Xarelto 10mg

Xarelto 10mg

rivaroxaban

Nhà sản xuất:

Bayer AG

Nhà tiếp thị:

Bayer (South East Asia)
Thông tin kê toa chi tiết tiếng Anh
Contents
Rivaroxaban.
Description
Each tablet contains 10 mg rivaroxaban.
Excipients/Inactive Ingredients:
Cellulose microcrystalline, croscarmellose sodium, hypromellose 5 cP, lactose monohydrate, magnesium stearate, sodium lauryl sulfate. Film-Coating: Ferric oxide red, hypromellose 15 cP, macrogol 3350, titanium dioxide.
Action
Pharmacology: Pharmacodynamics: Mechanism of Action: Rivaroxaban is a highly selective direct factor Xa inhibitor with oral bioavailability.
Activation of Factor X to Factor Xa (FXa) via the intrinsic and extrinsic pathway plays a central role in the cascade of blood coagulation.
Pharmacodynamic Effects: Dose-dependent inhibition of Factor Xa activity was observed in humans. Prothrombin time (PT) is influenced by rivaroxaban in a dose dependent way with a close correlation to plasma concentrations (r value equals 0.98) if Neoplastin is used for the assay. Other reagents would provide different results. The readout for PT is to be done in seconds, because the INR (International Normalized Ratio) is only calibrated and validated for coumarins and cannot be used for any other anticoagulant. In patients undergoing major orthopedic surgery, the 5/95 percentiles for PT (Neoplastin) 2-4 hours after tablet intake (i.e. at the time of maximum effect) ranged from 13 to 25 sec.
The activated partial thromboplastin time (aPTT) and HepTest are also prolonged dosedependently; however, they are not recommended to assess the pharmacodynamic effect of rivaroxaban. Anti-Factor Xa activity is also influenced by rivaroxaban; however, no standard for calibration is available.
There is no need for monitoring of coagulation parameters during treatment with Xarelto.
Clinical Efficacy and Safety: Prevention of venous thromboembolic events (VTE) in patients undergoing major orthopedic surgery of the lower limbs.
The rivaroxaban clinical program was designed to demonstrate the efficacy of Xarelto for the prevention of venous thromboembolic events (VTE), i.e. proximal and distal deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients undergoing major orthopedic surgery of the lower limbs. Over 9,500 patients (7,050 in total hip replacement surgery - 2,531 in total knee replacement surgery) were studied in controlled randomized double-blind phase III clinical studies, the RECORD-program.
Xarelto 10mg once daily started not earlier than 6 hours postoperatively was compared with enoxaparin 40 mg once daily started 12 hours preoperatively.
In all three phase III studies (see Table 1) rivaroxaban significantly reduced the rate of total VTE (any venographically detected or symptomatic DVT, non-fatal PE or death) and major VTE (proximal DVT, non-fatal PE and VTE-related death), the pre-specified primary and major secondary efficacy endpoints. Furthermore in all three studies the rate of symptomatic VTE (symptomatic DVT, non-fatal PE, VTE-related death) was lower in Xarelto treated patients compared to patients treated with enoxaparin.
The main safety endpoint, major bleeding, showed comparable rates for patients treatedwith Xarelto 10mg compared to enoxaparin 40 mg.


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The analysis of the pooled results of the phase III trials corroborated the data obtained in the individual studies regarding reduction of total VTE, major VTE and symptomatic VTE with Xarelto 10mg once daily compared to enoxaparin 40 mg once daily.
Special Population: Ethnic Differences: See Pharmacokinetics as follows.
Elderly/Gender: See Pharmacokinetics as follows.
Different Weight Categories: See Pharmacokinetics as follows.
Hepatic Impairment: See Pharmacokinetics as follows.
Renal Impairment: See Pharmacokinetics as follows.
Pharmacokinetics: Absorption and Bioavailability: Xarelto is rapidly absorbed with maximum concentrations (Cmax) appearing 2-4 hours after tablet intake.
Oral absorption of rivaroxaban is almost complete and oral bioavailability is high (80-100%) for the 10 mg tablet dose, irrespective of fasting/fed conditions. Intake with food does not affect rivaroxaban AUC or Cmax at the 10 mg dose. Xarelto 10 mg tablets can be taken with or without food (see Dosage & Administration).
Variability in rivaroxaban pharmacokinetics is moderate with inter-individual variability (CV%) ranging from 30% to 40%.
Avoid administration of rivaroxaban distal to the stomach which can result in reduced absorption and related drug exposure.
Bioavailability (AUC and Cmax) was comparable for 20 mg rivaroxaban administered orally as a crushed tablet mixed in applesauce, or suspended in water and administered via a gastric tube followed by a liquid meal, compared to a whole tablet. Given, the predictable, dose-proportional pharmacokinetic profile of rivaroxaban, the bioavailability results from this study are likely applicable to lower rivaroxaban doses.
Distribution: Plasma protein binding in humans is high at approximately 92% to 95%, with serum albumin being the main binding component. The volume of distribution is moderate with Vss being approximately 50 L.
Metabolism and Elimination: Of the administered rivaroxaban dose, approximately 2/3 undergoes metabolic degradation, with half then eliminated renally and the other half eliminated by the fecal route. The other 1/3 of the administered dose undergoes direct renal excretion as unchanged active substance in the urine, mainly via active renal secretion.
Rivaroxaban is metabolized via CYP3A4, CYP2J2 and CYP-independent mechanisms.
Oxidative degradation of the morpholinone moiety and hydrolysis of the amide bonds are the major sites of biotransformation. Based on in vitro investigations rivaroxaban is a substrate of the transporter proteins P-gp (P-glycoprotein) and Bcrp (breast cancer resistance protein).
Unchanged rivaroxaban is the most important compound in human plasma with no major or active circulating metabolites being present. With a systemic clearance of about 10 l/hr rivaroxaban can be classified as low-clearance drug. Elimination of rivaroxaban from plasma occurred with terminal half-lives of 5 to 9 hours in young individuals, and with terminal half-lives of 11 to 13 hours in the elderly.
Geriatric Patients: Elderly patients exhibited higher plasma concentrations than younger patients with mean AUC values being approximately 1.5-fold higher, mainly due to reduced (apparent) total and renal clearance (see Dosage & Administration).
Gender: There were no clinically relevant differences in pharmacokinetics between male and female patients (see Dosage & Administration).
Body Weight: Extremes in body weight (<50 kg vs >120 kg) had only a small influence on rivaroxaban plasma concentrations (less than 25%) (see Dosage & Administration).
Children (From Birth to 16 or 18 Years Depending on Local Law): Safety and efficacy have not been established for children and adolescents below 18 years (see Dosage & Administration).
Ethnic Differences: No clinically relevant interethnic differences among Caucasian, African-American, Hispanic, Japanese or Chinese patients were observed regarding pharmacokinetics and pharmacodynamics (see Dosage & Administration).
Hepatic Impairment: The effect of hepatic impairment on rivaroxaban pharmacokinetics has been studied in subjects categorized according to the Child Pugh classification, a standard procedure in clinical development. The Child Pugh classification's original purpose is to assess the prognosis of chronic liver disease, mainly cirrhosis. In patients for whom anticoagulation is intended, the critical aspect of liver impairment is the reduced synthesis of normal coagulation factors in the liver. Since this aspect is captured by only one of the five clinical/biochemical measurements composing the Child Pugh classification system, the bleeding risk in patients may not clearly correlate with this classification scheme. The decision to treat patients with an anticoagulant should therefore be made independently of the Child Pugh classification.
Xarelto is contraindicated in patients with hepatic disease which is associated with coagulopathy leading to a clinically relevant bleeding risk.
Cirrhotic patients with mild hepatic impairment (classified as Child Pugh A) exhibited only minor changes in rivaroxaban pharmacokinetics (1.2-fold increase in rivaroxaban AUC on average), nearly comparable to their matched healthy control group. No relevant difference in pharmacodynamic properties was observed between these groups.
In cirrhotic patients with moderate hepatic impairment (classified as Child Pugh B), rivaroxaban mean AUC was significantly increased by 2.3-fold compared to healthy volunteers, due to significantly impaired drug clearance which indicates significant liver disease. Unbound AUC was increased 2.6 fold. There are no data in patients with severe hepatic impairment.
The inhibition of Factor Xa activity was increased by a factor of 2.6 as compared to healthy volunteers; prolongation of PT was similarly increased by a factor of 2.1. Patients with moderate hepatic impairment were more sensitive to rivaroxaban resulting in a steeper PK/PD relationship between concentration and PT.
No data are available for Child Pugh C patients (see Dosage & Administration and Contraindications).
Renal Impairment: There was an increase in rivaroxaban exposure being inversely correlated to the decrease in renal function, as assessed via creatinine clearance measurements.
In individuals with mild (CrCl ≤80-50 mL/min), moderate (CrCl <50-30 mL/min) or severe (CrCl <30-15 mL/min) renal impairment, rivaroxaban plasma concentrations (AUC) were 1.4, 1.5 and 1.6-fold increased respectively as compared to healthy volunteers (see Dosage & Administration and Precautions).
Corresponding increases in pharmacodynamic effects were more pronounced (see Dosage & Administration Precautions).
In individuals with mild, moderate or severe renal impairment the overall inhibition of factor Xa activity was increased by a factor of 1.5, 1.9 and 2.0 respectively as compared to healthy volunteers; prolongation of PT was similarly increased by a factor of 1.3, 2.2 and 2.4, respectively.
There are no data in patients with CrCl <15 mL/min.
Use is not recommended in patients with creatinine clearance <15 ml/min. Xarelto is to be used with caution in patients with severe renal impairment creatinine clearance 15-30 ml/min (see Dosage & Administration and Precautions).
Preclinical Safety Data: The non-clinical safety evaluation in the data from conventional and appropriate studies of safety pharmacology, single and repeat-dose toxicity, genotoxicity, phototoxicity, and carcinogenicity and toxicity to reproduction reveal no special hazard for humans.
No organ-specific toxicity of rivaroxaban was observed up to the highest doses tested (150 mg/kg in all non-rodent studies).
Indications/Uses
Xarelto is indicated for the prevention of venous thromboembolism (VTE) in adult patients undergoing elective hip or knee replacement surgery.
Dosage/Direction for Use
VTE Prevention in Major Orthopedic Surgery: Recommended Usual Dose: 10 mg tablet once daily.
Duration of Treatment: After major hip surgery patients should be treated for 5 weeks.
After major knee surgery patients should be treated for 2 weeks.
Method and Frequency of Administration: One 10 mg tablet of Xarelto should be taken once daily.
The initial dose should be taken within 6-10 hours after surgery provided that hemostasis has been established.
Missed Dose: If a dose is missed the patient should take the 10 mg Xarelto dose immediately and continue on the following day with the once daily intake as before.
Children (From Birth to 16 or 18 Years Depending on Local Law): Safety and efficacy have not been established in children and adolescents below 18 years.
Therefore, Xarelto is not recommended for use in children below 18 years of age.
Elderly: No dose adjustment is required based on age.
Gender: No dose adjustment is required based on gender.
Body Weight: No dose adjustment is required based on body weight.
Ethnic Differences: No dose adjustment is required based on ethnic differences.
Hepatic Impairment: Xarelto is contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic patients with Child Pugh B and C.
Renal Impairment: Limited clinical data for patients with severe renal impairment (creatinine clearance 15-29 ml/min) indicate that rivaroxaban plasma concentrations are significantly increased.
Therefore, Xarelto is to be used with caution in these patients. Use is not recommended in patients with creatinine clearance <15 ml/min.
No dose adjustment is necessary in patients with mild renal impairment (creatinine clearance 50-80 ml/min) or moderate renal impairment (creatinine clearance 30-49 ml/min).
Converting from Vitamin K Antagonists (VKA) to Xarelto: When converting patients from VKAs to Xarelto, INR values will be falsely elevated after the intake of Xarelto. The INR is not valid to measure the anticoagulant activity of Xarelto, and therefore should not be used (see Interactions).
Converting from Xarelto to Vitamin K Antagonists (VKA): There is a potential for inadequate anticoagulation during the transition from Xarelto to VKA.
Continuous adequate anticoagulation should be ensured during any transition to an alternate anticoagulant. It should be noted that Xarelto can contribute to an elevated INR.
In patients converting from Xarelto to VKA, VKA should be given concurrently until the INR is ≥2.0. For the first two days of the conversion period, standard VKA dosing should be used followed by VKA dosing guided by INR testing. While patients are on both Xarelto and VKA, the INR should not be tested earlier than 24 hours (after the previous dose but prior to the next dose of Xarelto). Once Xarelto is discontinued INR testing may be done reliably 24 hours after the last dose (see Interactions).
Converting from Parenteral Anti-Coagulants to Xarelto: For patients currently receiving a parenteral anticoagulant, start Xarelto 0 to 2 hours before the time of the next scheduled administration of the parenteral drug (e.g. LMWH) or at the time of discontinuation of a continuously administered parenteral drug (e.g. intravenous unfractionated heparin).
Converting from Xarelto to Parenteral Anti-Coagulants: Discontinue Xarelto and give the first dose of parenteral anticoagulant at the time that the next Xarelto dose would be taken.
Administration: Oral use.
Xarelto 10 mg may be taken with or without food.
For patients who are unable to swallow whole tablets, Xarelto tablet may be crushed and mixed with water or soft foods such as applesauce immediately prior to use and administered orally. The crushed Xarelto tablet may be given through gastric tubes. Gastric placement of the tube should be confirmed before administering Xarelto. The crushed tablet should be administered in a small amount of water via a gastric tube after which it should be flushed with water (see Pharmacology: Pharmacokinetics under Actions).
Overdosage
Rare cases of overdose up to 600 mg have been reported without bleeding complications or other adverse reactions. Due to limited absorption a ceiling effect with no further increase in average plasma exposure is expected at supratherapeutic doses of 50 mg or above.
A specific antidote antagonizing the pharmacodynamic effect of rivaroxaban is not available.
The use of activated charcoal to reduce absorption in case of Xarelto overdose may be considered. Due to the high plasma protein binding rivaroxaban is not expected to be dialyzable.
Management of Bleeding: Should a bleeding complication arise in a patient receiving rivaroxaban, the next administration should be delayed or treatment should be discontinued as appropriate.
Rivaroxaban has a half-life of approximately 5 to 13 hours. Management should be individualized according to the severity and location of the hemorrhage. Appropriate symptomatic treatment could be used as needed, such as mechanical compression (e.g., for severe epistaxis), surgical hemostasis with bleeding control procedures, fluid replacement and hemodynamic support, blood products (packed red cells or fresh frozen plasma, depending on associated anemia or coagulopathy) or platelets.
If bleeding cannot be controlled by the above measures, administration of a specific procoagulant reversal agent should be considered, such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (APCC), or recombinant factor VIIa (r-FVIIa). However, there is currently very limited clinical experience with the use of these products in individuals receiving Xarelto (see Pharmacology: Pharmacodynamics under Actions).
Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban.
There is limited experience with tranexamic acid and no experience with aminocaproic acid and aprotinin in individuals receiving Xarelto. There is neither scientific rationale for benefit nor experience with the systemic hemostatics desmopressin in individuals receiving Xarelto.
Contraindications
Xarelto is contraindicated in patients with hypersensitivity to rivaroxaban or any excipient of the tablet (see Descriptions).
Xarelto is contraindicated in patients with clinically significant active bleeding (e.g., intracranial bleeding, gastrointestinal bleeding).
Xarelto is contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic patients with Child Pugh B and C. Xarelto is contraindicated in patients with lesion or condition, if considered to be a signigicant risk for major bleeding. This may include current or recent gastrointestinal ulceration, presence of malignant neoplasms at high risk of bleeding, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial haemorrhage, know or suspected oesophageal varices, arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities.
Xarelto is contraindicated in patients concomitantly treated with any other anticoagulants e.g. unfractionated heparin (UFH), low molecular weight heparins (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, etc.) oral anticoagulants (warfarin, dabigatran etexalate, apixaban, etc.) except under specific circumstances of switching anticoagulant therapy (see Dosage & Administration) or when UFH is given at doses necessary to maintain an open central venous or arterial catheter.
Safety and efficacy of Xarelto have not been established in pregnant women. Animal data show that Xarelto crosses the placental barrier. Therefore, use of Xarelto is contraindicated throughout pregnancy(see Pharmacology Toxicology: Preclinical Safety Data under Actions and Use in Pregnancy & Lactation).
Safety and efficacy of Xarelto have not been established in nursing mothers. Animal data indicate that Xarelto is secreted into breast milk. Therefore, Xarelto may only be administered after breastfeeding is discontinued (see Pharmacology Toxicology: Preclinical Safety Data under Actions and Use in Pregnancy & Lactation).
Special Precautions
Concomitant Medication: Xarelto is not recommended in patients receiving concomitant systemic treatment with azole-antimycotics (e.g. ketoconazole) or HIV protease inhibitors (e.g. ritonavir). These drugs are strong inhibitors of both CYP 3A4 and P-gp. Therefore, these drugs may increase Xarelto plasma concentrations to a clinically relevant degree (2.6 fold on average) which may lead to an increased bleeding risk. (see Interactions).
The Azole anti-mycotic fluconazole, a moderate Cyp3A4 inhibitor, has however less effect on Xarelto exposure and can be co-administered (see Interactions).
Renal Impairment: Xarelto is to be used with caution in patients with moderate renal impairment (creatinine clearance <50-30 mL/min) receiving co-medications leading to increased Xarelto plasma concentrations (see Interactions).
In patients with severe renal impairment Xarelto plasma levels may be significantly elevated (1.6-fold on average) which may lead to an increased bleeding risk.
Due to limited clinical data Xarelto should be used with caution in patients with CrCl <30-15 mL/min (see Pharmacology: Pharmacokinetics under Actions).
No clinical data are available for patients with severe renal impairment (CrCl <15 mL/min).
Therefore, use of Xarelto is not recommended in these patients. (see Pharmacology: Pharmacokinetics under Actions and Dosage & Administration).
Patients with severe renal impairment or increased bleeding risk and patients receiving concomitant systemic treatment with azole-antimycotics or HIV protease inhibitors are to be carefully monitored for signs of bleeding complications after initiation of treatment (see Interactions).
This may be done by regular physical examination of the patients, close observation of the surgical wound drainage and periodic measurements of hemoglobin.
Hip Fracture Surgery: Xarelto has not been studied in interventional clinical trials in patients undergoing hip fracture surgery. Therefore, rivaroxaban is not recommended for use in these patients.
Bleeding Risk: Xarelto like other antithrombotics should be used with caution in patients with an increased bleeding risk such as: Congenital or acquired bleeding disorders uncontrolled severe arterial hypertension; active ulcerative gastrointestinal disease; vascular retinopathy; bronchiectasis or history of pulmonary bleeding.
Care should be taken if patients are treated concomitantly with drugs affecting hemostasis such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet aggregation inhibitors, or other antithrombotics.
For patients at risk of ulcerative gastrointestinal disease, an appropriate prophylactic treatment may be considered (see Interactions).
Any unexplained fall in hemoglobin or blood pressure should lead to a search for a bleeding site.
Neuraxial (Epidural/Spinal) Anesthesia: When neuraxial (epidural/spinal) anesthesia or spinal puncture is performed, patients treated with antithrombotics for prevention of thromboembolic complications are at risk for development of an epidural or spinal hematoma which may result in long-term paralysis.
The risk of these events is even further increased by use of indwelling epidural catheters or the concomitant use of drugs affecting hemostasis. The risk may also be increased by traumatic or repeated epidural or spinal puncture.
Patients should be frequently monitored for signs and symptoms of neurological impairment (e.g., numbness or weakness of the legs, bowel or bladder dysfunction). If neurological deficits are noted, urgent diagnosis and treatment is necessary.
The physician should consider the potential benefit versus the risk before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis.
An epidural catheter should not be withdrawn earlier than 18 hours after the last administration of Xarelto.
Xarelto should be administered at earliest 6 hours after the removal of the catheter.
If traumatic puncture occurs the administration of Xarelto should be delayed for 24 hours.
Dosing recommendations before and after invasive procedures and surgical intervention other than elective hip or knee replacement surgery.
If an invasive procedure or surgical intervention is required, Xarelto should be stopped at least 24 hours before the intervention, if possible and based on the clinical judgement of the physician.
If the procedure cannot be delayed the increased risk of bleeding should be assessed against the urgency of the intervention.
Xarelto should be restarted after the invasive procedure or surgical intervention as soon as possible provided the clinical situation allows and adequate haemostasis has been established as determined by the treating physician.
Effect on Ability to Drive or Use Machines: Syncope and dizziness have been reported and may affect the ability to drive and use machines (see Adverse Reactions). Patients experiencing these adverse reactions should not drive or use machines.
Use in the Elderly: Increasing age may increase haemorrhagic risk.
Use In Pregnancy & Lactation
Use in Pregnancy: Safety and efficacy of Xarelto have not been established in pregnant women.
In rats and rabbits, rivaroxaban showed pronounced maternal toxicity with placental changes related to its pharmacological mode of action (e.g., hemorrhagic complications) leading to reproductive toxicity. No primary teratogenic potential was identified. Due to the intrinsic risk of bleeding and the evidence that Xarelto passes the placenta, Xarelto is contraindicated in pregnancy (see Contraindications and Pharmacology: Toxicology: Preclinical Safety Data under Actions).
Women of Childbearing Potential:
Rivaroxaban should be used in women of childbearing potential only with effective contraception.
Use in Lactation: Safety and efficacy of Xarelto have not been established in nursing mothers. In rats rivaroxaban is secreted into breast milk.
Therefore, Xarelto may only be administered after breastfeeding is discontinued (see Pharmacology: Toxicology: Preclinical Safety Data under Actions and Contraindications).
Adverse Reactions
Summary of the Safety Profile: The safety of Xarelto has been evaluated in four phase III studies including 6,097 patients exposed to 10 mg Xarelto undergoing major orthopedic surgery of the lower limbs (total hip replacement or total knee replacement) in 3,997 hospitalized medically ill patients treated up to 39 days, and in three phase III VTE treatment trials with 4,556 patients exposed either to 15 mg Xarelto twice daily for 3 weeks followed by 20 mg once daily or to 20 mg once daily treated up to 21 months.
Furthermore, safety of Xarelto has been also evaluated in 7,750 patients with non-valvular atrial fibrillation from two phase III trials with at least one dose of Xarelto as well as in 10,225 ACS patients with at least one dose of either 2.5 mg (twice daily) or 5 mg (twice daily) of Xarelto on top of either ASA or ASA plus clopidogrel or ticlopidine.
Due to the pharmacological mode of action, Xarelto may be associated with an increased risk of occult or overt bleeding from any tissue and organ which may result in post hemorrhagic anemia. The risk of bleedings may be increased in certain patient groups e.g. patients with uncontrolled severe arterial hypertension and/or on concomitant medication affecting haemostasis (see Precautions).
The signs, symptoms, and severity (including fatal outcome) will vary according to the location and degree or extent of the bleeding and/or anemia (see Overdosage).
Hemorrhagic complications may present as weakness, paleness, dizziness, headache or unexplained swelling, dyspnea, and unexplained shock. In some cases as a consequence of anemia, symptoms of cardiac ischemia 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 Xarelto. Therefore, the possibility of a hemorrhage should be considered in evaluating the condition in any anticoagulated patient.
Tabulated List of Adverse Reactions: The frequencies of ADRs reported with Xarelto are summarized in the table below. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are defined as: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000). (See Table 2.)


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Post-Marketing Observations: The following adverse reactions have been reported post-marketing in temporal association with the use of Xarelto: Immune System Disorders: Angioedema and allergic oedema.
Hepatobiliary Disorders: Cholestasis, hepatitis (including hepatocellular injury).
Blood and Lymphatic System Disorders: Thrombocytopenia.
Inform the physician about undesirable effects when using drug.
Drug Interactions
Pharmacokinetic Interactions: Xarelto is cleared mainly via cytochrome P450-mediated (CYP 3A4, CYP 2J2) hepatic metabolism and renal excretion of the unchanged drug, involving the P-glycoprotein (P-gp)/breast cancer resistance protein (Bcrp) transporter systems.
CYP Inhibition: Xarelto does not inhibit CYP 3A4 or any other major CYP isoforms.
CYP Induction: Rivaroxaban does not induce CYP 3A4 or any other major CYP isoforms.
Effects on Rivaroxaban: The concomitant use of Xarelto with strong CYP 3A4 and P-gp inhibitors, may lead to both reduced hepatic and renal clearance and thus significantly increased systemic exposure.
Co-administration of Xarelto with the azole-antimycotic ketoconazole (400 mg once daily) a strong CYP 3A4 and P-gp inhibitor, led to a 2.6-fold increase in mean Xarelto steady state
AUC and a 1.7-fold increase in mean rivaroxaban Cmax, with significant increases in its pharmacodynamic effects.
Co-administration of Xarelto with the HIV protease inhibitor ritonavir (600 mg twice daily), a strong CYP 3A4 and P-gp inhibitor, led to a 2.5-fold increase in mean Xarelto AUC and a 1.6-fold increase in mean rivaroxaban Cmax, with significant increases in its pharmacodynamic effects.
Therefore, Xarelto is not recommended in patients receiving concomitant systemic treatment with azole-antimycotics or HIV-protease inhibitors (see Precautions).
Other active substances strongly inhibiting only one of the rivaroxaban elimination pathways, either CYP 3A4 or P-gp, are expected to increase rivaroxaban plasma concentrations to a lesser extent.
Clarithromycin (500 mg twice daily), considered as strong CYP 3A4 inhibitor and moderate P-gp inhibitor, led to a 1.5 fold increase in mean rivaroxaban AUC and a 1.4 fold increase in Cmax. This increase, which is close to the magnitude of the normal variability of AUC and Cmax, is considered as clinically not relevant. Erythromycin (500 mg three times daily), which inhibits CYP 3A4 and P-gp moderately, led to a 1.3-fold increase in mean rivaroxaban AUC and Cmax. This increase is within the magnitude of the normal variability of AUC and Cmax and is considered as clinically not relevant.
In subjects with mild renal impairment, erythromycin (500 mg three times a day) led to a 1.8-fold increase in mean rivaroxaban AUC and 1.6-fold increase in Cmax when compared to subjects with normal renal function without co-medication. In subjects with moderate renal impairment, erythromycin led to a 2.0-fold increase in mean revaroxaban AUC and 1.6-fold increase in Cmax when compared to subjects with normal renal function without comedication (see Precautions).
Fluconazole (400 mg once daily), considered as moderate CYP 3A4 inhibitor, led to a 1.4-fold increase in mean rivaroxaban AUC and a 1.3-fold increase in mean Cmax. This increase is within the magnitude of the normal variability of AUC and Cmax and is considered as clinically not relevant (see Precautions).
CYP 3A4 and P-gp Inducer: Co-administration of Xarelto with the strong CYP 3A4 and P-gp inducer rifampicin led to an approximate 50% decrease in mean Xarelto AUC, with parallel decreases in its pharmacodynamic effects.
The concomitant use of Xarelto with other strong CYP 3A4 inducers (e.g., phenytoin, carbamazepine, phenobarbitone or St. John's Wort) may also lead to a decreased rivaroxaban plasma concentration.
The decrease in Xarelto plasma concentrations is considered as clinically not relevant for patients treated with 10 mg Xarelto once daily for prevention of VTE after elective hip or knee replacement surgery.
Pharmacodynamic Interactions: Anticoagulants: After combined administration of enoxaparin (40 mg single dose) with Xarelto (10 mg single dose), an additive effect on anti factor Xa activity was observed without any additional effects on clotting tests (PT, aPTT). Enoxaparin did not affect the pharmacokinetics of rivaroxaban (see Precautions).
Nonsteroidal Anti-inflammatory Drugs (NSAIDs)/Platelet Aggregation Inhibitors: No clinically relevant prolongation of bleeding time was observed after concomitant administration of rivaroxaban (15 mg) and 500 mg naproxen. Nevertheless, there may be individuals with a more pronounced pharmacodynamic response.
No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when rivaroxaban was co-administered with 500 mg acetylsalicylic acid.
Clopidogrel (300 mg loading dose followed by 75 mg maintenance dose) did not show a pharmacokinetic interaction (with Xarelto 15 mg) but a relevant increase in bleeding times was observed in a subset of patients which was not correlated to platelet aggregation, P-selectin or GPIIb / IIIa receptor levels (see Precautions).
Care is to be taken if patients are treated concomitantly with NSAIDs (including acetylsalicylic acid) and platelet aggregation inhibitors because these medicinal products typically increase the bleeding risk.
Warfarin: Converting patients from warfarin (INR 2.0 to 3.0) to Xarelto (20 mg) or from Xarelto (20 mg) to warfarin (INR 2.0 to 3.0) increased prothrombin time/INR (Neoplastin) more than additively (individual INR values up to 12 may be observed), whereas effects on aPTT, inhibition of factor Xa activity and endogenous thrombin potential were additive.
If it is desired to test the pharmacodynamic effects of Xarelto during the conversion period, anti-Factor Xa activity, PiCT, and HepTest can be used as these tests were not affected by warfarin. From day 4 after stopping warfarin onwards, all tests (including PT, aPTT, inhibition of Factor Xa activity and ETP) reflected only the effect of Xarelto (see Dosage & Administration).
If it is desired to test the pharmacodynamic effects of warfarin during the conversion period, INR measurement can be used at the Ctrough of rivaroxaban (24 hours after the previous intake of rivaroxaban) as this test is minimally affected by rivaroxaban at this time point.
No pharmacokinetic interaction was observed between warfarin and Xarelto.
Food and Dairy Products: 10 mg Xarelto can be taken with or without food (see Pharmacology: Pharmacokinetics under Actions).
Interactions with Laboratory Parameters: Clotting parameter tests (PT, aPTT, Hep Test) are affected as expected by the mode of action of Xarelto.
Storage
Store below 30°C.
Shelf-Life: 36 months.
ATC Classification
B01AF01 - rivaroxaban ; Belongs to the class of direct factor Xa inhibitors. Used in the treatment of thrombosis.
Presentation/Packing
Tab 10 mg x 10 x 1's.
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