Active ingredients: Apixaban
Eliquis 2.5 mg film-coated tablets
Eliquis package inserts are available for pack sizes:- Eliquis 2.5 mg film-coated tablets
- Eliquis 5 mg film-coated tablets
Indications Why is Eliquis used? What is it for?
Eliquis contains the active substance apixaban and belongs to a group of medicines called anticoagulants. This medicine helps prevent blood clots from forming by blocking Factor Xa, which is an important component of blood clotting.
Eliquis is used in adults:
- to prevent the formation of blood clots (deep vein thrombosis [DVT]) after hip or knee replacement surgery. After an operation on the hip or knee, you may be at increased risk of developing blood clots in the veins of the legs. This can cause swelling of the legs, with or without pain. If a blood clot travels from the leg to the lungs, it can block blood flow causing shortness of breath, with or without chest pain. This condition ( pulmonary embolism) can be life-threatening and requires immediate medical attention.
- to prevent blood clots in the heart in patients with an irregular heartbeat (atrial fibrillation) and with at least one additional risk factor. Blood clots can break off and travel to the brain, leading to stroke, or to other organs preventing normal blood flow to those organs (also known as systemic embolism). A stroke can be life threatening and requires immediate medical attention.
- to treat blood clots in the veins of the legs (deep vein thrombosis) and in the blood vessels of the lungs (pulmonary embolism) and to prevent blood clots from forming in the blood vessels of the legs and / or lungs.
Contraindications When Eliquis should not be used
Do not take Eliquis if:
- you are allergic to apixaban or any of the other ingredients of this medicine
- have excessive blood loss
- have a disease in a body organ that leads to an increased risk of severe bleeding (such as a recent or ongoing ulcer of the stomach or intestines, recent bleeding in the brain)
- have liver disease which leads to an increased risk of bleeding (liver coagulopathy)
- you are taking medicines to prevent blood clots (for example, warfarin, rivaroxaban, dabigatran or heparin), except when you are changing your anti-coagulant treatment or while you have a venous or arterial catheter and are taking heparin through it away to keep it open.
Precautions for use What you need to know before taking Eliquis
Talk to your doctor, pharmacist or nurse before taking this medicine if you have any of the following conditions:
an increased risk of bleeding, such as:
- bleeding disorders, including conditions that lead to reduced platelet activity
- very high blood pressure, not controlled by medical treatment
- if you are over 75 years old
- if you weigh 60 kg or less
- severe kidney disease or if you are on dialysis
- liver problems or a history of liver problems
Eliquis will be used with caution in patients with signs of impaired liver function.
- have a tube (catheter) or have had an "injection into the spine (for anesthesia or pain relief). Your doctor will tell you to take Eliquis 5 hours or more after removing the catheter.
- has a prosthetic heart valve
- if your doctor detects that your blood pressure is unstable or if another treatment or surgical procedure is planned to remove a blood clot from the lungs.
If you are having surgery or a procedure that may cause bleeding, your doctor may ask you to temporarily stop taking this medicine for a short time. If you are unsure whether a procedure may cause bleeding ask your doctor.
Children and adolescents
Eliquis is not recommended for children and adolescents under 18 years of age.
Interactions Which drugs or foods can change the effect of Eliquis
Tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other medicines.
Some medicines may increase the effect of Eliquis and others may decrease it. Your doctor will decide whether you should be treated with Eliquis when you take these medicines and how carefully you should be observed.
The following medicines may increase the effect of Eliquis and increase the chance of unwanted bleeding:
- some medicines for fungal infections (e.g. ketoconazole, etc.)
- some antiviral medicines for HIV / AIDS (eg ritonavir)
- other medicines used to reduce blood clotting (e.g. enoxaparin, etc.)
- anti-inflammatories or painkillers (e.g. aspirin or naproxen). Particularly if you are over 75 years of age and are taking aspirin you may have a greater chance of bleeding. - medicines for high blood pressure or heart problems (e.g. diltiazem)
The following medicines may reduce the effect of Eliquis in helping to prevent blood clots:
- medicines for epilepsy or seizures (eg phenytoin, etc.)
- St. John's wort (a herbal product used for depression)
- medicines to treat tuberculosis or other infections (e.g. rifampicin)
Warnings It is important to know that:
Pregnancy and breastfeeding
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor, pharmacist or nurse for advice before taking this medicine.
The effect of Eliquis on pregnancy and the unborn child is not known. You should not take Eliquis if you are pregnant. Contact your doctor immediately if you become pregnant while taking Eliquis.
It is not known if Eliquis passes into breast milk. Consult your doctor, pharmacist or nurse before taking this medicine while breastfeeding. They will advise you whether to discontinue breastfeeding or to discontinue / not initiate Eliquis therapy.
Driving and using machines
Eliquis had no effect on the ability to drive or use machines.
Eliquis contains lactose (a type of sugar).
If you have been told by your doctor that you have an "intolerance to some sugars, contact your doctor before taking this medicinal product.
Dose, Method and Time of Administration How to use Eliquis: Posology
Always take this medicine exactly as your doctor or pharmacist has told you. If in doubt, consult your doctor, pharmacist or nurse
Dose
Swallow the tablet with some water. Eliquis can be taken with or without food.
Take Eliquis as recommended:
To prevent blood clots from forming after hip or knee replacement operations.
The recommended dose is one Eliquis 2.5 mg tablet twice a day.
For example, one in the morning and one in the evening. Try to take the tablets at the same time each day to get the best effect from the treatment.
You must take the first tablet 12 to 24 hours after the operation.
If you have had a "hip operation" you will usually take the tablets for a period of 32 to 38 days. If you have had a knee operation, you will usually take the tablets for 10 to 14 days.
To prevent blood clots in the heart in patients with an irregular heartbeat and at least one additional risk factor
The recommended dose is one Eliquis 5 mg tablet twice a day.
The recommended dose is one Eliquis 2.5 mg tablet twice a day if:
- have severely reduced kidney function
- if it falls under two or more of the following conditions:
- blood test results suggest poor kidney function (serum creatinine value is 1.5 mg / dl (133 micromol / l) or higher)
- is "80 years of age or older
- its weight is 60 kg or less.
The recommended dose is one tablet twice a day, for example, once in the morning and once in the evening. Try to take the tablets at the same time each day to get the best effect from the treatment
Your doctor will decide how long you need to continue the treatment.
To treat blood clots in the veins of the legs and in the blood vessels of the lungs
The recommended dose is two Eliquis 5 mg tablets twice a day for the first 7 days, for example two in the morning and two in the evening.
After 7 days the recommended dose is one Eliquis 5 mg tablet twice a day, for example, one in the morning and one in the evening. Try to take the tablets at the same time each day to get the best effect from the treatment.
To prevent blood clots from re-forming after 6 months of treatment is completed
The recommended dose is one Eliquis 2.5 mg tablet twice a day, for example, one in the morning and one in the evening. Try to take the tablets at the same time each day to get the best effect from the treatment.
Your doctor will decide how long you need to continue the treatment.
Your doctor may change your anticoagulant treatment as follows:
- Switching from Eliquis to an anticoagulant medicine
Stop taking Eliquis. Start treatment with the anticoagulant medicine (for example heparin) when you should have taken the next tablet.
- Switching from an anticoagulant medicine to Eliquis
Stop taking the anticoagulant medicine. Start treatment with Eliquis when you should have taken the next dose of the anticoagulant medicine, then continue taking it as normal.
- Changing from anticoagulant treatment containing a vitamin K antagonist (e.g. warfarin) to Eliquis
Stop taking the medicine containing the vitamin K antagonist. Your doctor will need to do blood tests and instruct you on when to start treatment with Eliquis.
- Switching from Eliquis to treatment with an anticoagulant containing a vitamin K antagonist (e.g. warfarin).
If your doctor tells you to start taking a medicine containing a vitamin K antagonist, continue taking Eliquis for at least 2 days after the first dose of the medicine containing a vitamin K antagonist. Your doctor will need to do blood tests and to instruct you on when to stop taking Eliquis.
Overdose What to do if you have taken too much Eliquis
Tell your doctor immediately if you have taken more than the prescribed dose of Eliquis. Take the medicine pack with you, even if there are no tablets left. If you take more Eliquis than recommended, you may have a higher risk of bleeding. If bleeding occurs, you may need an operation or transfusion.
If you forget to take Eliquis
Take the tablet as soon as you remember and:
- take the next Eliquis tablet at the usual time
- then continue as planned.
If you are unsure what to do or if you have missed more than one dose, consult your doctor, pharmacist or nurse.
If you stop taking Eliquis
Do not stop taking Eliquis without talking to your doctor first, as the risk of developing a blood clot may be higher if you stop treatment too soon.
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.
Side Effects What are the side effects of Eliquis
Like all medicines, this medicine can cause side effects, although not everybody gets them. Eliquis can be given for two different medical conditions. The known side effects and the frequency with which they occur may be different and are listed separately below. For both conditions, the most common general side effect of Eliquis is bleeding which can potentially be life threatening and requires immediate medical attention.
The following side effects are known to occur when Eliquis is taken to prevent blood clots from forming after hip or knee replacement operations.
Common side effects (may affect up to 1 in 10 people)
- Anemia which can cause tiredness or pale skin
- Bleeding, including:
blood in the urine (which makes the urine pink or red)
bruising and swelling
vaginal bleeding
- Nausea (feeling sick)
Uncommon side effects (may affect up to 1 in 100 people)
- Reduction in the number of platelets in the blood (which can affect clotting)
- Bleeding, including:
- bleeding that occurs after the operation, including bruising and swelling, loss of blood or fluids from the wound / surgical incision (discharge from the wound)
- bleeding from the stomach, intestines or blood in the stool
- blood in the urine
- nose bleeding
- Low blood pressure which can cause you to feel weak or have a fast heartbeat
- Blood tests can show:
- abnormal liver function
- increase in some liver enzymes
- increase in bilirubin, a product of the breakdown of red blood cells, which can cause yellowing of the skin and eyes.
- Itching
Rare side effects (may affect up to 1 in 1000 people)
- Allergic (hypersensitivity) reactions which can cause: swelling of the face, lips, mouth, tongue and / or throat and difficulty in breathing. Contact your doctor immediately if you experience any of these symptoms.
- Bleeding:
- in the muscles
- in the eyes
- to the gums and blood in the sputum when coughing
- from the rectum
The following side effects are known to occur when Eliquis is taken to prevent blood clots in the heart in patients with an irregular heartbeat and with at least one additional risk factor.
Common side effects (may affect up to 1 in 10 people
- Bleeding, including:
- in the eyes
- in the stomach, intestines or dark / black blood in the stool
- blood in the urine found in laboratory tests
- from the nose
- from the gums
- bruising and swelling
Uncommon side effects (may affect up to 1 in 100 people)
- Bleeding, including:
- in the brain or spine
- in the mouth or blood in the sputum when coughing
- in the abdomen, rectum and vagina
- clear / red blood in the stool
- bleeding that occurs after any operation, including bruising and swelling, loss of blood or fluids from the surgical wound / incision (wound discharge) or from the injection site.
- Itching
- Allergic (hypersensitivity) reactions which can cause: swelling of the face, lips, mouth, tongue and / or throat and difficulty in breathing. Contact your doctor immediately if you experience any of these symptoms.
Rare side effects (may affect up to 1 in 1000 people)
- bleeding in the lungs or throat
- bleeding into the space behind the abdominal cavity
The following side effects are known to occur when Eliquis is taken to treat or prevent blood clots from forming in the veins of the legs and in the blood vessels of the lungs.
Common side effects (may affect up to 1 in 10 people)
- Bleeding, including:
- from the nose
- from the gums
- blood in the urine (which makes the urine pink or red)
- bruising and swelling
- in the stomach, intestines, rectum
Uncommon side effects (may affect up to 1 in 100 people)
- Bleeding, including:
- in the eye and eye bruises
- in the mouth or blood in the sputum when coughing
- dark / black blood in the stool
- in the uterus or vagina
- tests showing blood in the stool or urine
- bruising and swelling of a surgical wound or injection site
- Itching
Rare side effects (may affect up to 1 in 1000 people)
- abnormal tendency to spontaneous bleeding, loss of red blood cells due to bleeding
- Bleeding, including:
- in the brain
- in the abdomen, lungs or the membrane surrounding the heart
Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. 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. 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 blister after EXP or 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.
Contents of the pack and other information
What Eliquis contains
- The active ingredient is apixaban. Each tablet contains 2.5 mg of apixaban.
- The excipients are:
Tablet core: anhydrous lactose, microcrystalline cellulose, croscarmellose sodium, sodium lauryl sulfate, magnesium stearate (E470b).
Coating: lactose monohydrate, hypromellose (E464), titanium dioxide (E171), triacetin, yellow iron oxide (E172)
What Eliquis looks like and contents of the pack
The film-coated tablets are yellow, round, debossed with "893" on one side and "2½" on the other.
- They are contained in blisters packed in cartons of 10, 20, 60, 168 and 200 film-coated tablets.
- Single-dose perforated blisters are also available in cartons of 60 x 1 and 100 x 1 film-coated tablets for hospital distribution.
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
ELIQUIS 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 apixaban.
Excipients with known effects:
Each 2.5 mg film-coated tablet contains 51.43 mg of lactose (see section 4.4).
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Film-coated tablets (tablet)
Round, yellow tablets debossed with 893 on one side and 2½ on the other.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Prevention of venous thromboembolic events (VTE) in adult patients undergoing elective hip or knee replacement surgery.
Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation (NVAF), with one or more risk factors, such as a previous stroke or transient ischemic attack (TIA), age ≥ 75 years, hypertension, diabetes mellitus, symptomatic heart failure (NYHA class ≥ II).
Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) and prevention of recurrence of DVT and PE in adults (see section 4.4 for patients with haemodynamically unstable PE).
04.2 Posology and method of administration
Dosage
VTE prevention (pTEV): elective hip or knee replacement surgery
The recommended dose of Eliquis is 2.5 mg twice a day orally. The starting dose should be taken 12 to 24 hours after surgery.
In deciding the timing of administration within this time interval, clinicians may consider the potential benefits of earlier anticoagulation for VTE prophylaxis as well as the risk of post-surgical bleeding.
Patients undergoing hip replacement surgery
The recommended duration of treatment is 32 to 38 days.
Patients undergoing knee replacement surgery
The recommended duration of treatment is 10 to 14 days.
Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF)
The recommended dose of Eliquis is 5 mg twice a day orally.
Dose reduction
The recommended dose of Eliquis is 2.5 mg twice daily orally in patients with NVAF and at least two of the following: age ≥80 years, body weight ≤ 60 kg, or serum creatinine ≥ 1.5 mg / dL ( 133 micromoles / l).
Therapy must be continued long-term.
Treatment of DVT, treatment of PE and prevention of recurrence of DVT and PE (tTEV)
The recommended dose of Eliquis for the treatment of acute DVT and for the treatment of PE is 10 mg orally twice daily for the first 7 days followed by 5 mg orally twice daily. According to available medical guidelines, short-term treatment (at least 3 months) must be based on transient risk factors (such as recent surgery, trauma, immobilization).
The recommended dose of Eliquis for the prevention of recurrence of DVT and PE is 2.5 mg, orally, twice daily. When prevention of recurrence of DVT and PE is indicated, the daily dose of 2.5 mg, twice daily, should be started after the completion of six months of treatment with Eliquis 5 mg twice daily or with another anticoagulant. , as indicated below in Table 1 (see also section 5.1).
Table 1:
The overall duration of therapy should be individualized after careful consideration of the treatment benefits against the risk of bleeding (see section 4.4).
Forgetfulness of a dose
If a dose is missed, the patient should take Eliquis immediately and then continue taking it twice daily as before.
Switching
Switching from parenteral anticoagulant therapy to Eliquis, and vice versa, can be done when the next dose is scheduled (see section 4.5). These agents should not be administered concurrently.
Switching from vitamin K antagonist (AVK) therapy to Eliquis
When patients switch from vitamin K antagonist (VKA) therapy to Eliquis, stop warfarin or other VKA therapy and start Eliquis when the international normalized ratio (INR) is
Switching from Eliquis to AVK therapy
When patients switch from Eliquis to vitamin K antagonist therapy, continue Eliquis administration for at least two days after starting AVK therapy. After two days of co-administration of Eliquis and AVK therapy perform an INR test before the next scheduled dose of Eliquis. Continue co-administration of Eliquis and AVK therapy until the international normalized ratio (INR) is ≥ 2.0.
Patients with renal impairment
No dose adjustment is necessary in patients with mild or moderate renal impairment (see section 5.2).
In patients with severe renal impairment (creatinine clearance 15 - 29 ml / min) the following recommendations apply (see sections 4.4 and 5.2):
- for the prevention of VTE in elective hip or knee replacement surgery (pTEV), for the treatment of DVT, for the treatment of PE and prevention of recurrence of DVT and PE (tTEV) apixaban should be used with caution;
- For the prevention of stroke and systemic embolism in patients with NVAF, patients should receive the lowest apixaban dose of 2.5 mg twice daily.
Patients with serum creatinine ≥ 1.5 mg / dL (133 micromol / L) associated with age ≥ 80 years or body weight ≤ 60 kg should receive the lowest apixaban dose of 2.5 mg twice daily. .
In patients with creatinine clearance on dialysis, there is no clinical experience and therefore the use of apixaban is not recommended (see sections 4.4 and 5.2).
Patients with hepatic impairment
Eliquis is contraindicated in patients with hepatic disease associated with coagulopathy and a clinically significant risk of bleeding (see section 4.3).
It is not recommended in patients with severe hepatic impairment (see sections 4.4. And 5.2).
It should be used with caution in patients with mild or moderate hepatic impairment (Child Pugh A or B). No dose adjustment is necessary in patients with mild or moderate hepatic impairment (see sections 4.4 and 5.2).
Patients with elevated liver enzymes (ALT / AST> 2 x ULN) or total birilubin ≥ 1.5 x ULN were excluded from clinical studies. Eliquis should therefore be used with caution in this population (see sections 4.4 and 5.2). Liver function tests should be performed before starting treatment with Eliquis.
Body weight
pTEV and tTEV- No dose adjustment is required (see sections 4.4 and 5.2). NVAF- No dose adjustment is required unless the criteria for dose reduction are met (see Dose reduction at the beginning of paragraph 4.2).
Sex
No dose adjustment is necessary (see section 5.2).
Senior citizens
pTEV and tTEV - No dose adjustment is necessary (see sections 4.4 and 5.2).
NVAF - No dose adjustment is required unless the criteria for dose reduction are met (see Dose reduction at the beginning of section 4.2).
Cardioversion (NVAF)
Patients undergoing cardioversion can continue apixaban treatment.
Pediatric population
The safety and efficacy of Eliquis in children and adolescents below 18 years of age have not been established. There are no data available.
Method of administration
Oral use.
Eliquis must be swallowed with water, with or without food.
04.3 Contraindications
• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
• Clinically significant bleeding in progress.
• Liver disease associated with coagulopathy and clinically relevant bleeding risk (see section 5.2).
• Injuries or conditions considered significant risk factors for major bleeding.
These may include current or recent gastrointestinal ulcer, presence of malignant neoplasms with high risk of bleeding, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial haemorrhage, known or suspected esophageal varices, arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular anomalies.
• Concomitant treatment with any other anticoagulant agent such as unfractionated heparin (ENF), low molecular weight heparin (enoxaparin, dalteparin etc.), heparin derivatives (fondaparinux etc.), oral anticoagulants (warfarin, rivaroxaban, dabigatran etc. .)
except in specific circumstances of changing anticoagulant therapy (see section 4.2) or when ENF is administered at doses necessary to maintain an open central venous or arterial catheter (see section 4.5).
04.4 Special warnings and appropriate precautions for use
Risk of bleeding
As with other anticoagulants, patients taking Eliquis should be observed for any signs of bleeding. It is recommended to use it with caution in conditions of increased risk of bleeding. If severe bleeding occurs, administration of Eliquis should be discontinued (see sections 4.8 and 4.9).
Although apixaban treatment does not require routine monitoring of exposure level, a calibrated quantitative anti-FXa assay may be useful in exceptional circumstances when knowledge of apixaban exposure level can help support clinical decisions, for example, overdose and emergency surgery (see section 5.1).
Interaction with other medicinal products affecting haemostasis
Due to the increased risk of bleeding, concomitant treatment with any other anticoagulant is contraindicated (see section 4.3).
Concomitant use of Eliquis with antiplatelet agents increases the risk of bleeding (see section 4.5).
If patients are treated concomitantly with non-steroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid, caution should be used.
The concomitant use of Eliquis, following surgery, with other inhibitors of platelet aggregation is not recommended (see section 4.5).
In patients with atrial fibrillation and conditions requiring mono or dual antiplatelet therapy, a careful evaluation of the potential benefits against the potential risks must be made before combining such therapy with Eliquis.
In a clinical study in patients with atrial fibrillation, concomitant use of ASA increased the risk of major bleeding with apixaban from 1.8% per year to 3.4% per year and increased the risk of bleeding with warfarin. from 2.7% per year to 4.6% per year. Concomitant use with dual antiplatelet therapy in this clinical study was limited (2.1%). In a clinical study of high-risk patients post acute coronary syndrome, characterized by multiple cardiac and non-cardiac co-morbidities, receiving ASA o the combination of ASA and clopidogrel, a significantly increased risk of ISTH major bleeding was reported for apixaban (5.13% per year) compared to placebo (2.04% per year) .
Use of thrombolytic agents for the treatment of acute ischemic stroke
Experience with the use of thrombolytic agents for the treatment of acute ischemic stroke in patients administered apixaban is very limited.
Patients with a prosthetic heart valve
The safety and efficacy of Eliquis in patients with a prosthetic heart valve, with or without atrial fibrillation, have not been studied. Therefore, the use of Eliquis in this setting is not recommended.
Surgery and invasive procedures
Eliquis should be stopped at least 48 hours before an elective surgery or invasive procedure at risk of moderate or high bleeding. This includes interventions for which a clinically relevant probability of bleeding cannot be excluded or for which the risk of bleeding would not be acceptable.
Eliquis must be stopped at least 24 hours before an elective surgery or invasive procedure with low bleeding risk. This includes interventions for which the expected bleeding risk is minimal, not critical to its location or easily controlled.
If surgery or invasive procedures cannot be postponed, due caution should be exercised, taking into account an increased risk of bleeding. This bleeding risk must be weighed against the urgency of surgery.
Following invasive procedure or surgery, apixaban should be restarted as soon as possible provided the clinical situation permits and adequate haemostasis has been established (for cardioversion see section 4.2).
Temporary interruption
Discontinuation of anticoagulants, including Eliquis, for ongoing bleeding, elective surgery, or invasive procedures exposes patients to an increased risk of thrombosis. Pauses in therapy should be avoided and if anticoagulation with Eliquis is to be temporarily interrupted for any reason, therapy should be restarted as soon as possible.
Spinal / epidural anesthesia or puncture When using neuraxial anesthesia (spinal / epidural anesthesia) or spinal / epidural puncture, patients treated with antithrombotic agents for the prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma which can lead to prolonged or permanent paralysis.
The risk of these events may be increased with postoperative use of indwelling epidural catheters or concomitant use of medicinal products affecting haemostasis. Indwelling epidural or intrathecal catheters should be removed at least 5 hours before the first dose of Eliquis. The risk may also be increased with traumatic or repeated epidural or spinal puncture. Patients should be monitored frequently for signs and symptoms of neurologic deficit (eg numbness or weakness in the legs, bowel or bladder dysfunction). neurologic impairment is noted, immediate diagnosis and treatment are required Prior to neuraxial surgery, physicians should evaluate the potential benefit against the risk present in patients on anticoagulant therapy or in patients who need to take anticoagulants for thromboprophylaxis.
There is no clinical experience with the use of apixaban with indwelling intrathecal or epidural catheters. If this is the case, and based on general pharmacokinetic data characteristic of apixaban, a time interval of 20-30 hours (ie 2 times the half-life) should elapse between the last dose of apixaban and the removal of the catheter. , and at least one dose must be omitted before catheter removal. The next dose of apixaban should be administered at least 5 hours after catheter removal. As with all new anticoagulant drugs, experience with neuraxial block is limited, and extreme caution is therefore recommended in the use of apixaban in the presence of neuraxial block.
Patients with haemodynamically unstable PE or patients requiring pulmonary thrombolysis or embolectomy
Eliquis is not recommended as an alternative to unfractionated heparin in patients with pulmonary embolism who are haemodynamically unstable or who may be undergoing pulmonary thrombolysis or embolectomy, as the safety and efficacy of Eliquis in these clinical conditions have not been established.
Active cancer patients
The efficacy and safety of apixaban in the treatment of DVT, in the treatment of PE and in the prevention of recurrence of DVT and PE (tTEV) in patients with active cancer have not been established.
Renal impairment
Limited clinical data indicate that apixaban plasma concentrations in patients with severe renal impairment (creatinine clearance 15-29 ml / min) are increased, which may lead to an increased risk of bleeding.
Apixaban should be used with caution, in patients with severe renal impairment (creatinine clearance 15 - 29 ml / min), for the prevention of VTE in elective hip or knee replacement surgery (pTEV), for treatment DVT, for the treatment of PE and prevention of recurrence of DVT and PE (tTEV) (see sections 4.2 and 5.2).
For the prevention of stroke and systemic embolism in patients with NVAF, patients with severe renal impairment (creatinine clearance 15-29 mL / min) and patients with serum creatinine ≥ 1.5 mg / dL (133 micromol / L ) associated with age ≥ 80 years or body weight ≤ 60 kg should receive the lowest apixaban dose of 2.5 mg twice daily (see section 4.2). In patients with creatinine clearance
Elderly patients
With "increasing age" the risk of bleeding may increase (see section 5.2).
Co-administration of Eliquis with ASA in elderly patients should also be used with caution due to a potentially higher risk of bleeding.
Body weight
A low body weight (
Hepatic impairment
Eliquis is contraindicated in patients with hepatic disease associated with coagulopathy and at risk of clinically relevant bleeding (see section 4.3).
It is not recommended in patients with severe hepatic impairment (see section 5.2).
It should be used with caution in patients with mild or moderate hepatic impairment (Child Pugh A or B) (see sections 4.2 and 5.2).
Patients with elevated liver enzymes ALT / AST> 2 x ULN or total birilubin ≥ 1.5 x ULN were excluded from clinical studies. Eliquis should therefore be used with caution in this population (see section 5.2). Liver function tests should be performed before starting treatment with Eliquis.
Interaction with inhibitors of both cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp)
The use of Eliquis is not recommended in patients receiving concomitant systemic therapy with potent inhibitors of both CYP3A4 and P-gp, such as azole antifungals (eg, ketoconazole, itraconazole, voriconazole and posaconazole) and protease inhibitors. HIV (eg ritonavir).
These medicinal products may increase apixaban exposure by 2-fold (see section 4.5), or more in the presence of additional factors that increase apixaban exposure (eg severe renal impairment).
Interaction with inducers of both CYP3A4 and P-gp
Concomitant use of Eliquis with potent inducers of both CYP3A4 and P-gp (eg rifampicin, phenytoin, carbamazepine, phenobarbital or St. John's wort) can lead to an approximately 50% reduction in exposure to "apixaban. In a clinical study in patients with atrial fibrillation, a decrease in efficacy and a higher bleeding risk were observed with concomitant administration of apixaban and strong inducers of both CYP3A4 and P-gp than when apixaban was administered alone.
In patients receiving concomitant systemic treatment with potent inducers of both CYP3A4 and P-gp the following recommendations apply (see section 4.5):
- for the prevention of VTE in elective hip or knee replacement surgery, for the prevention of stroke and systemic embolism in patients with NVAF and the prevention of recurrence of DVT and PE, apixaban should be used with caution;
- For the treatment of DVT and the treatment of PE, apixaban should not be used as efficacy may be impaired.
Hip Fracture Surgery
The efficacy and safety of apixaban have not been evaluated in clinical studies in patients undergoing hip fracture surgery. Therefore, use in these patients is not recommended.
Laboratory parameters
As expected, coagulation tests (eg PT, INR and aPTT) are influenced by the mechanism of action of apixaban. The changes observed in these coagulation tests, at the intended therapeutic doses, are minimal and subject to a high degree of variability. (see section 5.1).
Information on excipients
Eliquis 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 apixaban and ketoconazole (400 mg once daily), a potent inhibitor of both CYP3A4 and P-gp, resulted in a 2-fold increase in mean apixaban AUC and a 1.6-fold increase. of the mean Cmax of apixaban.
The use of Eliquis is not recommended in patients receiving concomitant systemic therapy with potent inhibitors of both CYP3A4 and P-gp, such as azole antifungals (eg, ketoconazole, itraconazole, voriconazole and posaconazole) and protease inhibitors. HIV (e.g. ritonavir) (see section 4.4).
Active substances that are not considered strong inhibitors of CYP3A4 and P-gp (e.g. diltiazem, naproxen, amiodarone, verapamil, quinidine) are expected to increase apixaban plasma concentrations to a lesser extent. For example, diltiazem (360 mg once daily), considered a moderate inhibitor of CYP3A4 and a weak inhibitor of P-gp, resulted in a 1.4-fold increase in mean apixaban AUC and a 1.3-fold increase. -fold in Cmax. Naproxen (500 mg single dose), a P-gp but not CYP3A4 inhibitor, induced a 1.5- and 1.6-fold increase in mean AUC and mean Cmax of apixaban, respectively. . No dose adjustments of apixaban are required in case of concomitant therapy with less potent CYP3A4 and / or P-gp inhibitors.
Inducers of CYP3A4 and P-gp
Concomitant administration of apixaban and rifampicin, a potent inducer of both CYP3A4 and P-gp, resulted in approximately 54% and 42% decrease in mean AUC and Cmax of apixaban, respectively. Concomitant use of apixaban and other potent inducers of CYP3A4 and P-gp (eg phenytoin, carbamazepine, phenobarbital or St. John's wort) may lead to decreased plasma concentrations of apixaban. No dose adjustment of apixaban is required during concomitant therapy with these agents, however in patients receiving concomitant systemic treatment with potent inducers of both CYP3A4 and P-gp, apixaban should be used with caution for the prevention of VTE. elective hip or knee replacement surgery (pTEV), for the prevention of stroke and systemic embolism in patients with NVAF and for the prevention of recurrence of DVT and PE. Apixaban is not recommended for the treatment of DVT and PE in patients receiving concomitant systemic treatment with potent inducers of both CYP3A4 and P-gp as efficacy may be impaired (see section 4.4).
Anticoagulants, platelet aggregation inhibitors and NSAIDs
Due to the increased risk of bleeding, concomitant treatment with any other anticoagulant agent is contraindicated (see section 4.3).
Following administration of enoxaparin (40 mg single dose) in combination with apixaban (5 mg single dose) an additive effect on anti-factor Xa activity was observed.
No pharmacokinetic or pharmacodynamic interactions were observed when apixaban was co-administered with ASA at a dose of 325 mg once daily. In Phase I clinical trials, apixaban administered concomitantly with clopidogrel (75 mg once daily), or the combination of clopidogrel 75 mg and ASA 162 mg once daily, or with prasugrel (60 mg followed by 10 mg once daily) did not show a relevant increase in bleeding time, or "further inhibition of" platelet aggregation, compared with the administration of antiplatelet agents without apixaban. Increases in coagulation tests (PT, INR, and aPTT) were consistent with the effects of apixaban alone.
Naproxen (500 mg), a P-gp inhibitor, induced a 1.5- and 1.6-fold increase in the mean AUC and Cmax of apixaban, respectively. A corresponding increase in coagulation test results was observed. No changes in the effect of naproxen on arachidonic acid-induced platelet aggregation were observed, and no clinically relevant prolongation of bleeding time was observed following concomitant administration of apixaban and naproxen.
Despite these findings, there may be individuals with a more pronounced pharmacodynamic response when antiplatelet agents are co-administered with apixaban. Eliquis should be used with caution when given concomitantly with NSAIDs (including acetylsalicylic acid), because these medicines typically increase the risk of bleeding.In a clinical study, a significantly increased risk of bleeding was reported with the triple combination of apixaban, ASA and clopidogrel in patients with acute coronary syndrome (see section 4.4).
Agents associated with severe bleeding risk, such as thrombolytic agents, GP IIb / IIIa receptor antagonists, thienopyridines (e.g. clopidogrel), dipyridamole, dextran, and sulfinpyrazone are not recommended in concomitant therapy with Eliquis.
Other concomitant therapies
When apixaban was co-administered with atenolol or famotidine, no clinically significant pharmacokinetic or pharmacodynamic interactions were observed. Co-administration of apixaban 10 mg with atenolol 100 mg had no clinically relevant effect on apixaban pharmacokinetics.
After concomitant administration of the two medicinal products, the mean AUC and Cmax of apixaban were 15% and 18% lower than when given alone. Administration of apixaban 10 mg with famotidine 40 mg had no effect on AUC. o the Cmax of apixaban.
Effect of apixaban on other medicinal products
Studies in vitro on apixaban showed no inhibitory effect on CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2D6 or CYP3A4 activity (IC50> 45 μM) and showed a weak inhibitory effect on CYP2C19 activity (IC50> 20 μM) at concentrations significantly higher than the peak plasma concentrations observed in patients. Apixaban did not induce induction of CYP1A2, CYP2B6, CYP3A4 / 5 at a concentration up to 20 mcM. Therefore, apixaban is not expected to alter the metabolic clearance of concomitantly administered drugs that are metabolised by these enzymes. Apixaban is not a significant inhibitor of P-gp.
In studies conducted in healthy subjects, as described below, apixaban did not significantly alter the pharmacokinetics of digoxin, naproxen or atenolol.
Digoxin: Concomitant administration of apixaban (20 mg once daily) and digoxin (0.25 mg once daily), a substrate of P-gp, had no effect on digoxin AUC or Cmax. Therefore, apixaban it does not inhibit P-gp-mediated substrate transport.
Naproxen: Coadministration of a single dose of apixaban (10 mg) and naproxen (500 mg), a commonly used NSAID, had no effect on the AUC or Cmax of naproxen.
Atenolol: Coadministration of a single dose of apixaban (10 mg) and atenolol (100 mg), a common beta-blocker, did not alter the pharmacokinetics of atenolol.
Activated carbon
Administration of activated charcoal reduces apixaban exposure (see section 4.9).
04.6 Pregnancy and lactation
Pregnancy
There are no data on the use of apixaban in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. Apixaban is not recommended during pregnancy.
Pregnancy
It is unknown whether apixaban or its metabolites are excreted in human milk. Data from animal studies showed excretion of apixaban in breast milk. A high ratio of milk to maternal plasma (Cmax about 8, AUC about 30) was found in rat milk, possibly due to active transport into milk. A risk to newborns and infants cannot be excluded.
A decision must be made whether to discontinue breastfeeding or to discontinue / abstain from apixaban therapy.
Fertility
Studies in animals receiving doses of apixaban have shown no effects on fertility (see section 5.3).
04.7 Effects on ability to drive and use machines
Eliquis has no or negligible effects on the ability to drive or use machines.
04.8 Undesirable effects
Summary of the safety profile
The safety of apixaban was evaluated in 7 Phase III clinical trials that included more than 21,000 patients: more than 5,000 patients in the pTEV studies, more than 11,000 patients in the NVAF studies, and more than 4,000 patients in the VTE treatment studies ( tTEV) for a mean total exposure of 20 days, 1.7 years and 221 days, respectively (see section 5.1).
Common adverse reactions were: haemorrhages, contusions, epistaxis and hematoma (see Table 2 for adverse event profile and frequencies by indication).
In the pTEV studies, a total of 11% of patients treated with apixaban 2.5 mg twice daily experienced adverse reactions. The overall incidence of bleeding-related adverse reactions with apixaban was 10% in the apixaban studies. vs enoxaparin.
In the NVAF studies, the overall incidence of bleeding-related adverse reactions with apixaban was 24.3% in the apixaban vs warfarin study and 9.6% in the apixaban vs aspirin study. ISTH major gastrointestinal bleeding (including upper gastrointestinal bleeding, lower gastrointestinal bleeding and rectal bleeding) with apixaban was 0.76% / year. The incidence of ISTH major intraocular bleeding with apixaban was 0.18% / year.
In the tTEV studies, the overall incidence of bleeding-related adverse reactions with apixaban was 15.6% in the apixaban vs enoxaparin / warfarin study and 13.3% in the apixaban vs placebo study (see section 5.1).
Tabular list of adverse reactions
Table 2 shows adverse reactions classified by System Organ Class and by frequency using the following conventions: very common (≥ 1/10); common (≥ 1/100,
Table 2
Use of Eliquis may be associated with an increased risk of overt or occult bleeding into tissues or organs, which can lead to posthemorrhagic anemia. Signs, symptoms and severity will vary by site and grade or all. "extent of bleeding (see section 4.4 and section 5.1).
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. .
04.9 Overdose
There is no antidote to Eliquis. An overdose of apixaban can lead to an increased risk of bleeding. In case of bleeding complications, treatment should be stopped and the origin of the bleeding should be sought. Institution of appropriate treatment should be considered. surgical hemostasis or transfusion of fresh frozen plasma.
In controlled clinical trials, oral administration of apixaban to healthy subjects at doses up to 50 mg per day for a period of 3 to 7 days (25 mg twice daily (bid) for 7 days, or 50 mg once per day (OD) for 3 days) had no clinically relevant undesirable effects.
In healthy subjects, administration of activated charcoal 2 and 6 hours after ingestion of a 20-mg dose of apixaban reduced the mean AUC by 50% and 27%, respectively, and had no impact on Cmax. The mean half-life of apixaban decreased from 13.4 hours (when given alone), to 5.3 hours and 4.9 hours, when activated charcoal was given 2 and 6 hours after apixaban, respectively. Therefore, the administration of activated charcoal may be useful in the management of overdose or accidental ingestion of apixaban.
If life-threatening bleeding cannot be controlled by the measures described, administration of recombinant factor VIIa may be considered.
However, to date there is no experience with the use of recombinant factor VIIa in subjects treated with apixaban. A new dosage of recombinant factor VIIa could be considered and titrated, based on improvement in bleeding.
Based on local availability, consultation with a coagulation expert should be considered in the event of major bleeding.
When a single 5 mg dose of apixaban was administered orally in subjects with end stage renal disease (ESRD), hemodialysis decreased apixaban AUC by 14%.
Therefore, hemodialysis is unlikely to be an effective method of managing apixaban overdose.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: direct factor Xa inhibitors, ATC code: B01AF02
Mechanism of action
Apixaban is a potent oral, reversible, direct and highly selective active site inhibitor of factor Xa. It does not need antithrombin III to exert antithrombotic activity. Apixaban inhibits free and clot-bound factor Xa, and prothrombinase activity. Apixaban has no direct effect on platelet aggregation, but indirectly inhibits thrombin-induced platelet aggregation. By inhibiting factor Xa, apixaban prevents generation thrombin and thrombus development. Preclinical studies of apixaban in animal models have demonstrated antithrombotic efficacy in the prevention of arterial and venous thrombosis at doses that preserved haemostasis.
Pharmacodynamic effects
The pharmacodynamic effects of apixaban reflect the mechanism of action (inhibition of FXa). As a consequence of inhibition of FXa, apixaban prolongs clotting tests such as prothrombin time (PT), INR and activated partial thromboplastin time. (aPTT) The changes observed in these clotting tests at the intended therapeutic doses are small and subject to a high degree of variability These tests are not recommended for evaluating the pharmacodynamic effects of apixaban.
Apixaban also demonstrates anti-FXa activity as evidenced by the reduction of Factor Xa enzyme activity in multiple commercial anti-FXa kits, however the results between kits differ. Only data for the Rotachrom Heparin chromogenic method are available from clinical studies. L "anti-FXa activity exhibits a close direct linear relationship with apixaban plasma concentration, reaching peak values at the time of apixaban peak plasma concentrations. The relationship between apixaban plasma concentration and anti-FXa activity is approximately linear over a broad spectrum of apixaban doses.
Table 3 below shows the expected steady state exposure and anti-Xa factor activity for each indication. In patients taking apixaban for the prevention of VTE following hip or knee replacement surgery, results show a less than 1.6-fold fluctuation in peak and trough levels. In patients with non-valvular atrial fibrillation who taking apixaban for the prevention of stroke and systemic embolism, results show a less than 1.7-fold fluctuation in peak and trough levels. In patients taking apixaban for treatment of DVT and PE or for prevention of recurrent DVT and PE, the results demonstrate a less than 2.2-fold fluctuation in peak and trough levels.
Table 3: Apixaban Exposure Expected at Steady State and Anti-Xa Activity
* Dose adjusted by population according to 2 of 3 dose reduction criteria in the ARISTOTLE study
Although apixaban treatment does not require routine exposure monitoring, a calibrated quantitative anti-FXa assay may be useful in exceptional circumstances in which knowledge of apixaban exposure can help support clinical decisions, such as overdose and emergency surgery.
Clinical efficacy and safety
VTE prevention (pTEV): elective hip or knee replacement surgery
The apixaban clinical program was designed to demonstrate the efficacy and safety of apixaban in the prevention of venous thromboembolic events in a broad spectrum of adult patients undergoing elective hip or knee replacement. In total, 8,464 patients were randomized in two double-blind, multinational pilot studies comparing apixaban 2.5 mg administered orally twice daily (4,236 patients) and enoxaparin 40 mg once daily (4,228 patients).
Included in this total c "were 1,262 patients (618 in the apixaban group) aged 75 years or older, 1,004 patients (499 in the apixaban group) with low body weight (≤ 60 kg), 1,495 patients (743 in the apixaban group) with BMI ≥ 33 kg / m2, and 415 patients (203 in the apixaban group) with moderate renal impairment.
The ADVANCE-3 study included 5,407 patients undergoing elective hip replacement, and the ADVANCE-2 study included 3,057 patients undergoing elective knee replacement. Subjects received either apixaban 2.5 mg administered orally twice daily. (per os bid) or enoxaparin 40 mg administered subcutaneously once daily (sc od). The first dose of apixaban was administered 12 to 24 hours after surgery, while enoxaparin was started from 9 to 15 hours before the intervention. Both apixaban and enoxaparin were administered for 32-38 days in the ADVANCE-3 study and for 10-14 days in the ADVANCE-2 study.
Based on the clinical history of patients in the ADVANCE-3 and ADVANCE-2 study population (8,464 patients), 46% had hypertension, 10% had hyperlipidemia, 9% had diabetes, and 8% had coronary artery disease .
In elective replacement surgery of both hip and knee, apixaban demonstrated a statistically significant reduction compared to enoxaparin for the primary endpoint, consisting of the combination of VTE events / deaths from any cause, and for the major VTE endpoint, consisting of the ensemble of proximal DVT, non-fatal pulmonary embolism (PE), and VTE-related death, (see Table 4).
Table 4 efficacy results from the phase III pilot studies
The safety endpoints of major bleeding, the combination of major and clinically relevant non-major bleeding (CRNM), and all bleeds showed similar rates for patients treated with apixaban 2.5 mg compared to enoxaparin 40 mg ( see Table 5.) All bleeding parameters included surgical site bleeding.
Table 5: Bleeding results from the pivotal phase III studies *
* All bleeding parameters included surgical site bleeds
1 Includes events that occurred after the first dose of enoxaparin (pre-surgery)
2 Includes events that occurred after the first dose of apixaban (post-surgery)
In Phase II and Phase III clinical trials in elective hip and knee replacement surgery, the total incidences of adverse reactions of bleeding, anemia, and transaminase changes (eg, alanine aminotransferase levels) were numerically lower in patients treated with apixaban versus enoxaparin.
In the knee replacement surgery clinical trial, 4 cases of PE were diagnosed in the apixaban arm during the intended treatment period, compared with none in the enoxaparin arm. No explanation can be given for this increased number of PE cases.
Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF)
A total of 23,799 patients were randomized into the clinical program (ARISTOTLE: apixaban versus warfarin, AVERROES: apixaban versus ASA) which included 11,927 randomized to apixaban.
The program was designed to demonstrate the efficacy and safety of apixaban in the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF) and one or more additional risk factors such as:
• previous stroke or transient ischemic attack (TIA)
• age ≥ 75 years
• hypertension
• diabetes mellitus
• symptomatic heart failure (NYHA class ≥ II)
STUDIO ARISTOTLE
In the ARISTOTLE study a total of 18,201 patients were randomized to double-blind treatment with apixaban 5 mg twice daily (or 2.5 mg twice daily in selected patients [4.7%], see section 4.2) o warfarin (INR target range 2.0-3.0); patients were exposed to study drug for an average of 20 months.
The mean age was 69.1 years, the mean CHADS2 score was 2.1, and 18.9% of patients had had a previous stroke or TIA.
In the study, apixaban achieved statistically significant superiority in the primary goal of prevention of stroke (haemorrhagic or ischemic) and systemic embolism over warfarin (see Table 6).
Table 6: Efficacy Results in Patients with Atrial Fibrillation in the ARISTOTLE Study
For patients randomized to warfarin, the median percentage of time in therapeutic interval (TTR) (INR 2-3) was 66%.
Apixaban showed a reduction in stroke and systemic embolism compared to warfarin across different levels of TTR per center; within the top quartile of center-related TTR, the hazard ratio for apixaban vs warfarin was 0.73 (95% CI, 0.38, 1.40).
The secondary endpoint of major bleeding and all-cause mortality was tested in a pre-specified hierarchical strategy to control the overall type 1 error in the study. Statistically significant superiority was also achieved in the key secondary endpoints of both bleeding. greater and all-cause mortality (see Table 7). With improved monitoring of INR the observed benefit with apixaban relative to warfarin in all-cause mortality decreases.
Table 7: Secondary Objectives in Patients with Atrial Fibrillation in the ARISTOTLE study
* Major bleeding defined according to the criteria of the International Society on Thrombosis and Hemostasis (ISTH).
In the ARISTOTLE study, the overall discontinuation rate due to adverse reactions was 1.8% for apixaban and 2.6% for warfarin.
Efficacy results for pre-specified subgroups, including CHADS2 score, age, body weight, gender, renal function status, previous stroke or TIA, and diabetes were consistent with the primary efficacy results for the overall study population.
The incidence of ISTH major gastrointestinal bleeding (including upper, lower and rectal gastrointestinal bleeding) was 0.76% / year with apixaban and 0.86% / year with warfarin.
Major bleeding results for pre-specified subgroups, including CHADS2 score, age, body weight, gender, renal function status, previous stroke or TIA, and diabetes were consistent with the primary efficacy results for the overall study population.
STUDIO AVERROES
In the AVERROES study a total of 5,598 patients considered by investigators ineligible for VKA were randomized to treatment with apixaban 5 mg twice daily (or 2.5 mg twice daily in selected patients [6.4%], see section 4.2) or ASA. ASA was administered at a single daily dose of 81 mg (64%), 162 (26.9%), 243 (2.1%), or 324 mg (6.6%) at the investigator's discretion. Patients were exposed to study drug for an average of 14 months. The mean age was 69.9 years, the mean CHADS2 score was 2.0, and 13.6% of patients had had a previous stroke or TIA.
In the AVERROES study, common reasons for ineligibility for AVK therapy included inability / unlikely to achieve an INR at the required intervals (42.6%), patient refusal of AVK treatment (37.4%), CHADS2 score = 1, AVK not recommended by the physician (21.3%), patient unreliability in following instructions on taking AVK (15.0%), and expected difficulty / difficulty in contacting the patient in case of an urgent change of dose (11.7%).
AVERROES was discontinued early based on a recommendation from the independent Data Monitoring Committee due to clear evidence of reduced stroke and systemic embolism with an acceptable safety profile.
In the AVERROES study, the overall discontinuation rate due to adverse reactions was 1.5% for apixaban and 1.3% for ASA.
In the study, apixaban achieved statistically significant superiority over ASA in the primary goal of prevention of stroke (haemorrhagic, ischemic or unspecified) or systemic embolism (see Table 8).
Table 8: Main Efficacy Results in Patients with Atrial Fibrillation in the AVERROES Study
* Evaluated using a sequential analysis strategy designed to control overall type I error in the study
† Secondary objective.
There were no statistically significant differences in the incidence of major bleeding between apixaban and ASA (see Table 9).
Table 9: Bleeding Events in Patients with Atrial Fibrillation in the AVERROES Study
* Major bleeding defined according to the criteria of the International Society on Thrombosis and Hemostasis (ISTH).
Treatment of DVT, treatment of PE and prevention of recurrence of DVT and PE (tTEV)
The clinical program (AMPLIFY: apixaban versus enoxaparin / warfarin, AMPLIFY-EXT: apixaban versus placebo) was designed to demonstrate the efficacy and safety of apixaban in the treatment of DVT and / or PE (AMPLIFY), and the extension of therapy for the prevention of recurrence of DVT and PE after 6-12 months of anticoagulant treatment for DVT and / or PE (AMPLIFY-EXT).
Both studies were multinational, randomized, parallel group, double-blind, in patients with symptomatic proximal DVT or symptomatic PE. All key efficacy and safety endpoints were blinded as such by an independent committee.
AMPLIFY STUDIO
In the AMPLIFY study a total of 5,395 patients were randomized to treatment with apixaban 10 mg twice daily orally for 7 days followed by apixaban 5 mg twice daily orally for 6 months, or enoxaparin 1 mg / kg two. times daily subcutaneously for at least 5 days (up to INR ≥ 2) and warfarin (target INR in the range 2.0-3.0) orally for 6 months.
The mean age was 56.9 years and 89.8% of randomized patients had experienced unprovoked VTE events.
For patients randomized to warfarin, the mean percentage of time in the therapeutic range (INR 2.0-3.0) was 60.9. Apixaban showed a reduction in symptomatic VTE recurrence or VTE-related death between the different levels by center of TTR; within the top quartile of center-related TTR, the relative risk for apixaban vs enoxaparin / warfarin was 0.79 (95% CI; 0.39; 1.61).
In the study, apixaban was shown to be non-inferior to enoxaparin / warfarin in the combined primary endpoint of symptomatic recurrent VTE (non-fatal DVT or non-fatal PE) or adjudicated VTE-related death (see Table 10).
Table 10: Efficacy Results in the AMPLIFY Study
* Not inferior to enoxaparin / warfarin (p-value
The efficacy of apixaban in the initial treatment of VTE was consistent among patients treated for PE [Relative Risk 0.9; 95% CI (0.5, 1.6)] or DVT [Relative Risk 0.8; 95% CI (0.5, 1.3)].
Efficacy across subgroups, including age, gender, body mass index (BMI), renal function, PE index extension, DVT thrombus site, and previous use of injecting heparin, was generally consistent.
The primary safety endpoint was major bleeding. In the study, apixaban was significantly superior to enoxaparin / warfarin in the primary safety endpoint [Relative Risk 0.31; 95% confidence interval (0.17; 0.55), p-value
Table 11: Bleeding results in the AMPLIFY study
Major bleeding and CRNM bleeding at any adjudicated anatomical site were generally lower in the apixaban group than in the enoxaparin / warfarin group.
ISTH major gastrointestinal bleeding occurred in 6 patients (0.2%) treated with apixaban and in 17 (0.6%) patients treated with enoxaparin / warfarin.
STUDIO AMPLIFY-EXT
In the AMPLIFY-EXT study, a total of 2,482 patients were randomized to treatment with apixaban 2.5 mg twice daily, orally, apixaban 5 mg twice daily orally, or placebo for 12 months after completing 6 to 12 months of initial anticoagulant treatment. Of these 836 patients (33.7%) participated in enrollment in the AMPLIFY study prior to enrollment in the AMPLIFY-EXT study.
The mean age was 56.7 years and 91.7% of randomized patients had experienced unprovoked VTE events.
In the study, both doses of apixaban were statistically superior to placebo in the primary endpoint of recurrent symptomatic VTE (non-fatal DVT or non-fatal PE) or death from all causes (see Table 12).
Table 12: Efficacy Results in the AMPLIFY-EXT Study
¥ p-value
* For patients with more than one contributing event to the composite endpoint, only the first event was reported (for example, if a subject reported DVT and then also PE, only DVT was reported)
† Individual subjects may report more than one event and be represented in both classifications
The efficacy of apixaban in preventing VTE recurrence was maintained across subgroups, including age, gender, BMI and renal function.
The primary safety endpoint was major bleeding during the treatment period.
In the study, the incidence of major bleeding for both doses of apixaban was not statistically different from placebo. There was no statistically significant difference in the incidence of major bleeding + CRNM, minor, and all bleeding between apixaban 2.5 mg twice daily and placebo treatment groups (see Table 13).
Table 13: Bleeding results in the AMPLIFY-EXT study
ISTH awarded major gastrointestinal bleeding occurred in 1 patient (0.1%) treated with apixaban 5mg twice daily, in no patient treated with apixaban 2.5mg twice daily and in 1 (0.1%) patient treated with placebo.
Pediatric population
The European Medicines Agency has deferred the obligation to submit the results of studies with Eliquis in one or more subsets of the pediatric population in venous and arterial embolism and thrombosis (see section 4.2 for information on pediatric use).
05.2 Pharmacokinetic properties
Absorption
The bioavailability of apixaban is approximately 50% for doses up to 10 mg. Apixaban is rapidly absorbed with peak concentrations (Cmax) occurring 3 to 4 hours after tablet intake. Intake with food does not affect apixaban AUC or Cmax at a dose of 10 mg.
Apixaban can be taken regardless of food.
Apixaban demonstrates linear pharmacokinetics with dose proportional increases in exposure for oral doses up to 10 mg. At doses ≥ 25 mg apixaban exhibits limited absorption from dissolution, with decreased bioavailability. Apixaban exposure parameters show variability from low to moderate, which is reflected in a variability of approximately 20% CV and approximately 30% CV, in the same subject and between different subjects, respectively.
Distribution
Human plasma protein binding is approximately 87%. The volume of distribution (Vss) is approximately 21 liters.
Biotransformation and elimination
Apixaban has multiple elimination routes. Of the administered dose of apixaban in humans, approximately 25% was detected as metabolites, with the majority occurring in faeces. Renal excretion of apixaban accounts for approximately 27% of the total clearance. Additional contributions observed in clinical and non-clinical studies were biliary and direct intestinal excretion, respectively.
Apixaban has a total clearance of approximately 3.3 l / h and a half-life of approximately 12 hours.
O-demethylation and 3-oxopiperidinyl hydroxylation are the main sites of biotransformation.
Apixaban is metabolised primarily via CYP3A4 / 5 with minor contributions from CYP1A2, 2C8, 2C9, 2C19, and 2J2. Unchanged apixaban is the major drug related component present in human plasma, with no active metabolites in circulation. Apixaban is a substrate of P-gp transport proteins and breast cancer resistance protein (BCRP).
Renal impairment
There was no impact of renal impairment on apixaban plasma peak. C "was an increase in apixaban exposure correlated with a decrease in renal function, as assessed by creatinine clearance measurement.In individuals with mild (creatinine clearance 51 - 80 ml / min), moderate (creatinine clearance 30 - 50 ml / min) and severe (creatinine clearance 15 - 29 ml / min) renal impairment, plasma concentrations of apixaban ( AUC) increased by 16, 29, and 44%, respectively, compared to subjects with normal creatinine clearance. Renal impairment had no obvious effect on the relationship between apixaban plasma concentrations and anti-FXa activity.
In subjects with end stage renal disease (ESRD), when a single 5 mg dose of apixaban was administered immediately after hemodialysis, the AUC of apixaban increased by 36%, compared to that seen in subjects with renal function. normal. Hemodialysis initiated two hours after administration of a single 5 mg apixaban dose decreased apixaban AUC by 14% in subjects with ESRD, which corresponds to apixaban dialysis clearance of 18 mL / min. Therefore, hemodialysis is unlikely to be an effective method of managing apixaban overdose.
Hepatic impairment
In a study comparing 8 patients with mild hepatic impairment, Child-Pugh A score 5 (n = 6) and 6 (n = 2), and 8 patients with moderate hepatic impairment, score 7 (n = 6) , and Child-Pugh B score 8 (n = 2) compared to 16 healthy control subjects, the pharmacokinetics and pharmacodynamics of apixaban single 5 mg dose were not altered in patients with hepatic impairment. The changes in anti-Factor Xa activity and INR were comparable between subjects with mild to moderate hepatic impairment and healthy subjects.
Senior citizens
Elderly patients (over 65 years) had higher plasma concentrations than younger patients, with mean AUC values approximately 32% higher and no difference in Cmax.
Sex
Exposure to apixaban was approximately 18% higher in women than in men.
Ethnic origin and race
Results from all phase I studies showed no discernable differences in apixaban pharmacokinetics between White / Caucasian, Asian and Black / African American subjects. The results of a pharmacokinetic analysis in patients who received apixaban were generally consistent with the phase I results.
Body weight
Compared to "apixaban exposure in subjects weighing 65 to 85 kg, body weight> 120 kg was associated with" approximately 30% lower exposure and body weight
Pharmacokinetic / pharmacodynamic relationship
The pharmacokinetic / pharmacodynamic (PK / PD) relationship between plasma concentrations of apixaban and various PD endpoints (anti-FXa activity, INR, PT, aPTT) was evaluated after administration of a broad spectrum of doses (0.5 - 50 mg ). The relationship between apixaban plasma concentrations and anti-factor Xa activity was best illustrated by a linear model. The PK / PD ratio observed in patients was consistent with that established in healthy subjects.
05.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, fertility, embryo-fetal development and juvenile toxicity.
In repeated dose toxicity studies, the greatest effects observed were those related to the pharmacodynamic action of apixaban on blood coagulation parameters. In toxicity studies, a tendency for slight to no increase in bleeding was observed. However, as this may be due to a lower sensitivity of the non-clinical species compared to humans, this result must be interpreted with caution when extrapolated to humans.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Tablet core:
Anhydrous lactose
Microcrystalline cellulose (E460)
Croscarmellose sodium
Sodium lauryl sulfate
Magnesium stearate (E470b)
Coating:
Lactose monohydrate
Hypromellose (E464)
Titanium dioxide (E171)
Triacetin (E1518)
Yellow iron oxide (E172)
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
Aluminum-PVC / PVdC blisters. Cartons of 10, 20, 60, 168 and 200 film-coated tablets.
Aluminum-PVC / PVdC single dose blister pack of 60x1 and 100x1 film-coated tablets.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
No special instructions.
Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.
07.0 MARKETING AUTHORIZATION HOLDER
Bristol-Myers Squibb / Pfizer EEIG, Bristol-Myers Squibb House,
Uxbridge Business Park, Sanderson Road, Uxbridge, Middlesex
UB8 1DH
UK
08.0 MARKETING AUTHORIZATION NUMBER
EU / 1/11/691/001
041225018
EU / 1/11/691/002
041225020
EU / 1/11/691/003
041225032
EU / 1/11/691/004
041225044
EU / 1/11/691/005
041225057
EU / 1/11/691/013
041225133
EU / 1/11/691/015
041225158
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 18 May 2011
10.0 DATE OF REVISION OF THE TEXT
February 2015
