Active ingredients: Rivaroxaban
Xarelto 2.5 mg film-coated tablets
Xarelto package inserts are available for pack sizes:- Xarelto 2.5 mg film-coated tablets
- Xarelto 10 mg film-coated tablets
- Xarelto 15 mg film-coated tablets, Xarelto 20 mg film-coated tablets
Indications Why is Xarelto used? What is it for?
You were given Xarelto because you have been diagnosed with acute coronary syndrome (a set of conditions that includes heart attack and unstable angina, a severe form of chest pain) and have seen an increase in some cardiac markers in blood tests.
In adults, Xarelto reduces the risk of another heart attack or the risk of dying from a disease related to the heart or blood vessels.
Xarelto contains the active substance rivaroxaban and belongs to a group of medicines called antithrombotic agents. Its action is due to the blocking of a clotting factor (Factor Xa) which is followed by a reduced tendency of the blood to form clots.
Xarelto will not be given to you alone. Your doctor will also prescribe you:
- acetylsalicylic acid (also known as aspirin) or
- acetylsalicylic acid plus clopidogrel or ticlopidine.
Contraindications When Xarelto should not be used
Do not take Xarelto
- if you are allergic to rivaroxaban or any of the other ingredients of this medicine (listed in section 6)
- if you have excessive bleeding (bleeding)
- if you have a disease or condition in a part of the body that increases the risk of severe bleeding (e.g. stomach ulcers, wounds or bleeding in the brain, recent brain or eye surgery)
- if you are taking medicines to prevent clotting (e.g. warfarin, dabigatran, apixaban or heparins), except if you change your anticoagulant therapy or when you are receiving heparins through a venous or arterial catheter to keep it open.
- if you have acute coronary syndrome and have previously had a bleeding or blood clot in the brain (stroke)
- if you have liver disease which increases the risk of bleeding,
- during pregnancy or breastfeeding
Do not take Xarelto and tell your doctor if any of the conditions described apply to you.
Precautions for use What you need to know before you take Xarelto
Talk to your doctor or pharmacist before taking Xarelto
Take special care with Xarelto
- if you have an increased risk of bleeding, as it could be if you have:
- severe kidney disease, as kidney function can change the amount of medicine that is active in the body
- if you are taking other medicines to prevent clotting (e.g. warfarin, dabigatranetexilate, apixaban or heparin), if you change your anticoagulant therapy or when you are receiving heparin through a venous or arterial catheter to keep it open (see section "Other medicines and Xarelto ")
- bleeding disorders
- very high blood pressure, not controlled with medicines
- diseases of the stomach or intestines which could cause bleeding, such as inflammation of the intestines or stomach, or inflammation of the esophagus, for example caused by gastroesophageal reflux disease (disease in which the acidity of the stomach rises up the esophagus)
- a disorder of the blood vessels in the back of the eye (retinopathy)
- a lung disease with enlarged, pus-filled bronchi (bronchiectasis), or previous bleeding from the lungs
- a tumor located in a critical organ of the body
- is over 75 years old
- weighs 60 kg or less
If any of the above apply to you, tell your doctor before taking Xarelto. Your doctor will decide if you should be treated with this medicine and if you should be kept under close observation.
If you need to have surgery:
- It is very important that you take Xarelto before and after your surgery exactly at the times indicated by your doctor.
Children and adolescents
Xarelto is not recommended for people under 18 years of age. There is insufficient information on its use in children and adolescents.
Interactions Which drugs or foods may change the effect of Xarelto
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including medicines obtained without a prescription.
- If you are taking:
- some medicines for fungal infections (e.g. ketoconazole, itraconazole, voriconazole, posaconazole), unless they are only applied to the skin
- some antiviral medicines for HIV / AIDS (e.g. ritonavir)
- other medicines used to inhibit clotting (e.g. enoxaparin, clopidogrel or vitamin K antagonists such as warfarin and acenocoumarol)
- anti-inflammatory and anti-pain medicines (e.g. naproxen or acetylsalicylic acid)
- dronedarone, a medicine used to treat atrial fibrillation
If any of the conditions described apply to you, tell your doctor before taking Xarelto, as the effect of Xarelto may be enhanced. Your doctor will decide if you should be treated with this medicine and if you should be closely monitored.
If your doctor thinks you have an increased risk of developing stomach or bowel ulcers, he may prescribe preventive ulcer treatment.
- If you are taking:
- some medicines to treat epilepsy (phenytoin, carbamazepine, phenobarbital)
- St. John's Wort (Hypericum perforatum), a herbal medicine used for depression
- rifampicin, an antibiotic
If any of the above apply to you, tell your doctor before taking Xarelto, as the effects of Xarelto may be reduced. Your doctor will decide if you should be treated with Xarelto and if you should be closely monitored.
Warnings It is important to know that:
Pregnancy and breastfeeding
Do not take Xarelto if you are pregnant or breastfeeding. If there is a possibility of becoming pregnant, use a reliable method of birth control while taking Xarelto. If you become pregnant while taking this medicine, tell your doctor immediately, who will decide how to continue the treatment.
Driving and using machines
Xarelto can cause dizziness (common side effect) or fainting (uncommon side effect) (see section 4, "Possible side effects"). If these symptoms appear, do not drive or use machines.
Xarelto contains lactose.
If you have been told by your doctor that you have "intolerance to some sugars, contact your doctor before taking this medicinal product.
Dose, Method and Time of Administration How to use Xarelto: Posology
Always take this medicine exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.
What dose to take
The recommended dose is one 2.5 mg tablet twice a day. Always take Xarelto at the same time of day (for example, one tablet in the morning and one in the evening). This medicine can be taken with or without meals.
If you have difficulty swallowing the tablet whole, ask your doctor how to take Xarelto otherwise. The tablet can be crushed and mixed with a little water or apple puree immediately before taking it.
If needed, your doctor may give you the crushed Xarelto tablet through a tube inserted into your stomach.
Xarelto will not be given to you alone. Your doctor will also prescribe you:
- acetylsalicylic acid (also known as aspirin) or
- acetylsalicylic acid plus clopidogrel or ticlopidine.
Your doctor will prescribe the correct dose of these medicines (usually 75 to 100 mg of acetylsalicylic acid per day or a daily dose of 75 - 100 mg of acetylsalicylic acid plus a daily dose of 75 mg of clopidogrel or a standard daily dose of ticlopidine. ).
When to get started with Xarelto
Treatment with Xarelto should begin as soon as possible after stabilization of the acute coronary syndrome, not earlier than 24 hours after hospitalization and at the time when parenteral anticoagulation (by injection) would normally be stopped. long continue his treatment.
Overdose What to do if you have taken too much Xarelto
If you take more Xarelto than you should
Contact your doctor immediately if you have taken too many Xarelto tablets. If you have taken too much Xarelto, the risk of bleeding increases.
If you forget to take Xarelto
Do not take a double dose to make up for a forgotten dose. If you miss a dose, take your next dose at the usual time.
If you stop taking Xarelto
Take Xarelto regularly for as long as your doctor prescribes.
Do not stop taking Xarelto without talking to your doctor first. If you stop taking this medicine, it may increase the risk of a new heart attack or stroke or of dying from heart or blood vessel disease. .
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Side Effects What are the side effects of Xarelto
Like all medicines, Xarelto can cause side effects, although not everybody gets them.
Like other similar medicines (antithrombotic agents), Xarelto can cause potentially life-threatening bleeding. Massive bleeding can cause a sudden drop in blood pressure (shock). In some cases, bleeding may not occur. be obvious.
Possible side effects that may indicate bleeding:
Tell your doctor immediately if you notice any of the following side effects:
- prolonged or excessive blood loss
- unusual weakness, tiredness, pale skin, dizziness, headache, swelling of unknown origin, breathlessness, chest pain or angina pectoris, which may be signs of bleeding,
Your doctor may decide to monitor you closely or change the type of treatment.
Overall list of possible side effects:
Common (may affect up to 1 in 10 users)
- haemorrhage in the stomach or intestines, urogenital haemorrhage (including blood in the urine and heavy menstruation), nosebleed, gingival haemorrhage
- haemorrhage in the eye (including haemorrhage in the white of the eye)
- bleeding into tissues or a cavity of the body (hematoma, bruising)
- coughing up blood
- bleeding from the skin or under the skin
- bleeding after surgery
- loss of blood or fluid from the surgical wound
- swelling in the limbs
- pain in the limbs
- fever
- reduction in the number of red blood cells, which can cause paleness and weakness or breathlessness
- stomach pain, indigestion, nausea or vomiting, constipation, diarrhea
- low blood pressure (symptoms include dizziness or fainting when standing)
- decreased strength and energy (weakness, tiredness), headache, dizziness,
- rash, itching
- kidney malfunction (can be ascertained with tests performed by the doctor)
- increase in some liver enzymes in blood tests
Uncommon (may affect up to 1 in 100 users)
- hemorrhage in the brain or inside the skull
- bleeding in one joint, causing pain and swelling
- fainting
- malaise
- dry mouth
- rapid heartbeat
- allergic reactions, including allergic skin reactions
- urticaria
- liver malfunction (this can be ascertained by tests performed by the doctor)
- blood tests may show an increase in bilirubin, some enzymes in the pancreas or liver, or in the number of platelets
Rare (may affect up to 1 in 1,000 users)
- bleeding in a muscle
- localized swelling
- yellowing of the skin and eyes (jaundice)
- formation of a buildup of blood (hematoma) in the groin as a complication of a heart procedure that involves inserting a catheter into the artery of the leg (pseudoaneurysm)
Frequency not known (frequency cannot be estimated from the available data)
- increased pressure in the muscles of the legs or arms after a "bleed, causing pain, swelling, changes in sensation, numbness or paralysis (compartment syndrome after a" bleeding)
- renal impairment after severe bleeding
The following side effects have been observed since the medicine was authorized: angioedema and allergic edema (swelling of the face, lips, mouth, tongue or throat).
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the carton and each blister after EXP / EXP. The expiry date refers to the last day of that month.
This medicine does not require any special storage conditions.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Composition and pharmaceutical form
What Xarelto contains
- The active ingredient is rivaroxaban. Each tablet contains 2.5 mg of rivaroxaban.
- The other ingredients are:
Tablet core: microcrystalline cellulose, croscarmellose sodium, lactose monohydrate, hypromellose, sodium lauryl sulfate, magnesium stearate.
Tablet overlay: macrogol 3350, hypromellose, titanium dioxide (E 171), yellow iron oxide (E 172).
What Xarelto looks like and contents of the pack
Xarelto 2.5 mg film-coated tablets are light yellow, round, biconvex, with the BAYER cross debossed on one side and "2.5" and a triangle debossed on the other side.
The tablets are supplied in blisters in cartons of 14, 28, 30, 56, 60, 98, 168 or 196 film-coated tablets or perforated unit dose blisters in cartons of 10 x 1 or 100 x 1 film-coated tablets or in pack sizes multiples comprising 10 packs each containing 10 x 1 film-coated tablets.
Not all pack sizes may be marketed.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
XARELTO 2.5 MG TABLETS COATED WITH FILM
▼ Medicinal product subject to additional monitoring. This will allow the rapid identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for information on how to report adverse reactions.
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains 2.5 mg of rivaroxaban.
Excipient with known effects:
each film-coated tablet contains 33.92 mg of lactose (as monohydrate), see section 4.4.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Film-coated tablet (tablet).
Round, biconvex, light yellow tablets (diameter 6 mm, radius of curvature mm), with the BAYER cross debossed on one side and "2.5" and a triangle debossed on the other side.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Xarelto, given together with acetylsalicylic acid alone (acetylsalicylic acid, ASA) or with ASA and clopidogrel or ticlopidine, is indicated for the prevention of atherothrombotic events in adult patients after acute coronary syndrome (ACS) with elevated cardiac biomarkers (see sections 4.3, 4.4 and 5.1).
04.2 Posology and method of administration
Dosage
The recommended dose is 2.5 mg twice a day.
In addition, patients should take a daily dose of 75-100 mg of ASA or a daily dose of 75-100 mg of ASA in addition to either a daily dose of 75 mg of clopidogrel or a standard daily dose of ticlopidine.
The treatment must be regularly evaluated in the individual patient considering on the one hand the risk of ischemic events and on the other the risks of bleeding. An extension of treatment beyond 12 months must be evaluated on the basis of each individual patient, because the experiences up to 24 months are limited (see section 5.1)
Treatment with Xarelto should begin as soon as possible after stabilization of the ACS event (including revascularization procedures); no earlier than 24 hours after hospitalization and when parenteral anticoagulation would normally be stopped.
If a dose is missed, the patient should continue with the recommended regular dose according to the established dosing schedule. A double dose should not be taken to make up for a forgotten dose.
Switching from Vitamin K (AVK) antagonists to Xarelto
In patients who switch from VKA to Xarelto, after taking Xarelto the "International Normalized Ratio (INR) will be falsely high. The INR is not intended to measure the anticoagulant activity of Xarelto and therefore should not be used (see section 4.5).
Switching from Xarelto to VitaminK Antagonists (AVK)
During the transition from Xarelto to AVK there is a possibility of an inadequate anticoagulant effect. Whenever a change is made to another anticoagulant, an adequate and continuous level of anticoagulation must be ensured. Note that Xarelto can help raise the INR.
In patients switching from Xarelto to VKAs, VKAs should be given in combination until the INR is ≥2.0. In the first two days of the transition phase, the VKA posology should be the initial standard and thereafter will be based on the "INR. In the concomitant treatment phase with Xarelto and AVK, the INR should be determined not earlier than 24 hours after the previous dose of Xarelto, but before the next dose. After discontinuation of Xarelto, the INR can be reliably determined. after at least 24 hours have elapsed since the last dose (see sections 4.5 and 5.2).
Switching from parenteral anticoagulants to Xarelto
In patients being treated with a parenteral anticoagulant, discontinue treatment with the parenteral anticoagulant and initiate Xarelto therapy 0 to 2 hours before the next time the parenteral medicinal product is due (eg low molecular weight heparin). ) or upon discontinuation of a continuous parenteral medicinal product (eg intravenous unfractionated heparin).
Switching from Xarelto to parenteral anticoagulants
Administer the first dose of parenteral anticoagulant when the next dose of Xarelto should have been given.
Special populations
Renal impairment
Limited clinical data in patients with severe renal impairment (creatinine clearance 15-29ml / min) indicate that rivaroxaban plasma concentrations are significantly increased. Therefore Xarelto should be used with caution in these patients. It is not recommended for use in patients with creatinine clearance
No dose adjustments are required in patients with mild renal impairment (creatinine clearance 50-80ml / min) or moderate renal impairment (creatinine clearance 30-49ml / min) (see section 5.2).
Hepatic impairment
Xarelto is contraindicated in patients with hepatic disease associated with coagulopathy and clinically significant risk of bleeding, including cirrhotic patients with Child Pugh B and C (see sections 4.3 and 5.2).
Elderly population
No dose adjustment ù (see sections 4.4 and 5.2).
Body weight
No dose adjustment (see sections 4.4 and 5.2).
Sex
No dose adjustment (see section 5.2).
Pediatric population
The safety and efficacy of Xarelto in children aged 0-18 have not been established. No data are available, therefore Xarelto is not recommended for use in children below 18 years of age.
Method of administration
For oral use.
Xarelto can be taken with or without food (see sections 4.5 and 5.2).
For patients unable to swallow tablets whole, the Xarelto tablet can be crushed and mixed with some water or apple puree immediately prior to use and administered orally.
Once crushed, the Xarelto tablet can also be administered via a gavage, subject to confirmation of the correct placement of the tube. The crushed tablet should be administered with a small amount of water via a gavage, which should then be rinsed with water (see section 5.2).
04.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Clinically significant bleeding in progress.
Injuries or conditions that pose a significant risk of major bleeding. These may include recent or ongoing gastric ulceration, presence of malignant neoplasms with high risk of bleeding, recent brain or spinal trauma, brain, spinal or ophthalmic surgery, recent intracranial haemorrhage, known or suspected esophageal varices, arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular dysfunctions.
Concomitant treatment with other anticoagulants, such as unfractionated heparins, low molecular weight heparins (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, etc.), oral anticoagulants (warfarin, dabigatran etexilate, apixaban, etc.), except in the specific case of change in anticoagulant therapy (see section 4.2) or when unfractionated heparins are administered at doses necessary to maintain an open central catheter, venous or arterial (see section 4.5).
Concomitant treatment of ACS with antiplatelet therapy in patients with a previous stroke or transient ischemic attack (transient ischaemic attack, TIA) (see section 4.4).
Hepatic disorders associated with coagulopathy and clinically significant bleeding risk, including cirrhotic patients with Child PughB and C (see section 5.2).
Pregnancy and lactation (see section 4.6).
04.4 Special warnings and appropriate precautions for use
The efficacy and safety of Xarelto were studied in combination with the antiplatelet agents aspirin and clopidogrel / ticlopidine.Treatment with other antiplatelet agents, such as eg. prasugel or ticagrelor has not been studied and is not recommended.
Surveillance according to the usual practice in the patient on anticoagulant therapy is recommended for the entire duration of treatment.
Bleeding risk
As with other anticoagulants, patients taking Xarelto should be closely monitored for signs of bleeding. It is recommended to use it with caution in conditions of increased risk of bleeding. Administration of Xarelto must be discontinued in case of severe bleeding.
In clinical studies, mucosal bleeding (eg, epistaxis, gingival, gastrointestinal and genitourinary bleeding) and anemia were reported more frequently during long-term treatment with rivaroxaban in addition to single or dual antiplatelet therapy. Therefore, in addition to adequate clinical surveillance, it may be important, if deemed appropriate, to carry out laboratory checks on hemoglobin / hematocrit to detect occult bleeding.
Several subpopulations of patients, described in detail below, have an increased risk of bleeding. Therefore, the use of Xarelto in combination with dual antiplatelet therapy in patients known to be at increased risk of bleeding should be weighed against the benefit in terms of prevention of atherothrombotic events. In addition, such patients should be carefully monitored for onset. for signs and symptoms of bleeding complications and anemia after initiation of treatment (see section 4.8).
A reduction in hemoglobin or blood pressure of unknown origin should lead to the search for a hemorrhagic focus.
Although rivaroxaban treatment does not require continuous exposure monitoring, measuring rivaroxaban levels with a calibrated quantitative anti-factor Xa assay may be useful in exceptional situations when knowledge of rivaroxaban exposure can be helpful. in making a clinical decision, such as in cases of overdose and emergency surgery (see sections 5.1 and 5.2).
Renal impairment
In patients with severe renal impairment (creatinine clearance plasma levels of rivaroxaban may increase significantly (on average 1.6 times), which may increase the risk of bleeding. Xarelto should be used with caution in patients with creatinine clearance between 15 and 29ml / min. Not recommended for use in patients with creatinine clearance
In patients with moderate renal impairment (creatinine clearance 30-49ml / min) who are taking other medicinal products that increase rivaroxaban plasma concentrations, Xarelto should be used with caution (see section 4.5).
Interactions with other medicines
The use of Xarelto is not recommended in patients being treated concomitantly with systemic azole antifungals (such as ketoconazole, itraconazole, voriconazole and posaconazole) or HIV protease inhibitors (eg ritonavir). These active substances are potent inhibitors of CYP3A4. and P-gp and may therefore increase rivaroxaban plasma concentrations to a clinically relevant extent (on average 2.6 times) which may result in an increased risk of bleeding (see section 4.5).
Use caution if patients are being treated concomitantly with medicinal products that affect haemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), acetylsalicylic acid and antiplatelet agents. Appropriate prophylactic treatment may be considered for patients at risk of peptic ulcer (see section 4.5).
After an acute coronary syndrome, the patient being treated with Xarelto and ASA or with Xarelto and ASA plus clopidogrel / ticlopidine should receive concomitant NSAID treatment only if the benefit outweighs the bleeding risk.
Other bleeding risk factors
As with other antithrombotics, rivaroxaban is not recommended in patients at increased bleeding risk, such as:
• congenital or acquired bleeding disorders
• severe uncontrolled arterial hypertension
• other gastrointestinal disease without active ulceration that can potentially lead to bleeding complications (for example inflammatory bowel disease, esophagitis, gastritis and gastroesophageal reflux disease)
• vascular retinopathy
• bronchiectasis or a history of pulmonary haemorrhage
It should be used with caution in ACS patients:
•> 75 years of age when given together with ASA alone or with ASA plus clopidogrel or ticlopidine
• with low body weight (
Patients with a previous stroke or TIA
Xarelto 2.5 mg is contraindicated for the treatment of ACS in patients with a previous stroke or TIA (see section 4.3). Some ACS patients with prior stroke or TIA have been studied, but the limited efficacy data available indicate that these patients do not benefit from treatment.
Spinal / epidural anesthesia or puncture
In case of neuraxial anesthesia (spinal / epidural anesthesia) or spinal / epidural puncture, patients treated with antithrombotic agents for the prevention of thromboembolic complications are at risk of epidural or spinal hematoma, which can cause prolonged or permanent paralysis. This risk may be increased in the case of postoperative use of indwelling epidural catheters or the combined use of medicinal products that alter haemostasis. The risk may also increase in the event of traumatic or repeated epidural or spinal puncture. Patients should be monitored frequently. regarding signs and symptoms of neurological changes (eg numbness or weakness in the lower limbs, bowel or bladder dysfunction). Immediate diagnosis and treatment is required in the presence of neurological impairment. relationship between the expected benefit and the risk present in patients on anticoagulant therapy or in patients for whom anticoagulation therapy is planned for antithrombotic prophylaxis. There is no clinical experience with the use of rivaroxaban 2.5 mg with ASA alone or with ASA plus clopidogrel or ticlopidine in these situations.
In order to reduce the potential risk of bleeding associated with concomitant use of rivaroxaban and neuraxial (epidural / spinal) anesthesia or spinal puncture, the pharmacokinetic profile of rivaroxaban should be considered. It is preferable to place or remove an epidural catheter or perform a puncture. lumbar spine when the anticoagulant effect of rivaroxaban is estimated to be low (see section 5.2). However, the exact time to achieve a sufficiently low anticoagulant effect in each patient is not known.
Antiplatelet agents should be discontinued according to the manufacturer's instructions.
Dosage recommendations before and after invasive procedures and surgery
If an invasive procedure or surgery is required, treatment with Xarelto 2.5 mg should be stopped, if possible and based on the physician's clinical judgment, at least 12 hours prior to surgery. If a patient is to undergo surgery elective surgery and antiplatelet effect is not desired, administration of antiplatelet agents should be discontinued according to the manufacturer's instructions.
If the procedure cannot be postponed, the increased risk of bleeding must be evaluated in relation to the urgency of the intervention.
Treatment with Xarelto should be resumed as soon as possible after the invasive procedure or surgery, as soon as the clinical situation permits and adequate haemostasis has been achieved, based on the physician's assessment (see section 5.2).
Elderly population
Older age may cause an increased risk of bleeding (see section 5.2).
Information on excipients
Xarelto contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
04.5 Interactions with other medicinal products and other forms of interaction
CYP3A4 and P-gp inhibitors
Concomitant administration of rivaroxaban and ketoconazole (400mg once daily) or ritonavir (600mg twice daily) resulted in a 2.6 / 2.5-fold increase in the mean rivaroxaban AUC and a 1.7 / 1.6-fold increase. mean Cmax of rivaroxaban, with significantly increased pharmacodynamic effects: this may be due to an increased risk of bleeding. Therefore, the use of Xarelto is not recommended in patients receiving systemic concomitant treatment with azole antifungals, such as ketoconazole, itraconazole. , voriconazole and posaconazole, or HIV protease inhibitors. These active substances are potent inhibitors of CYP3A4 and P-gp (see section 4.4).
Active substances that significantly inhibit only one of rivaroxaban's metabolic pathways, CYP3A4 or P-gp, are thought to increase rivaroxaban plasma concentrations to a lesser extent. Clarithromycin (500mg twice daily), for example, considered a potent CYP3A4 inhibitor and a weak to moderate inhibitor of P-gp, induced a 1.5-fold increase in rivaroxaban mean AUC and a 1-fold increase. 4 times the Cmax This increase is not considered clinically relevant (for patients with renal impairment: see section 4.4).
Erythromycin (500mg three times daily), which inhibits CYP3A4 and P-gp moderately, resulted in a 1.3-fold increase in mean AUC and mean C of rivaroxaban. This increase is not considered clinically relevant.
In subjects with mild renal impairment, erythromycin (500mg three times daily) induced a mean 1.8-fold increase in the mean AUC of rivaroxaban and a 1.6-fold increase in C as compared to subjects with normal renal function. In subjects with moderate renal impairment, erythromycin induced a mean 2.0-fold increase in the mean AUC of rivaroxaban and a 1.6-fold increase in C compared to subjects with normal renal function. The effect of erythromycin is additive to that of renal insufficiency (see section 4.4).
Fluconazole (400mg once daily), considered a moderate inhibitor of CYP3A4, increased the mean AUC of rivaroxaban by 1.4 times and the mean C by 1.3 times. This increase is not considered clinically relevant. renal insufficiency: see section 4.4).
Due to the limited clinical data available with dronedarone, its concomitant administration with rivaroxaban should be avoided.
Anticoagulants
After co-administration of enoxaparin (40mg single dose) and rivaroxaban (10mg single dose) an additive effect on anti-factor Xa activity was observed in the absence of other effects on coagulation tests (PT, aPTT). Enoxaparin has no modified the pharmacokinetics of rivaroxaban.
Due to the increased bleeding risk, caution should be exercised in case of concomitant treatment with any other anticoagulant (see sections 4.3 and 4.4).
NSAIDs / antiplatelet agents
No clinically relevant increases in bleeding time were observed after concomitant administration of rivaroxaban (15mg) and naproxen (500mg). However, some people may have a more pronounced pharmacodynamic response.
No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when co-administered with rivaroxaban and 500mg acetylsalicylic acid.
Clopidogrel (300mg loading dose, followed by 75mg maintenance dose) did not show any pharmacokinetic interaction with rivaroxaban (15mg), but a relevant increase in bleeding time, unrelated to degree of platelet aggregation or P-selectin or GPIIb / IIIa receptor levels.
Use caution if patients are being treated concomitantly with NSAIDs (including acetylsalicylic acid) and antiplatelet agents, as these medicinal products typically increase the risk of bleeding (see section 4.4).
Warfarin
The transition from the vitamin K antagonist warfarin (INR between 2.0 and 3.0) to rivaroxaban (20mg) or from rivaroxaban (20mg) to warfarin (INR between 2.0 and 3.0) resulted in an increase in prothrombin time / INR (Neoplastin) rather than additive (single INR values up to 12 can be observed), while the effects on aPTT, inhibition of factor Xa activity and endogenous thrombin potential (ETP) were additive.
If the pharmacodynamic effects of rivaroxaban during the transition period are desired, tests for anti-factor Xa, PiCT and Heptest activity can be used, because they are not affected by warfarin. On the fourth day after the last dose of warfarin, all tests (including PT, aPTT, inhibition of Xa activity and ETP) only reflect the effect of rivaroxaban.
If it is desired to check the pharmacodynamic effects of warfarin during the transition period, the INR can be used at the trough concentration (Cvalle) of rivaroxaban (24 hours after previous rivaroxaban intake) because, at that time, this test is minimally affected by rivaroxaban.
No pharmacokinetic interactions were observed between warfarin and rivaroxaban.
CYP3A4 inducers
Concomitant administration of rivaroxaban and the potent CYP3A4 inducer rifampicin resulted in an approximately 50% reduction in the mean AUC of rivaroxaban, with parallel reduction of its pharmacodynamic effects. Concomitant use of rivaroxaban and other potent CYP3A4 inducers ( e.g. phenytoin, carbamazepine, phenobarbital or St. John's wort (Hypericum perforatum)) may decrease rivaroxaban plasma concentrations. Therefore, concomitant administration of strong CYP3A4 inducers should be avoided unless the patient is carefully monitored for signs and symptoms of thrombosis.
Other concomitant therapies
No clinically significant pharmacokinetic or pharmacodynamic interactions were observed with concomitant administration of rivaroxaban and midazolam (CYP3A4 substrate), digoxin (P-gp substrate), atorvastatin (CYP3A4 and P-gp substrate) or omeprazole (inhibitor of proton pump). Rivaroxaban does not inhibit or induce any of the major CYP isoforms, such as CYP3A4.
No clinically relevant interactions with food were observed (see section 4.2).
Laboratory parameters
Coagulation parameters (eg PT, aPTT, HepTest) are predictably altered due to rivaroxaban's mechanism of action (see section 5.1).
04.6 Pregnancy and breastfeeding
Pregnancy
The safety and efficacy of Xarelto in pregnant women have not been established. Animal studies have shown reproductive toxicity (see section 5.3). For potential reproductive toxicity, inherent bleeding risk and evidence that rivaroxaban crosses the placenta. , Xarelto is contraindicated during pregnancy (see section 4.3).
Women of childbearing potential should avoid becoming pregnant while being treated with rivaroxaban.
Feeding time
The safety and efficacy of Xarelto in breastfeeding women have not been established. Animal data indicate that rivaroxaban is excreted in human milk. Therefore, Xarelto is contraindicated during lactation (see section 4.3). A decision must be made whether to discontinue breastfeeding or to discontinue / abstain from therapy.
Fertility
No specific studies have been conducted with rivaroxaban to determine its effects on fertility in men and women. No effects were observed in a male and female fertility study in rats (see section 5.3).
04.7 Effects on ability to drive and use machines
Xarelto has a slight influence on the ability to drive and use machines. Adverse reactions such as syncope (frequency: uncommon) and dizziness (frequency: common) have been reported (see section 4.8). Patients in whom these occur. adverse reactions should not drive vehicles or operate machinery.
04.8 Undesirable effects
Summary of the safety profile
The safety of rivaroxaban was determined in eleven phase III studies involving 32,625 patients exposed to rivaroxaban (see Table 1).
Table 1: Number of patients studied, maximum daily dose and duration of treatment in the phase III studies
* Patients exposed to at least one dose of rivaroxaban
The most commonly reported adverse reactions in rivaroxaban treated patients were bleeding (see section 4.4 and "Description of particular adverse reactions" below). The most commonly reported bleeding (≥4%) were epistaxis (5.9%) and gastrointestinal tract haemorrhage (4.2%).
In total, treatment-related adverse events were observed in approximately 67% of patients exposed to at least one dose of rivaroxaban. Approximately 22% of patients experienced adverse events considered related to treatment by investigators.In patients treated with 10mg of Xarelto and undergoing hip or knee replacement surgery and in patients hospitalized for medical reasons, bleeding events occurred in 6.8% and 12.6% of patients, respectively, and anemia occurred respectively. in 5.9% and 2.1% of patients. Bleeding events have occurred in patients treated with 15mg of Xarelto twice daily followed by 20mg once daily for treatment of DVT or PE, or 20mg once daily for prevention of recurrence of DVT and PE. in approximately 27.8% of patients and anemia occurred in approximately 2.2% of patients. In patients treated for the prevention of stroke and systemic embolism, bleeding of any type or extent has been reported with a frequency of 28 per 100 patient-years and anemia with a frequency of 2.5 per 100 patient-years. In patients treated for the prevention of atherothrombotic events after acute coronary syndrome (ACS), bleeding of any severity has been reported with a frequency of 22 per 100 patient-years. Anemia was reported with a frequency of 1.4 per 100 patient-years.
Table of adverse reactions
Adverse reactions observed with Xarelto are listed in table 2 below, classified by system organ (according to MedDRA) and by frequency.
Frequencies are defined as follows:
very common (≥1 / 10)
common (≥1 / 100,
uncommon (≥1 / 1,000,
rare (≥1 / 10,000,
very rare (
not known (frequency cannot be estimated from the available data).
Table 2: All treatment-related adverse reactions reported in patients in phase III studies
A observed in the prevention of venous thromboembolism (VTE) in adult patients undergoing elective hip or knee replacement surgery
B observed in the treatment of DVT and PE and in the prevention of relapses as very common in women
C observed as uncommon in the prevention of atherothrombotic events in patients after ACS (following percutaneous coronary intervention)
Description of particular adverse reactions
Due to its pharmacological mechanism of action, the use of Xarelto may be associated with an increased risk of overt or occult bleeding in any tissue or organ, which can lead to post-haemorrhagic anemia. The signs, symptoms and severity (including fatal outcome) vary according to the location and degree or extent of the bleeding and / or anemia (see section 4.9 Management of bleeding). In clinical studies, mucosal bleeding (eg, epistaxis, gingival, gastrointestinal and genitourinary bleeding) and anemia were reported more frequently, compared to treatment with VKA, during long-term treatment with rivaroxaban. to an adequate clinical surveillance, it may be important, if deemed appropriate, to carry out laboratory checks on hemoglobin / hematocrit to detect occult bleeding. The bleeding risk may be increased in certain patient categories, eg. in patients with severe uncontrolled arterial hypertension and / or undergoing concomitant treatments with effects on haemostasis (see Haemorrhagic risk in section 4.4). Menstruation may be of longer intensity and / or duration. Bleeding complications may manifest as weakness, paleness, dizziness, headache or swelling of unknown origin, dyspnoea and shock of unknown origin. In some cases, symptoms of cardiac ischaemia such as chest pain or angina pectoris have been observed as a consequence of anemia.
Known complications of severe bleeding, such as compartment syndrome and renal impairment due to hypoperfusion, have been reported with Xarelto. Therefore, in evaluating the conditions of patients on anticoagulant therapy, the possibility of a haemorrhage should be considered.
Remarks post-marketing
The following adverse reactions have been reported post-marketing in temporal association with the use of Xarelto. The frequency of these adverse reactions reported in experience post-marketing cannot be estimated.
Immune system disorders: Angioedema and allergic edema (In pooled phase III studies, these events were uncommon (≥1 / 1,000,
Hepatobiliary disorders: Cholestasis, Hepatitis (including hepatocellular injury) (In pooled phase III studies, these events were rare (≥ 1 / 10,000,
Blood and lymphatic system disorders: Thrombocytopenia (In pooled phase III studies, these events were uncommon (≥ 1 / 1,000,
Reporting of suspected adverse reactions
The reporting of suspected adverse reactions that occur after the authorization of the medicinal product is important, as it allows continuous monitoring of the benefit / risk ratio of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Italian Medicines Agency. , website: http://www.agenziafarmaco.gov.it/it/responsabili.
04.9 Overdose
Rare cases of overdose up to 600mg without bleeding complications or other adverse reactions have been reported. Due to limited absorption, a ceiling effect is expected without further increases in mean plasma exposure at supratherapeutic doses of 50mg rivaroxaban or higher.
There is no specific antidote available that can antagonize the pharmacodynamic effects of rivaroxaban.
In the event of an overdose of rivaroxaban, the use of activated charcoal may be considered to reduce absorption.
Management of bleeding
If a bleeding complication occurs in a patient treated with rivaroxaban, subsequent rivaroxaban administration should be postponed or treatment discontinued, as appropriate. Rivaroxaban has a half-life of approximately 5 to 13 hours (see section 5.2). Patient management should be individualized based on the severity and location of the bleeding. As needed, suitable symptomatic treatment can be carried out such as mechanical compression (for example in the case of severe epistaxis), surgical haemostasis with bleeding control procedures, fluid restoration and haemodynamic support, administration of blood products (concentrates erythrocytes or fresh frozen plasma, depending on the associated anemia or coagulopathy) or platelets.
If bleeding cannot be controlled by the measures described, a specific procoagulant agent for reversing the anticoagulant effect, such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (APCC) or recombinant factor VIIa (r-FVIIa).
However, to date there is very limited clinical experience with the use of these products in subjects treated with rivaroxaban. The recommendation is also based on limited pre-clinical data. Consideration should be given to repeat administration of recombinant factor VIIa, adjusting the dose based on improvement in bleeding. Based on local availability, a coagulation expert should be consulted in the event of major bleeding (see section 5.1). .
Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban. There is limited experience with tranexamic acid in subjects treated with rivaroxaban, while there is no experience with aminocaproic acid and aprotinin. There is no scientific rationale for a possible benefit or experience with the systemic hemostat desmopressin in subjects treated with rivaroxaban. Due to its high plasma protein binding, rivaroxaban is unlikely to be dialysable.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: Direct factor Xa inhibitor, ATC code: B01AF01
Mechanism of action
Rivaroxaban is a direct and highly selective inhibitor of Xa factor, with oral bioavailability. Inhibition of factor Xa disrupts the intrinsic and extrinsic pathways of the coagulation cascade and inhibits both thrombin formation and thrombus development. Rivaroxaban does not inhibit thrombin (activated factor II) and has not been shown to have any effect on platelets.
Pharmacodynamic effects
In humans, a dose-dependent inhibition of factor Xa activity was observed. If tested with Neoplastin, prothrombin time (PT) is affected by rivaroxaban in a dose-dependent manner, with a close correlation with the plasma concentrations (r-value equal to 0.98). Different results are obtained with other reagents. The PT must be expressed in seconds, because the INR (International Normalized Ratio) is calibrated and validated for coumarins only and cannot be used for other anticoagulants.
In a clinical pharmacology study investigating the potential to antagonize the pharmacodynamic effects of rivaroxaban in healthy adult subjects (n = 22), the effects of single doses (50 IU / kg) of two different types of PCC, one PCC at 3 factors (Factors II, IX and X) and a 4-factor PCC (Factors II, VII, IX and X). The 3-factor PCC reduced mean PT values with Neoplastin by approximately 1.0 second within 30 minutes, compared with the reduction of approximately 3.5 seconds seen with the 4-factor PCC. In contrast, 3-factor PCC had a greater and more rapid overall effect of antagonizing changes in endogenous thrombin generation than 4-factor PCC (see section 4.9).
Activated partial thromboplastin time (aPTT) and HepTest increased in a dose-dependent manner; however, they are not recommended for determining the pharmacodynamic effects of rivaroxaban. During treatment with rivaroxaban, monitoring of coagulation parameters is not necessary in clinical practice. However, where clinically indicated, rivaroxaban levels can be measured by an appropriately calibrated quantitative anti-factorXa test (see section 5.2).
Clinical efficacy and safety
The rivaroxaban clinical program was created to demonstrate the efficacy of Xarelto in the prevention of cardiovascular (CV) death, myocardial infarction or stroke in people with recent ACS (ST-elevation myocardial infarction). infarction, STEMI], myocardial infarction without ST elevation [non-ST-elevation myocardial infarction, NSTEMI] or unstable angina [unstable angina, UA]). In the pivotal double-blind study ATLAS SCA 2 TIMI 51, 15,526 patients were randomized in a 1: 1: 1 ratio to one of three treatment groups: Xarelto 2.5 mg orally twice daily, 5mg orally twice daily or placebo twice daily, co-administered with ASA alone or with ASA plus a thienopyridine (clopidogrel or ticlopidine). Patients with ACS and less than 55 years of age were required to have either diabetes mellitus or a previous myocardial infarction. The median treatment time was 13 months and the duration of maximum treatment duration was approximately 3 years. 93.2% of patients received ASA plus thienopyridine jointly and 6.8% only ASA. Of patients treated with dual antiplatelet therapy, 98.8% received clopidogrel, 0.9% received ticlopidine and 0.3% received prasugrel. Patients received the first dose of Xarelto no earlier than 24 hours and up to 7 days (mean 4.7 days) after hospitalization, but as soon as possible after stabilization of the ACS event, including revascularization procedures, and in the at which time parenteral anticoagulant therapy would be suspended.
Both rivaroxaban regimens, 2.5 mg twice daily and 5 mg twice daily, were effective in further reducing the incidence of CV events on top of standard antiplatelet treatment. The 2.5 mg regimen twice daily reduced mortality and there is evidence of a lower bleeding risk related to the lower dose: therefore, rivaroxaban 2.5 mg twice daily, given together with acetylsalicylic acid (ASA) alone or with ASA and a thienopyridine (clopidogrel or ticlopidine) is recommended for the prevention of atherothrombotic events in adult patients after ACS with elevated cardiac biomarkers.
Compared to placebo, Xarelto significantly reduced the primary composite endpoint of CV death, myocardial infarction or stroke. The benefit was determined by a reduction in CV death and myocardial infarction which appeared in a short time and with consistent treatment. had effect throughout the treatment period itself (see Table 3 and Figure 1). The first secondary endpoint (death from any cause, myocardial infarction or stroke) was also significantly reduced. A "further retrospective analysis showed a nominally significant reduction in the incidence rates of stent thrombosis compared to placebo (see Table 3). The incidence rates of the primary safety outcome (non-CABG TIMI major bleeding events) were higher in patients treated with Xarelto compared to patients who received placebo (see Table 5). However, the incidence rates were similar. with Xarelto and placebo in terms of fatal bleeding events, hypotension requiring treatment with intravenous inotropic agents and surgery for persistent bleeding.
Table 4 shows the efficacy results in patients undergoing percutaneous coronary intervention (PCI). The safety results in this subgroup of patients were comparable with the overall safety results.
Patients with elevated biomarkers (troponin or CK-MB) and without prior stroke / TIA made up 80% of the study population. The results from this patient population were also consistent with the overall efficacy and safety results.
b) vs. placebo; Log-Rank p-value * statistically superior ** nominally significant
b) vs. placebo; Log-Rank p-value ** nominally significant
a) population assessable for safety purposes, undergoing treatment
b) vs. placebo; Log-Rank p-value
* statistically significant
Pediatric population
The European Medicines Agency has deferred the obligation to submit the results of studies with Xarelto in one or more subsets of the pediatric population in the treatment of thromboembolic events. The European Medicines Agency has waived the obligation to submit the results of studies with Xarelto in all subsets of the pediatric population in the prevention of thromboembolic events (see section 4.2 for information on pediatric use).
05.2 Pharmacokinetic properties
Absorption
Rivaroxaban is rapidly absorbed and peak concentrations (Cmax) occur 2-4 hours after taking the tablet.
The oral absorption of rivaroxaban is nearly complete and the oral bioavailability for the 2.5 mg and 10 mg tablet is high (80-100%), regardless of fasting or food intake. Intake with food does not affect rivaroxaban AUC or Cmax at 2.5mg and 10mg doses. Rivaroxaban 2.5mg and 10mg tablets can be taken with or without food.
Rivaroxaban pharmacokinetics are roughly linear up to approximately 15mg once daily. At higher doses, absorption is limited by dissolution, with a reduction in bioavailability and rate of absorption as the dose increases. This aspect is more pronounced in fasting conditions than after meals. The variability in rivaroxaban pharmacokinetics is moderate, with inter-individual variability (CV%) ranging from 30% to 40%.
The absorption of rivaroxaban is dependent on the release site in the gastrointestinal tract. A 29% and 56% reduction in AUC and Cmax compared to the tablet has been reported when rivaroxaban granules are released into the proximal small intestine. Exposure is further reduced when rivaroxaban is released into the distal small intestine or ascending colon. Therefore, administration of rivaroxaban distal to the stomach should be avoided as the absorption of rivaroxaban and therefore exposure may be reduced.
Bioavailability (AUC and Cmax) was comparable for 20 mg of rivaroxaban administered orally as a crushed tablet mixed with apple puree or resuspended in water and administered by gavage followed by a liquid meal, compared to the whole tablet. In view of rivaroxaban's predictable and dose-proportional pharmacokinetic profile, the bioavailability results obtained in this study are likely to apply even to lower doses of rivaroxaban.
Distribution
In humans, plasma protein binding is high and reaches approximately 92% -95%. The major component of binding is serum albumin. The volume of distribution is moderate, with a Vss of about 50 liters.
Biotransformation and elimination
Approximately 2/3 of the administered dose of rivaroxaban undergoes metabolic degradation; one half is then eliminated by the kidney and the other half by the faecal route. The remaining 1/3 of the administered dose is excreted directly via the kidney, as unchanged active ingredient in the urine, mainly by active renal secretion.
Rivaroxaban is metabolised via CYP3A4, CYP2J2 and by mechanisms independent of CYP. The oxidative degradation of the morpholinone group and the hydrolysis of the amide bonds are the main sites of biotransformation. Based on the data obtained in vitro, rivaroxaban is a substrate of the transport proteins P-gp (P-glycoprotein) and Bcrp (breast cancer resistance protein).
Unchanged rivaroxaban is the main compound present in human plasma, in which no important or active circulating metabolites are detected. With a systemic clearance of approximately 10l / h, rivaroxaban can be described as a low-clearance substance. After intravenous administration of a 1 mg dose, the elimination half-life is approximately 4.5 hours. After oral administration, elimination is limited by the rate of absorption. Elimination of rivaroxaban from plasma occurs with a terminal half-life of 5-9 hours in young subjects and 11-13 hours in the elderly.
Special populations
Sex
There were no clinically significant differences in pharmacokinetics and pharmacodynamics between male and female patients.
Elderly population
Higher plasma concentrations were observed in elderly patients than in young patients, with mean AUC values approximately 1.5 times higher, mainly due to (apparent) decreased total and renal clearance. No dose adjustment is necessary.
Weight categories
Extremes of body weight (120kg) had only a "reduced" influence on rivaroxaban plasma concentrations (less than 25%). No dose adjustment is necessary.
Inter-ethnic differences
No clinically relevant inter-ethnic differences were observed between Caucasian, African American, Hispanic, Japanese or Chinese patients regarding rivaroxaban pharmacokinetics and pharmacodynamics.
Hepatic impairment
In cirrhotic patients with mild hepatic impairment (classified as Child Pugh A), only slight changes in rivaroxaban pharmacokinetics (mean 1.2-fold increase in rivaroxaban AUC) were observed, almost comparable to those in the healthy control group. cirrhotic with moderate hepatic impairment (classified as Child Pugh B), the mean AUC of rivaroxaban was significantly increased 2.3-fold compared to healthy volunteers. Unbound AUC was increased 2.6-fold. These patients also had reduced renal elimination of rivaroxaban, similar to patients with moderate renal impairment. No data are available for patients with severe hepatic impairment.
Inhibition of factor Xa activity was increased 2.6 times in patients with moderate hepatic impairment compared to healthy volunteers; PT prolongation was also increased by 2.1 times. Patients with moderate hepatic impairment were more sensitive to rivaroxaban, resulting in an increase in the slope of the PK / PD correlation line between concentration and PT.
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 (see section 4.3).
Renal impairment
There was an increase in rivaroxaban exposure related to decreased renal function, based on creatinine clearance determination. In subjects with mild (creatinine clearance 50-80ml / min), moderate (creatinine clearance 30- 49ml / min) and severe (creatinine clearance 15-29ml / min), rivaroxaban plasma concentrations (AUC) were increased by 1.4, 1.5 and 1.6 times, respectively. Corresponding increases in pharmacodynamic effects were more pronounced. In subjects with mild, moderate and severe renal impairment, overall inhibition of factor Xa activity was increased by 1.5, 1.9, and 2.0-fold, respectively, compared to healthy volunteers; similarly, the PT was increased by 1.3, 2.2 and 2.4-fold, respectively. No data are available in patients with creatinine clearance.
Due to its high plasma protein binding, rivaroxaban is not expected to be dialyzable.
It is not recommended for use in patients with creatinine clearance
Pharmacokinetic data in patients
In patients receiving rivaroxaban 2.5 mg twice daily for the prevention of atherothrombotic events in ACS patients, the geometric mean concentration (prediction range 90%) after 2-4 hours and approximately 12 hours after dosing (which roughly represent the maximum and minimum concentration in the intake range) was 47 (13-123) and 9.2 (4.4-18) mcg / l, respectively.
Pharmacokinetic / pharmacodynamic relationship
The pharmacokinetic / pharmacodynamic (FC / FD) relationship between rivaroxaban plasma concentration and different FD endpoints (factor Xa inhibition, PT, aPTT, HepTest) was evaluated after administration of a broad spectrum of doses (5 - 30mg twice daily). day). The relationship between rivaroxaban concentration and factor Xa activity is best described by an Emax model. For PT, the linear regression model generally best describes the data. Depending on the different reagents used, the slope differs considerably. When Neoplastin was used for the PT, the baseline PT was about 13s and the slope about 3-4 s / (100mcg / l). The results of the analysis of FC / FD in phase II and III are comparable with the data obtained in healthy subjects.
Pediatric population
The safety and efficacy in children and adolescents up to 18 years have not been verified.
05.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, single dose toxicity, phototoxicity, genotoxicity, carcinogenic potential and juvenile toxicity.
Effects observed in repeat dose toxicity studies were predominantly due to the excessive pharmacodynamic activity of rivaroxaban. In rats, increased plasma levels of IgG and IgA were observed at clinically relevant exposure levels.
In the rat, no effects on male or female fertility were observed. Animal studies have shown reproductive toxicity related to rivaroxaban's pharmacological mechanism of action (eg bleeding complications). At clinically relevant plasma concentrations, embryo-fetal toxicity (post-implantation loss, delayed / progressed ossification, multiple light liver spots), increased incidence of common malformations and placental abnormalities In the pre- and postnatal study in rats, a reduction in the viability of the offspring was observed at maternally toxic doses.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Core of the tablet
Microcrystalline cellulose
Croscarmellose sodium
Lactose monohydrate
Hypromellose
Sodium lauryl sulfate
Magnesium stearate
Coating film
Macrogol 3350
Hypromellose
Titanium dioxide (E 171)
Yellow iron oxide (E 172)
06.2 Incompatibility
Not relevant.
06.3 Period of validity
3 years
06.4 Special precautions for storage
This medicine does not require any special storage conditions.
06.5 Nature of the immediate packaging and contents of the package
PP / aluminum blisters in cartons of 14, 28, 30, 56, 60, 98, 168 or 196 film-coated tablets or perforated unit dose blisters in cartons of 10x1 or 100x1 or in multipacks containing 100 film-coated tablets (10 packs of 10x1).
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
No special instructions for disposal.
07.0 MARKETING AUTHORIZATION HOLDER
Bayer Pharma AG
13342 Berlin
Germany
08.0 MARKETING AUTHORIZATION NUMBER
14 tablets blister (PP / alu) EU / 1/08/472/025 038744254 / E
28 tablets blister (PP / alu) EU / 1/08/472/026 038744266 / E
56 tablets blister (PP / alu) EU / 1/08/472/027 038744278 / E
60 tablets blister (PP / alu) EU / 1/08/472/028 038744280 / E
98 tablets blister (PP / alu) EU / 1/08/472/029 038744292 / E
168 tablets blister (PP / alu) EU / 1/08/472/030 038744304 / E
196 tablets blister (PP / alu) EU / 1/08/472/031 038744316 / E
10 x 1 tablets blister (PP / alu) EU / 1/08/472/032 038744328 / E
100 x 1 tablets blister (PP / alu) EU / 1/08/472/033 038744330 / E
10 x 10 x 1 tablets blister (PP / alu) EU / 1/08/472/034
30 tablets blister (PP / alu) EU / 1/08/472/035
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 30 September 2008
Date of most recent renewal: May 22, 2013
10.0 DATE OF REVISION OF THE TEXT
05/2015
