Xarelto, 15 mg 28 pcs

Xarelto is a direct-acting anticoagulant. Rivaroxaban is a highly selective direct factor Xa inhibitor with high bioavailability when taken orally. Activation of factor X with the formation of factor Xa through the internal and external clotting pathways plays a central role in the coagulation cascade.

Indications

Active ingredient

Composition

1 tablet contains rivaroxaban micronized 15 mg.

Additional Ingredients:

microcrystalline cellulose – 37.5 mg,

croscarmellose sodium – 3 mg,

hypromellose 5cP – 3 mg,

lactose monohydrate – 25.4 mg,

magnesium stearate – 600 µg,

sodium lauryl sulfate – 500 µg.

Shell composition:

Red iron oxide dye – 150 µg,

Hypromellose 15cP – 1.5 mg,

Macrogol 3350 – 500 µg,

Titanium dioxide – 350 µg.

How to take, the dosage

The drug is taken orally with meals.

If the patient is unable to swallow the tablet whole, the Xarelto® tablet may be crushed and mixed with water or a liquid food such as apple puree immediately before ingestion. After taking the crushed Xarelto® 15 mg or 20 mg tablet, a meal should be taken immediately.

The crushed Xarelto® tablet can be administered via a gastric tube. The position of the tube in the gastrointestinal tract should be further coordinated with the physician before taking Xarelto®. The crushed tablet should be inserted through the gastric tube in a small amount of water, after which a small amount of water should be introduced to wash out the drug residues from the walls of the tube. After taking crushed Xarelto® 15 mg or 20 mg tablets, enteral feeding should be started immediately.

Prevention of stroke and systemic thromboembolism in patients with non-valvular atrial fibrillation

The recommended dose is 20 mg once daily.

For patients with impaired renal function (CKR 49-30 ml/min), the recommended dose is 15 mg once daily. The recommended maximum daily dose is 20 mg. Xarelto® therapy should be considered a long-term treatment as long as the benefit of treatment exceeds the risk of possible complications.

Activities for missed doses

If the next dose is missed, the patient should take Xarelto® immediately and continue regular administration the next day according to the recommended regimen.

The dose taken should not be doubled to make up for a previously missed dose.

Treatment of DVT and TELA and prevention of recurrent DVT and TELA

The recommended starting dose in the treatment of acute DVT or TELA is 15 mg 2 times daily for the first 3 weeks followed by transition to a dose of 20 mg once daily for further treatment and prevention of recurrent DVT and TELA.

The maximum daily dose is 30 mg for the first 3 weeks of treatment and 20 mg for further treatment.

The duration of treatment is determined on an individual basis after careful weighing of the ratio of the benefits of treatment to the risk of bleeding. The minimum duration of treatment (at least 3 months) should be based on an assessment regarding reversible risk factors (i.e., previous surgery, trauma, period of immobilization). The decision to extend treatment for a longer period of time is based on an assessment concerning permanent risk factors, or in the case of idiopathic DVT or TELA.

Activities for missed doses

It is important to adhere to the established dosing regimen.

If the next dose is missed on the 15 mg twice-daily dosing regimen, the patient should take Xarelto® immediately to reach the daily dose of 30 mg. Thus, two 15 mg tablets can be taken in one sitting. The next day, the patient should continue the regular intake of the drug according to the recommended regimen.

If the next dose is missed at 20 mg once daily, the patient should take Xarelto® immediately and continue regular administration the next day according to the recommended regimen.

Separate patient groups

There is no need for dose adjustments based on patient age (>65 years), gender, body weight, or ethnicity.

Xarelto® is contraindicated in patients with liver disease accompanied by coagulopathy, which causes a clinically significant risk of bleeding. Patients with other liver diseases do not require dose changes. The limited clinical data available in patients with moderate hepatic impairment (class B according to Child-Pugh classification) indicate a significant increase in pharmacological activity of the drug. No clinical data are available for patients with severe hepatic impairment (Child-Pugh class C).

When prescribing Xarelto® in patients with renal impairment (CK of 80-50 ml/min) no dose adjustment is required.

In prophylaxis of stroke and systemic thromboembolism in patients with atrial fibrillation of non-valvular origin with renal insufficiency (KC 49-30 ml/min), the recommended dose is 15 mg once daily.

When treating DVT and TELA and preventing recurrence of DVT and TELA in patients with renal insufficiency (KKR 49-30 ml/min) no dose adjustment is required.

Limited clinical data available in patients with renal impairment (KC 29-15 mL/min) demonstrate a significant increase in rivaroxaban concentrations in these patients. Xarelto® should be used with caution to treat this category of patients.

The use of Xarelto® in patients with CK< 15 ml/min is not recommended.

Transfer patients from vitamin K antagonists (VKAs) to Xarelto®

In the prevention of stroke and systemic thromboembolism, discontinue VKA treatment and initiate Xarelto® treatment at MHO≤3.

In case of DVT and TELA, discontinue AVC treatment and start Xarelto® treatment at MHO≤2.5.

When patients switch from AVC to Xarelto®, MHO values will be erroneously elevated after taking Xarelto®. The MHO value is not suitable for determining the anticoagulant activity of Xarelto® and therefore should not be used for this purpose.

Transition from Xarelto® to vitamin K antagonists (VKAs)

There is a possibility of insufficient anticoagulant effect when switching from Xarelto® to VKAs. Therefore, it is necessary to ensure continuous sufficient anticoagulant effect during such transition with alternative anticoagulants. It should be noted that Xarelto® may contribute to increased MHO. Patients transitioning from Xarelto® to AVC should take AVC concomitantly until MHO reaches ≥2. During the first two days of the transition period, the standard dose of AVC should be used, followed by the dose of AVC determined according to the MHO value. Thus, during concomitant use of Xarelto® and AVC, MHO should be determined no earlier than 24 h after the previous dose, but before the next dose of Xarelto®. After discontinuation of Xarelto®, the MHO value can be reliably determined 24 hours after the last dose.

Transition from parenteral anticoagulants to Xarelto®

. In patients receiving parenteral anticoagulants, the use of Xarelto® should be started 0-2 h before the time of the next scheduled parenteral administration of the drug (e.g., low molecular weight heparin) or at the time of discontinuation of continuous parenteral administration of the drug (e.g., intravenous infusion of unfractionated heparin).

Transition from Xarelto® to parenteral anticoagulants

The first dose of Xarelto® should be stopped and the first dose of parenteral anticoagulant administered at the time the next dose of Xarelto® should be taken.

Cardioversion in the prevention of stroke and systemic thromboembolism

The treatment with Xarelto® may be initiated or continued in patients who may require cardioversion. In transesophageal echocardiography-controlled cardioversion (TECCG) in patients who have not previously received anticoagulant therapy, treatment with Xarelto® should be initiated at least 4 hours before cardioversion to ensure adequate anticoagulation.

Interaction

Pharmacokinetic interaction

Elimination of rivaroxaban is primarily through metabolism in the liver mediated by the cytochrome P450 system (CYP3A4, CYP2J2) and through renal excretion of the unchanged drug by the P-gp/Bcrp (P-glycoprotein/milk cancer resistance protein) transporter systems.

Rivaroxaban does not inhibit or induce the CYP3A4 isoenzyme or other important cytochrome isoforms.

The concomitant use of rivaroxaban and strong CYP3A4 and P-glycoprotein isoenzyme inhibitors may lead to decreased renal and hepatic clearance and thus significantly increase systemic exposure.

The co-administration of rivaroxaban and the azole antifungal agent ketoconazole (400 mg once daily), which is a strong CYP3A4 and P-glycoprotein inhibitor, resulted in a 2.6-fold and increased the mean Cmax of rivaroxaban by 1.7-fold, which was accompanied by a significant increase in the pharmacodynamic action of the drug.

The co-administration of Xarelto® and the HIV protease inhibitor ritonavir (600 mg 2 times/day), a potent CYP3A4 and P-glycoprotein inhibitor, resulted in a 2.5-fold and increased the mean Cmax of rivaroxaban by 1.6-fold, which was accompanied by a significant increase in the pharmacodynamic action of the drug. Therefore, Xarelto® is not recommended for use in patients receiving systemic treatment with azole antifungals or HIV protease inhibitors.

Clarithromycin (500 mg 2 times daily), a potent CYP3A4 isoenzyme inhibitor and moderate P-glycoprotein inhibitor, caused 1.5-fold increase in AUC values and 1.4-fold increase in Cmax of rivaroxaban. This increase is of the order of the normal variability of AUC and Cmax and is considered clinically insignificant.

Eritromycin (500 mg 3 times daily), a moderate inhibitor of the CYP3A4 isoenzyme and P-glycoprotein, caused a 1.3-fold increase in the AUC and Cmax values of rivaroxaban. This increase is of the order of the normal variability of AUC and Cmax and is considered clinically insignificant.

Fluconazole (400 mg once daily), a moderate CYP3A4 isoenzyme inhibitor, caused a 1.4-fold increase in mean AUC of rivaroxaban and a 1.3-fold increase in mean Cmax. This increase is of the order of the normal variability of AUC and Cmax is considered clinically insignificant.

The concomitant use of rivaroxaban with dronedarone should be avoided due to limited clinical data on co-administration.

The co-administration of Xarelto® and rifampicin, which is a strong inducer of CYP3A4 and P-glycoprotein, resulted in a reduction of the mean AUC of rivaroxaban by approximately 50% and a concomitant reduction of its pharmacodynamic effects.

The co-administration of rivaroxaban with other strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, phenobarbital or preparations of St. John’s wort) may also lead to decreased plasma concentrations of rivaroxaban. Decreased plasma concentrations of rivaroxaban have been found to be clinically insignificant.

Powerful CYP3A4 inducers should be used with caution.

Special Instructions

The use of rivaroxaban has not been studied in clinical trials in surgical interventions undertaken for hip fractures.

If there is an unexplained decrease in hemoglobin or BP, look for the source of bleeding.

There has been no observed prolongation of the QT interval during treatment with rivaroxaban.

When performing spinal tap and epidural/spinal anesthesia for patients receiving platelet aggregation inhibitors to prevent thromboembolic complications, there is a risk of epidural or spinal hematoma, which may lead to prolonged paralysis. The risk of these events is further increased by the use of permanent catheters or the concomitant use of medications that affect hemostasis. Trauma from an epidural or spinal tap or repeated puncture may also contribute to the risk.

Patients should be monitored for signs or symptoms of neurologic disorders (e.g., numbness or weakness in the legs, bowel or bladder dysfunction). If neurological disorders are detected, immediate diagnosis and treatment is necessary. The physician should weigh the potential benefit against the risk before performing a spinal intervention in patients receiving anticoagulants or preparing to receive anticoagulants for thrombosis prevention. The epidural catheter should not be removed before 18 h after the last dose of rivaroxaban. Rivaroxaban should not be administered earlier than 6 h after removal of the epidural catheter. In case of traumatic puncture the administration of rivaroxaban should be postponed for 24 h.

Safety data from preclinical studies

With the exception of effects associated with enhanced pharmacologic action (bleeding), no specific hazards to humans were found in preclinical data analysis from pharmacologic safety studies.

Impact on driving and operating machinery

There have been no studies of the effect of rivaroxaban on driving and operating potentially dangerous moving machinery.

In the postoperative period, fainting and dizziness have been infrequently reported. Patients who experience these adverse reactions should not drive motor vehicles or operate moving machinery.

Contraindications

The use of rivaroxaban has not been studied in clinical trials in surgical interventions in patients with femoral fractures. Therefore, the use of rivaroxaban is not recommended for this category of patients.

There are no clinical data on the use of rivaroxaban in patients with severe renal impairment (CK < 15 ml/min). Therefore, the use of rivaroxaban is not recommended for this category of patients.

Hereditary lactose or galactose intolerance (e.g., caused by lactase deficiency or glucose-galactose malabsorption) because this drug contains lactose.

Side effects

The safety of rivaroxaban at a dose of 10 mg was evaluated in four phase III studies involving 6,097 patients undergoing major orthopedic lower extremity surgery (total knee or hip replacement) who received treatment for up to 39 days.

The adverse reactions are classified by frequency of occurrence and organ systems, and should be interpreted with the surgical situation in mind.

Per the mechanism of action, use of rivaroxaban may be accompanied by an increased risk of occult or overt bleeding from any organs and tissues, which may lead to post-hemorrhagic anemia. Signs, symptoms and severity (including possible death) vary depending on the location, severity or duration of bleeding and/or anemia. The risk of bleeding may increase in patients with uncontrolled arterial hypertension and/or when co-administered with drugs that affect hemostasis. Hemorrhagic complications may be manifested by weakness, pallor, dizziness, headache, shortness of breath, and limb enlargement or shock unexplained by other causes. In some cases, symptoms of myocardial ischemia, such as chest pain and angina, may develop due to anemia. Therefore, the possibility of hemorrhage should be considered when evaluating a patient receiving anticoagulants.

The frequency of adverse reactions reported for Xarelto® is summarized in the table below. In the frequency groups, the adverse effects are presented in decreasing order of severity. Frequent (≥ 1/100 and < 1/10), infrequent (≥ 1/1000 and < 1/100) and rare adverse reactions (≥ 1/10,000 and < 1/1000) were distinguished according to the frequency of occurrence. Adverse reactions that have been identified only in post-marketing observational studies or for which frequency estimates could not be made are designated as “frequency unknown”.

Listed below are all adverse reactions that occurred during treatment in patients participating in phase III clinical trials.

Hematopoietic system disorders: infrequent – anemia (including relevant laboratory parameters), thrombocythemia (including increased platelet count).

Cardiovascular system disorders: infrequent – tachycardia, hypotension (including decreased BP, hypotension during procedures), hematoma (including rare cases of muscle hemorrhage), GI bleeding (including bleeding from the gums, rectum, bloody vomiting), urinary tract hemorrhage, nasal bleeding.

Digestive system disorders: frequent – nausea, increased levels of GGT, transaminases (including ALT, ACT); infrequent – constipation, diarrhea, abdominal pain (including upper abdominal pain, feeling of stomach discomfort), dyspepsia (including epigastric discomfort), dry mouth, vomiting, increased lipase activity, amylase, increased bilirubin concentration, increased LDH activity, ALP; rarely – liver function disorders, increased concentration of conjugated bilirubin (with or without concomitant increase in ALT activity).

CNS disorders: infrequent dizziness, headache; rarely – short-term loss of consciousness (including syncopal conditions).

Urinary system disorders: infrequent – renal failure (including increased concentration of creatinine, increased concentration of urea).

Skin disorders: infrequent itching (including rare cases of generalized itching), rash, post-traumatic hematoma; rare urticaria (including rare cases of generalized urticaria), allergic dermatitis.

Muscular system disorders: infrequent – pain in the extremities.

The body in general: often – fever, peripheral edema; infrequent – local edema, worsening of general well-being (including weakness, asthenia); rarely – feeling unwell (including discomfort).

Others: often – bleeding after procedures (including postoperative anemia and bleeding from the wound); infrequent – discharge from the wound.

In other clinical trials of rivaroxaban, isolated cases of adrenal and conjunctival hemorrhage and fatal bleeding from a GI ulcer have been described; jaundice and hypersensitivity have been reported in rare cases; hemoptysis is infrequent. Single intracranial bleedings have been described (especially in patients with arterial hypertension and/or taking concomitant drugs that affect hemostasis (e.g., NSAIDs, antiaggregants or other antithrombotic agents), which in some cases can be potentially life-threatening.

Other clinical studies have reported the occurrence of vascular pseudoaneurysms after percutaneous interventions.

Other clinical studies and post-marketing observational studies have reported known bleeding complications such as compartment syndrome. In addition, the development of acute renal failure and renal failure that resulted from bleeding of sufficient intensity to cause hypoperfusion has been reported.

Overdose

Rare cases of overdose have been reported when taking rivaroxaban up to 600 mg without the development of bleeding or other adverse reactions. Due to limited absorption, saturation effects are expected without further increase in mean plasma levels of rivaroxaban at hypertherapeutic doses of 50 mg or higher.

The specific antidote for rivaroxaban is unknown. In case of overdose, activated charcoal may be used to reduce absorption of rivaroxaban. Given the intense binding to plasma proteins, rivaroxaban is not expected to be excreted by dialysis.