dose tested (60 mg/kg/day) were 2-and 4-times, respectively, the human exposure.

Rivaroxaban was not mutagenic in bacteria (Ames-Test) or clastogenic in V79 Chinese hamster lung cells in vitro or in the mouse micronucleus test in vivo.

No impairment of fertility was observed in male or female rats when given up to 200 mg/kg/day of rivaroxaban orally. This dose resulted in exposure levels, based on the unbound AUC, at least 13 times the exposure in humans given 20 mg rivaroxaban daily.

Description

Rivaroxaban, a factor Xa (FXa) inhibitor, is the active ingredient in RIVAZEST Tablets with the chemical name 5-Chloro-N-({(5S)-2-oxo-3-- 1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide. The molecular formula of rivaroxaban is C19H18ClN3O5S and the molecular weight is 435.89. The structural formula is:

Rivaroxaban is a pure (S )-enantiomer. It is an odorless, non-hygroscopic, white to yellowish powder. Rivaroxaban is only slightly soluble in organic solvents (e.g., acetone, polyethylene glycol 400) and is practically insoluble in water and aqueous media. Each RIVAZEST tablet contains 2.5 mg, 10 mg, 15 mg, or 20 mg of rivaroxaban. The inactive ingredients of RIVAZEST are: microcrystalline cellulose, lactose monohydrate, hypromellose, croscarmellose sodium, sodium lauryl sulfate, and magnesium stearate. Additionally, the proprietary film coating mixture used is macrogol, hypromellose titanium dioxide and red iron oxide.

Pharmaceutical Particulars

Shelf Life

 24 Months

Incompatibilities

Not applicable

Packaging Information

RIVAZEST  2.5……. Blister pack of 14 Tablets

RIVAZEST  10……. Blister pack of 14 Tablets

RIVAZEST  15……. Blister pack of 14 Tablets

RIVAZEST  20……. Blister pack of 14 Tablets

Storage and Handling Instructions

Store at 25°C (77°F) or room temperature; excursions permitted to 15°-30°C (59°-86°F). Keep out of the reach of children

Patient Counselling Information

Instructions for Patient Use

  • Advise patients to take RIVAZEST only as directed.
  • Remind patients to not discontinue RIVAZEST without first talking to their healthcare professional.
  • Advise patients with atrial fibrillation to take RIVAZEST once daily with the evening meal.
  • Advise patients for initial treatment of DVT and/or PE to take RIVAZEST 15 mg or 20 mg tablets with food at approximately the same time every day.
  • Advise patients who are at a continued risk of recurrent DVT and/or PE after at least 6 months of initial treatment, to take RIVAZEST 10 mg once daily with or without food.
  • Advise patients who cannot swallow the tablet whole to crush rivaroxaban tablets and combine with a small amount of applesauce followed by food.
  • For patients requiring an NG tube or gastric feeding tube, instruct the patient or caregiver to crush the rivaroxaban tablet and mix it with a small amount of water before administering via the tube.
  • If a dose is missed, advise the patient to take rivaroxaban as soon as possible on the same day and continue the following day with their recommended daily dose regimen.

Bleeding Risks

  • It is necessary to report any unusual bleeding or bruising to the physician. It might take them longer than usual to stop bleeding, and that they may bruise and/or bleed more easily when they are treated with rivaroxaban.
  • If patients have had neuraxial anesthesia or spinal puncture, and particularly, if they are taking concomitant NSAIDs or platelet inhibitors, advise patients to watch for signs and symptoms of spinal or epidural hematoma, such as back pain, tingling, numbness (especially in the lower limbs), muscle weakness, and stool or urine incontinence. If any of these symptoms occur, advise the patient to contact the physician immediately.

Like all medicines, rivaroxaban can cause side effects, although not everybody gets them.

Like other similar medicines (antithrombotic agents), rivaroxaban may cause bleeding which may potentially be life threatening. Excessive bleeding may lead to a sudden drop in blood pressure (shock). In some cases the bleeding may not be obvious.

Possible Side Effects which may be a Sign of Bleeding

Tell your doctor immediately if you experience any of the following side effects:

  • long or excessive bleeding
  • exceptional weakness, tiredness, paleness, dizziness, headache, unexplained swelling,
  • breathlessness, chest pain or angina pectoris, which may be signs of bleeding.

Your doctor may decide to keep you under closer observation or change how you should be treated.

Possible Side Effects which may be a Sign of Severe Skin Reaction

Tell your doctor immediately if you experience skin reactions such as:

  • spreading intense skin rash, blisters or mucosal lesions, e.g. in the mouth or eyes (Stevens Johnson syndrome/toxic epidermal necrolysis). The frequency of this side effect is very rare (up to 1 in 10,000).
  • a drug reaction that causes rash, fever, inflammation of internal organs, hematologic abnormalities and systemic illness (DRESS syndrome). The frequency of this side effect is very rare (up to 1 in 10,000).

Possible Side Effects which may be a Sign of Severe Allergic Reactions

Tell your doctor immediately if you experience any of the following side effects related to bleeding.

Invasive or Surgical Procedures

Instruct patients to inform their healthcare professional that they are taking rivaroxaban before any invasive procedure (including dental procedures) is scheduled.

Concomitant Medication and Herbals

Advise patients to inform their physicians and dentists if they are taking, or plan to take, any prescription or over-the-counter drugs or herbals, so their healthcare professionals can evaluate potential interactions.

Pregnancy and Pregnancy-Related Hemorrhage

  • Advise patients to inform their physician immediately if they become pregnant or intend to become pregnant during treatment with rivaroxaban
  • Advise pregnant women receiving rivaroxaban to immediately report to their physician any bleeding or symptoms of blood loss.

Lactation

Advise patients to discuss with their physician the benefits and risks of rivaroxaban for the mother and for the child if they are nursing or intend to nurse during anticoagulant treatment

Females and Males of Reproductive Potential

Advise patients who can become pregnant to discuss pregnancy planning with their physician.

Details of Manufacturer

Mfd. By CIPLA LTD.

Registered Office: Cipla House, Peninsula Business Park, Ganpatrao Kadam Marg, Lower Parel, Mumbai-400 013, India.

Date of Revision

31/10/2020