Active ingredients: Fondaparinux (fondaparinux sodium)
Arixtra 1.5 mg / 0.3 ml solution for injection
Arixtra package inserts are available for pack sizes:- Arixtra 1.5 mg / 0.3 ml solution for injection
- Arixtra 2.5 mg / 0.5 ml solution for injection
- Arixtra 5 mg / 0.4 ml solution for injection, Arixtra 7.5 mg / 0.6 ml solution for injection, Arixtra 10 mg / 0.8 ml solution for injection
Why is Arixtra used? What is it for?
Arixtra is a drug that helps prevent blood clots from forming in blood vessels (antithrombotic agent).
Arixtra contains a substance called fondaparinux sodium. It works by inhibiting the activity of clotting factor Xa ("ten-A") in the blood, thereby preventing the formation of blood clots (thrombosis) in the blood vessels.
Arixtra is used for:
- prevent blood clots from forming in the blood vessels of the legs or lungs after orthopedic surgery (such as hip or knee surgery) or after abdominal surgery;
- prevent the formation of blood clots during and immediately after a period of limited mobility due to an acute illness;
- the treatment of blood clots in the superficial blood vessels of the legs (superficial vein thrombosis).
Contraindications When Arixtra should not be used
Do not use Arixtra:
- if you are allergic to fondaparinux sodium or any of the other ingredients of this medicine
- if you have heavy bleeding;
- if you have a "bacterial heart infection;
- if you have very severe kidney disease.
Tell your doctor if you think any of these apply to you. In that case, you should not use Arixtra.
Precautions for use What you need to know before taking Arixtra
Take special care with Arixtra:
Talk to your doctor or pharmacist before taking Arixtra:
- if you are at risk of uncontrolled bleeding (haemorrhages) which include: stomach ulcer haemorrhagic disease recent brain haemorrhage (intracranial bleeding) recent brain, spine or eye surgery
- if you have severe liver disease
- if you have kidney disease
- if you are 75 or older
- if you weigh less than 50 kg.
Tell your doctor if you think any of these apply to you.
Children and adolescents
Arixtra has not been tested for use in children and adolescents below 17 years of age.
Interactions Which drugs or foods may change the effect of Arixtra
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. This also includes those bought without a prescription. Some other medicines can affect the way Arixtra works or can be affected by Arixtra.
Warnings It is important to know that:
Pregnancy and breastfeeding
Arixtra should not be prescribed to pregnant women unless specifically necessary. Breastfeeding is not recommended while taking Arixtra. If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before using this medicine.
Arixtra contains sodium
Each dose of this medicinal product contains less than 23 mg of sodium and therefore is essentially sodium-free.
The Arixtra syringe contains latex
The needle cover of the syringe contains latex which has the potential to cause allergic reactions in latex sensitive individuals.
- Tell your doctor if you have a latex allergy before being treated with Arixtra.
Dose, Method and Time of Administration How to use Arixtra: Posology
Always use this medicine exactly as your doctor or pharmacist has told you. If in doubt, consult your doctor or pharmacist.
The recommended dose is 2.5 mg once a day, to be injected at about the same time each day.
If you have kidney disease, the dose can be reduced to 1.5 mg once a day.
How Arixtra is given
- Arixtra is given by injection under the skin (subcutaneously) into a skin fold in the lower abdominal area. The syringes are pre-filled with the exact dose needed. The 2.5 mg and 1.5 mg dosing syringes are different. For the "Instructions for use" point by point see the end of the sheet.
- Do not inject Arixtra into the muscle.
How long should Arixtra be taken for
You must continue Arixtra treatment for as long as your doctor prescribes, as Arixtra prevents the development of serious diseases
Overdose What to do if you have taken too much Arixtra
If you inject too much Arixtra
Contact your doctor or pharmacist as soon as possible for advice, as this increases the risk of bleeding.
If you forget to take Arixtra
- Give the dose as soon as you remember. Do not inject a double dose to make up for a forgotten dose.
- If you are not sure what to do, consult your doctor or pharmacist.
Do not stop using Arixtra without medical advice
If you stop treatment earlier than prescribed by your doctor, you are at risk of developing a blood clot in a vein in your legs or in the lungs. Contact your doctor or pharmacist before stopping treatment.
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 Arixtra
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Conditions for which it is necessary to ask for help
Severe allergic reactions (anaphylaxis): are very rare in people taking Arixtra (up to 1 in 10,000 people). Symptoms include:
- swelling, sometimes of the face or mouth (angioedema), causing difficulty in swallowing or breathing
- collapse.
Contact your doctor immediately if you experience such symptoms. Stop taking Arixtra.
Common side effects
They may affect more than one in 100 people treated with Arixtra:
- bleeding (for example at the site of the operation, from a pre-existing stomach ulcer, from the nose, from the gums),
- anemia (a reduction in the number of red blood cells).
Uncommon side effects
They may affect up to one in 100 people treated with Arixtra:
- bruising or swelling (edema)
- feeling or being sick (nausea or vomiting)
- chest pain
- shortness of breath
- redness or itching
- fluid oozing from the wound from surgery
- fever
- decrease or increase in the number of platelets (blood cells needed for clotting)
- increase in some substances (enzymes) produced by the liver
Rare side effects
They may affect up to 1 in 1,000 people treated with Arixtra:
- allergic reactions (including itching, swelling, rash)
- internal brain or abdominal bleeding
- anxiety or confusion
- headache
- fainting or dizziness, low blood pressure
- drowsiness or tiredness
- hot flashes
- cough
- leg pain or stomach pain
- diarrhea or constipation
- indigestion
- wound infection
- increase in bilirubin (a substance produced by the liver) in the blood
- reduction of potassium in the blood.
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.
- Store below 25 ° C. Do not freeze.
- Arixtra must not be kept in the refrigerator.
Do not use this medicine:
- after the expiry date which is stated on the label and box
- if you notice the presence of particles in the solution, or if the solution has an abnormal color
- if you notice that the syringe is damaged
- if you have opened a syringe and do not use it immediately.
Disposal of syringes:
Do not throw any medicine or syringe into 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 Arixtra contains
- The active substance is 1.5 mg of fondaparinux sodium in 0.3 ml of solution for injection.
- The other ingredients are sodium chloride, water for injections, and hydrochloric acid and / or sodium hydroxide for pH adjustment.
Arixtra does not contain any products of animal origin.
Description of what Arixtra looks like and contents of the pack
Arixtra is a clear and colorless solution for injection. It is supplied with a pre-filled, disposable syringe, complete with a protection system that has been designed to protect against accidental needle sticks after use. It is available in packs of 2, 7, 10 and 20 pre-filled syringes ( not all pack sizes may be marketed).
POINT BY POINT USING ARIXTRA GUIDE
Instructions for Use
These instructions are valid for both types of syringes (automatic and manual needle guard system)
Where the instructions for each syringe are different this is clearly stated.
1. Wash your hands thoroughly with soap and water and then dry them with a towel.
2. Take the syringe out of the case and check that:
- the expiration date has not passed
- the solution is clear and colorless and does not contain particles
- the syringe has not been opened or damaged
3. Sit or lie down in a comfortable position.
Choose a point in the lower abdominal area, at least 5 cm below the umbilicus
Switch the left and right sides of the lower abdominal area with each injection. This will help reduce discomfort at the injection site.
If injection into the lower abdominal area is not possible, consult your nurse or doctor for advice.
4. Clean the injection site with an alcohol swab.
5. Remove the needle cover by first twisting it and then pulling it straight away from the body of the syringe. Remove the cap.
Important note
- Do not touch the needle and make sure it does not come into contact with other surfaces before you inject.
- The presence of a small air bubble in the syringe is normal. Do not try to remove small air bubbles before injecting to make sure you do not lose any product.
6. Lightly pinch the disinfected area of skin to form a fold. Hold the fold between your thumb and forefinger throughout the injection
7. Hold the syringe firmly between your fingers.
Insert perpendicularly (at a 90 ° angle) the entire length of the needle into the skin fold
8. Inject ALL the contents of the syringe by pushing the plunger down as far as it will go
Syringe with automatic system
9. Release the plunger and the needle will automatically withdraw from the skin into the safety sleeve where it will remain permanently closed
Syringe with manual system
9. After injection, hold the syringe in one hand while holding the safety sleeve, use the other hand to hold the handle and pull back firmly. This unlocks the sleeve. Slide the sleeve through the body of the syringe until until it clicks into place over the needle
Do not dispose of the used syringe with household waste. Throw away the used syringe following the instructions given to you by your doctor or pharmacist
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
ARIXTRA 1.5 MG / 0.3 ML
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each pre-filled syringe (0.3 ml) contains 1.5 mg of fondaparinux sodium.
Excipients with known effects: Contains less than 1 mmol sodium (23 mg) per dose, and therefore is essentially sodium-free.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Injectable solution.
The solution is a clear, colorless liquid.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Prevention of Venous Thromboembolic Episodes (VTE) in adults undergoing major orthopedic surgery of the lower limbs such as hip fracture, major knee surgery or hip replacement surgery.
Prevention of Venous Thromboembolic Episodes (VTE) in adults undergoing abdominal surgery considered to be at high risk of thromboembolic complications, such as patients undergoing abdominal surgery for cancer (see section 5.1).
Prevention of Venous Thromboembolic Episodes (VTE) in medically relevant adults who are considered to be at high risk of VTE and who are immobilized due to an acute condition such as heart failure and / or acute respiratory disease and / or acute inflammatory disease or infection.
Treatment of adults with acute spontaneous symptomatic superficial vein thrombosis of the lower extremities in the absence of concomitant deep vein thrombosis (see sections 4.2 and 5.1).
04.2 Posology and method of administration
Dosage
Patients undergoing major orthopedic or abdominal surgery
The recommended dose of fondaparinux is 2.5 mg administered once daily after surgery by subcutaneous injection.
The initial dose should be administered 6 hours after the end of surgery once haemostasis has been ensured.
Treatment should be continued until the risk of venous thromboembolism decreases, usually until the patient resumes walking, at least 5-9 days after surgery. Experience shows that in patients undergoing hip fracture surgery the risk of VTE persists beyond 9 days after surgery. In these patients the use of prolonged fondaparinux prophylaxis should be considered for up to an additional 24 days (see section 5.1).
Medically relevant patients who are at high risk for thromboembolic complications based on an individual risk assessment
The recommended dose of fondaparinux is 2.5 mg once daily administered by subcutaneous injection. Treatment lasting 6-14 days has been clinically studied in medically relevant patients (see section 5.1).
Treatment of superficial vein thrombosis
The recommended fondaparinux dose is 2.5 mg per day, administered by subcutaneous injection. Patients eligible for treatment with fondaparinux 2.5 mg must exhibit spontaneous, acute, symptomatic and isolated superficial venous thrombosis of the lower limbs, at least 5 cm in length and documented by ultrasound or other physical examinations. Treatment should be started as soon as possible immediately after diagnosis and after the exclusion of concomitant deep vein thrombosis (DVT) or superficial vein thrombosis within 3 cm of the sapheno-femoral junction. Treatment should be continued for a minimum of 30 days and up to a maximum of 45 days in patients at high risk of thromboembolic complications (see sections 4.4 and 5.1).
Patients should be recommended to self-inject the product when in the judgment of the physician they are willing and able to do so. Physicians should provide clear instructions for self-injection.
• Patients who need to undergo surgery or other invasive procedures
In patients with superficial vein thrombosis who need to undergo surgery or other invasive procedures, fondaparinux should, where possible, not be administered during the 24 hours prior to surgery. Fondaparinux treatment can restart at least 6 hours after surgery. surgical provided that haemostasis has been achieved.
Special categories of patients
In patients undergoing surgery, the administration time of the first fondaparinux injection requires strict compliance in patients ≥ 75 years of age and / or renal insufficiency weight with a creatinine clearance between 20 and 50 ml / min.
The first administration of fondaparinux should be given no earlier than 6 hours after the end of surgery. The injection should not be given without established haemostasis (see section 4.4).
Kidney failure -
• VTE prevention - Fondaparinux should not be used in patients with creatinine clearance 50 ml / min).
• Treatment of superficial vein thrombosis - Fondaparinux should not be used in patients with creatinine clearance 50 ml / min). The safety and efficacy of 1.5 mg have not been studied (see section 4.4).
Liver failure -
• VTE prevention - No dose adjustment is necessary in patients with mild or moderate hepatic impairment. In patients with severe hepatic impairment, fondaparinux should be used with caution as it has not been studied in this patient group (see sections 4.4 and 5.2).
• Treatment of superficial vein thrombosis - The safety and efficacy of fondaparinux have not been studied in patients with severe hepatic impairment, therefore the use of fondaparinux is not recommended in these patients (see section 4.4).
Pediatric population - Fondaparinux is not recommended for use in children below 17 years of age due to a lack of data on safety and efficacy.
Low body weight
• VTE prevention - Patients with bleeding body weight. The elimination of fondaparinux decreases with weight. Fondaparinux should be used with caution in these patients (see section 4.4).
• Treatment of superficial vein thrombosis - The safety and efficacy of fondaparinux have not been studied in patients weighing less than 50 kg, therefore fondaparinux is not recommended for use in these patients (see section 4.4).
Method of administration
Fondaparinux is to be administered by deep subcutaneous injection, with the patient in the supine position. The injection site should alternate between the left and right anterolateral side and between the left and right posterolateral side of the abdominal wall. To avoid loss of medicine when using the pre-filled syringe, do not expel air bubbles from the syringe before injection. The entire length of the needle must be inserted perpendicularly into a skin fold held between thumb and forefinger; the skin fold must be maintained for the duration of the injection.
For further instructions on use and disposal see section 6.6.
04.3 Contraindications
- Known hypersensitivity to the active substance or to any of the excipients listed in section 6.1
- bleeding in progress, clinically significant
- acute bacterial endocarditis
- severe renal insufficiency defined as creatinine clearance
04.4 Special warnings and appropriate precautions for use
Fondaparinux is intended for subcutaneous use only. Not to be administered intramuscularly.
Hemorrhages
Fondaparinux should be used with caution in patients who have an increased risk of bleeding, such as those with congenital or acquired bleeding disorders (e.g. platelet count 3), active ulcerative gastrointestinal disease and recent or shortly after brain, spinal or intracranial bleeding. ophthalmic and in special patient groups as indicated below.
• For the prevention of VTE - Agents that may increase the risk of haemorrhage should not be administered concomitantly with fondaparinux. Such substances include desirudin, fibrinolytic agents, GP IIb / IIIa receptor antagonists, heparin, heparinoids or Low Molecular Weight Heparin (LMWH). If required, concomitant therapy with vitamin K antagonists should be administered according to the directions in section 4.5. Other antiplatelet drugs (acetylsalicylic acid, dipyridamole, sulfinpyrazone, ticlopidine or clopidogrel) and NSAIDs should be used with caution. If co-administration is essential, close monitoring is required.
• For the treatment of superficial vein thrombosis - Fondaparinux should be used with caution in patients receiving concomitant medications that increase the risk of bleeding.
Patients with superficial vein thrombosis
The presence of superficial venous thrombosis at a distance greater than 3 cm from the sapheno-femoral junction must be confirmed before starting treatment with fondaparinux and the presence of DVT must be excluded by compression ultrasound (CUS) or other objective methods. There are no data on the use of fondaparinux 2.5 mg in patients with superficial vein thrombosis associated with concomitant DVT or with superficial vein thrombosis within 3 cm of the sapheno-femoral junction (see sections 4.2 and 5.1).
The safety and efficacy of fondaparinux 2.5 mg have not been studied in the following groups: patients with superficial vein thrombosis after sclerosing therapy or as a consequence of an intravenous line, patients with a history of superficial vein thrombosis within the previous 3 months, patients with a history of venous thromboembolic disease within the previous 6 months, or patients with an active tumor (see sections 4.2 and 5.1).
Spinal / epidural anesthesia
In patients undergoing major orthopedic surgery, with the concomitant use of fondaparinux and spinal / epidural anesthesia or spinal puncture the occurrence of epidural or spinal hematomas which may result in prolonged or permanent paralysis cannot be excluded. The risk of these rare events it may increase with the postoperative use of indwelling epidural catheters or with the concomitant use of other drugs that act on haemostasis.
Elderly patients
The elderly population has an increased risk of bleeding. As renal function generally decreases with age, elderly patients may show reduced elimination and increased exposure to fondaparinux (see section 5.2). Fondaparinux should be used with caution in elderly patients (see section 4.2).
Low body weight
• VTE prevention - Patients with body weight
• Treatment of superficial vein thrombosis - There are no clinical data available for the use of fondaparinux for the treatment of superficial vein thrombosis in patients weighing less than 50 kg. Consequently, fondaparinux is not recommended for the treatment of superficial vein thrombosis in these patients (see section 4.2).
Kidney failure
• VTE prevention - Fondaparinux is known to be mainly excreted by the kidneys. Patients with creatinine clearance
• Treatment of superficial vein thrombosis - Fondaparinux must not be used in patients with creatinine clearance
Severe hepatic insufficiency
• VTE prevention - No fondaparinux dose adjustment is necessary. However, the use of fondaparinux in patients with severe hepatic insufficiency should be considered with caution due to an increased risk of bleeding due to the deficiency of coagulation factors in patients with severe hepatic insufficiency (see section 4.2).
• Treatment of superficial vein thrombosis - There are no clinical data available for the use of fondaparinux for the treatment of superficial vein thrombosis in patients with
severe hepatic insufficiency. Consequently, fondaparinux is not recommended for the treatment of superficial vein thrombosis in these patients (see section 4.2).
Patients with heparin-induced thrombocytopenia
Fondaparinux should be used with caution in patients with a history of Heparin Induced Thrombocytopenia (HIT). The efficacy and safety of fondaparinux in patients with type II HIT have not been formally studied. Fondaparinux does not bind to coagulation factor 4 and does not cross-react with the plasma of patients with type II HIT. Rare spontaneous reports of HIT have been received in patients treated with fondaparinux. To date, a causal association between fondaparinux treatment and the onset of HIT has not been established.
Latex allergy
The needle cover of the pre-filled syringe contains dry natural rubber latex which may cause allergic reactions in latex sensitive individuals.
04.5 Interactions with other medicinal products and other forms of interaction
Concomitant administration of fondaparinux and substances that may increase the risk of haemorrhage increases the risk of bleeding (see section 4.4).
Oral anticoagulants (warfarin), platelet inhibitors (acetylsalicylic acid), NSAIDs (piroxicam) and digoxin did not interact with fondaparinux pharmacokinetics. The dose of fondaparinux (10 mg) in the interaction studies was higher than the recommended dose for the current indications. Fondaparinux does not affect either the INR activity of warfarin, or the bleeding time under treatment with acetylsalicylic acid or piroxicam, or the steady state pharmacokinetics of digoxin.
Continuation of treatment with another anticoagulant drug
If continued treatment is to be initiated with heparin or LMWH, as a general rule the first injection should be given 1 day after the last fondaparinux injection.
If continuation of treatment with a vitamin K antagonist is required, fondaparinux treatment should be continued until the established INR value is reached.
04.6 Pregnancy and lactation
Pregnancy
There are insufficient data from the use of fondaparinux in pregnancy. Animal studies are insufficient with respect to the effects on pregnancy, embryonic / fetal development, parturition and postnatal development due to limited exposure. Fondaparinux should not be prescribed for pregnant women unless strictly necessary.
Breastfeeding
Fondaparinux is excreted in rat milk but it is not known whether fondaparinux is excreted in human milk. Breastfeeding is not recommended during fondaparinux treatment. Oral absorption by the infant is however unlikely.
Fertility
There are no data available on the effect of fondaparinux on human fertility. Animal studies have shown no effect on fertility.
04.7 Effects on ability to drive and use machines
No studies on the ability to drive and use machines have been performed.
04.8 Undesirable effects
The most commonly reported serious adverse reactions with fondaparinux are bleeding complications (at various sites including rare cases of intracranial / intracerebral and retroperitoneal bleeding) and anemia. Fondaparinux should be used with caution in patients who have an increased risk of haemorrhage (see section 4.4).
The safety of fondaparinux 2.5 mg was evaluated in 3,595 patients undergoing major orthopedic surgery of the lower limbs treated for up to 9 days, in 327 patients undergoing hip fracture surgery treated for 3 weeks following an initial prophylaxis of 1 week, in 1,407 patients undergoing abdominal surgery treated for up to 9 days, and in 425 medically relevant patients (not undergoing surgical treatments) at risk of thromboembolic complications treated for up to 14 days.
Adverse reactions reported by investigators as at least possibly related to fondaparinux are presented within each frequency group (very common ≥1 / 10; common: ≥ 1/100,
In other studies or in post-marketing experience, rare cases of intracranial / intracerebral and retroperitoneal bleeding have been reported.
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions that occur after authorization of the medicinal product is important. 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. "Annex V.
04.9 Overdose
Doses of fondaparinux in excess of the recommended regimen may lead to an increased risk of bleeding. There are no known antidotes to fondaparinux.
Overdose associated with bleeding complications must involve discontinuation of treatment and seeking the primary cause. Appropriate therapy such as surgical haemostasis, blood transfusion, fresh plasma transfusion, plasmapheresis should be considered.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: antithrombotic agents.
ATC code: B01AX05.
Pharmacodynamic effects
Fondaparinux is a synthetic and selective inhibitor of activated Factor X (Xa). The antithrombotic activity of fondaparinux is the result of selective inhibition of Factor Xa mediated by antithrombin III (ATIII). Through selective binding to ATIII, fondaparinux enhances (approximately 300 times) the natural neutralization of factor Xa by ATIII. of Factor Xa interrupts the blood coagulation cascade and inhibits both thrombin formation and thrombus development Fondaparinux does not inactivate thrombin (activated Factor II) and has no effect on platelets.
At the 2.5 mg dose, fondaparinux does not affect routine coagulation tests such as activated partial thromboplastin time (aPTT), activated clotting time (ACT) or prothrombin time (PT) / International Normalized Ratio (INR ) in plasma, nor bleeding time or fibrinolytic activity. However, only rare reports of aPTT prolongation have been received.
Fondaparinux does not cross-react with serum from patients with heparin-induced thrombocytopenia.
Clinical studies
Prevention of venous thromboembolism (VTE) in patients undergoing major orthopedic surgery of the lower limbs treated for up to 9 days: the fondaparinux clinical plan was designed to demonstrate the efficacy of fondaparinux in the prevention of venous thromboembolic events (VTE), ie thrombosis proximal and distal deep vein (DVT) and pulmonary embolism (PE) in patients undergoing major orthopedic surgery of the lower extremities such as hip fracture, major knee surgery or hip replacement surgery. In Phase II and III controlled clinical trials over 8,000 patients were studied (hip fracture - 1,711, hip replacement - 5,829, major knee surgery - 1,367). Fondaparinux 2.5 mg once daily started 6-8 hours after surgery was compared with enoxaparin 40 mg once daily started 12 hours before surgery, or 30 mg twice daily orno started 12-24 hours after surgery.
In a pooled analysis of these studies, the recommended dose regimen of fondaparinux versus enoxaparin was associated with a significant decrease (54% -95% CI, 44%; 63%) in the incidence of VTE estimated up to 11th day after surgery, regardless of the type of surgery performed. The majority of the "end-point" events were diagnosed with a predetermined venography and were mainly composed of distal DVT, but the incidence of proximal DVT was also significantly reduced. The incidence of symptomatic VTE, including PE, was not significantly different. between treatment groups.
In the studies versus enoxaparin 40 mg once daily started 12 hours before surgery, severe bleeding was observed in 2.8% of patients treated with fondaparinux at the recommended dose compared to 2.6% with enoxaparin.
Prevention of venous thromboembolism (VTE) in patients undergoing hip fracture surgery treated for up to 24 days following an initial 1 week prophylaxis: In a randomized double-blind clinical trial, 737 patients were treated with fondaparinux 2,5 mg once daily for 7 ± 1 days after hip fracture surgery. At the end of this period, 656 patients were randomized to receive fondaparinux 2.5 mg once daily or placebo for an additional 21 ± 2 days. Fondaparinux gave a significant reduction in the overall incidence of VTE compared to placebo [3 patients (1.4%) vs 77 patients (35%), respectively]. The majority (70/80) of reported VTE episodes were cases of asymptomatic DVT detected phlebographically. Fondaparinux also gave a significant reduction in the incidence of symptomatic VTE (DVT and / or PE) [1 (0.3%) vs 9 (2.7%) patients, respectively] including 2 fatal PEs reported in the placebo group. Serious bleeding, all surgical and none fatal, was observed in 8 patients (2.4%) treated with fondaparinux 2.5 mg compared to 2 (0.6%) with placebo.
Prevention of Venous Thromboembolic Episodes (VTE) in patients undergoing abdominal surgery considered to be at high risk for thromboembolic complications, such as patients undergoing abdominal surgery for cancer: In a double-blind clinical study, 2,927 patients were randomized to receive fondaparinux 2, 5 mg once daily or dalteparin 5000 IU once daily by pre-operative injection of 2500 IU and first post-operative injection of 2500 IU for 7 + 2 days. Major sites of surgery were colorectal, gastric, hepatic, cholecystectomy, or other biliary interventions. Sixty-nine percent of patients underwent cancer surgery. Patients underwent urological (excluding kidney) or gynecological surgery , laparoscopic or vascular surgery were not included in the study.
In this study, the incidence of total VTE was 4.6% (47 / 1,027) with fondaparinux, compared to 6.1% (62 / 1,021) with dalteparin: reduction in odd ratio (95% CI) = - 25.8% (-49.7%, 9.5%). The difference in the frequency of total VTE between treatment groups, which was not statistically significant, was mainly due to the reduction in distal DVT. The incidence of Symptomatic DVT was similar between the two treatment groups: 6 patients (0.4%) in the fondaparinux group versus 5 patients (0.3%) in the dalteparin group. In the large subgroup of patients undergoing cancer surgery (69% of the patient population), the frequency of VTE was 4.7% in the fondaparinux group compared to 7.7% in the dalteparin group.
Serious bleeding was observed in 3.4% of fondaparinux-treated patients and 2.4% of the dalteparin-treated group.
Prevention of Venous Thromboembolic Episodes (VTE) in medically relevant patients at high risk of thromboembolic complications due to impaired mobility during acute disease: In a randomized double-blind clinical trial, 839 patients were treated for 6 to 14 days with fondaparinux 2.5 mg once daily or with placebo. This study included medically relevant acute patients aged ≥ 60 years who were expected to be bedridden for at least four days, and hospitalized for NYHA class III / IV congestive heart failure and / or acute respiratory disease. and / or acute infectious or inflammatory pathology. Fondaparinux compared to placebo significantly reduced the overall incidence of VTE [18 patients (5.6%) vs 34 patients (10.5%), respectively]. The majority of events were asymptomatic distal DVT. Fondaparinux also reduced significantly the incidence of PE considered fatal [0 patients (0.0%) vs 5 patients (1.2%), respectively]. Severe bleeding was observed in 1 patient (0.2%) of each group.
Treatment of patients with spontaneous symptomatic acute superficial vein thrombosis without concomitant deep vein thrombosis (DVT)
A randomized, double-blind clinical trial (CALISTO) included 3002 patients with spontaneous, acute, symptomatic and isolated superficial vein thrombosis in the lower limbs, at least 5 cm in length, confirmed by compression ultrasound (CUS). Patients were not included if they had concomitant DVT or superficial vein thrombosis within 3 cm of the sapheno-femoral junction. Patients were excluded if they had severe hepatic insufficiency, severe renal insufficiency (creatinine clearance
Patients were randomized to receive fondaparinux 2.5 mg once daily or placebo for 45 days in addition to stockings, analgesics, and / or topical non-steroidal anti-inflammatory drugs (NSAIDs). Follow-up continued until Day 77. The study population was 64% female, with a median age of 58 years, 4.4% had creatinine clearance.
The primary efficacy outcome, a composite outcome of symptomatic PE, symptomatic DVT, extension of symptomatic superficial venous thrombosis, recurrence of symptomatic superficial venous thrombosis, or Death at Day 47, was significantly reduced by 5.9% in patients in the placebo group. 0.9% in those receiving fondaparinux 2.5 mg (relative risk reduction: 85.2%; 95% CI, 73.7% to 91.7% [p
The incidence of each thromboembolic component of the primary outcome was also significantly reduced in fondaparinux patients as described below: symptomatic PE [0 (0%) vs 5 (0.3%) (p = 0.031)], symptomatic DVT [3 (0.2%) vs 18 (1.2%); relative risk reduction 83.4% (p
Mortality rates were low and similar between the treatment groups with 2 (0.1%) deaths in the fondaparinux group versus 1 (0.1%) death in the placebo group.
Efficacy was maintained through Day 77 and was consistent across all predefined subgroups including patients with varicose veins and patients with superficial vein thrombosis located below the knee.
Major bleeding during treatment occurred in 1 (0.1%) patient on fondaparinux and in 1 (0.1%) patient on placebo. Clinically relevant non-major bleeding occurred in 5 (0.3%) patients on fondaparinux and in 8 (0.5%) patients on placebo.
05.2 Pharmacokinetic properties
Absorption
After subcutaneous administration, fondaparinux is completely and rapidly absorbed (100% absolute bioavailability). Following a single subcutaneous injection of fondaparinux 2.5 mg to healthy young subjects, peak plasma concentration (mean C = 0.34 mg / l) is achieved 2 hours after administration. Plasma concentrations equal to half of the mean Cmax values are reached 25 minutes after administration.
Fondaparinux pharmacokinetics are linear over a dose range of 2 to 8 mg subcutaneously in healthy elderly subjects. After once daily dosing, steady state plasma levels are achieved 3 to 4 days later, with a 1.3-fold increase in Cmax and AUC.
The mean (CV%) of the estimated steady state parameters of fondaparinux in hip replacement surgery patients who received fondaparinux 2.5 mg once daily are: Cmax (mg / l) - 0.39 (31% ), Tmax (h) - 2.8 (18%) and Cmin (mg / l) - 0.14 (56%). In patients with hip fracture associated with old age, fondaparinux plasma concentrations at steady state are: Cmax (mg / l) - 0.50 (32%), Cmin (mg / l) - 0.19 (58%).
Distribution
The volume of distribution of fondaparinux is limited (7 - 11 liters). In vitro, fondaparinux is highly and specifically bound to antithrombin protein with a dose-dependent plasma concentration binding (98.6% to 97.0% over a concentration range of 0.5 to 2 mg / l). Fondaparinux does not bind significantly to other plasma proteins, including platelet factor 4 (PF4).
Since fondaparinux does not bind significantly to plasma proteins other than ATIII, no interaction with other drugs is expected by shifting protein binding.
Biotransformation
Although not fully evaluated, there is no evidence of fondaparinux metabolism and in particular of formation of active metabolites.
Fondaparinux does not inhibit in vitro the CYP450 system (CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4). Therefore fondaparinux is not expected to interact in vivo with other drugs by inhibiting CYP-mediated metabolism.
Elimination
The elimination half-life (t½) is approximately 17 hours in healthy young subjects and approximately 21 hours in healthy elderly subjects. Fondaparinux is excreted by 64 to 77% by the kidneys as unchanged compound.
Special categories of patients:
Pediatric population - Fondaparinux has not been studied in this class of patients for the prevention of VTE or for the treatment of superficial vein thrombosis.
Elderly patients - Renal function may decrease with age and therefore the elimination capacity of fondaparinux may be reduced in the elderly. In patients> 75 years of age undergoing surgery, the estimated plasma clearance was 1.2 to 1.4 times lower than in patients with age
Kidney failure - Compared with patients with normal renal function (creatinine clearance> 80 ml / min), plasma clearance is 1.2 to 1.4 times lower in patients with mild renal impairment (creatinine clearance 50 to 80 ml / min) and on average 2 times lower in patients with moderate renal impairment (creatinine clearance 30 to 50 ml / min). In severe renal insufficiency (creatinine clearance
Gender - There was no difference between the sexes after adjustment for body weight.
Race - Pharmacokinetic differences due to race have not been studied prospectively. However, studies performed in Asian (Japanese) healthy subjects did not reveal a different pharmacokinetic profile compared to Caucasian healthy subjects. Similarly, no differences in plasma clearance were observed between black and Caucasian patients undergoing orthopedic surgery.
Body weight - Plasma clearance of fondaparinux increases with body weight (9% increase per 10 kg).
Hepatic insufficiency - Following a single subcutaneous dose of fondaparinux in subjects with moderate hepatic impairment (Child-Pugh Category B), total (i.e., both bound and unbound) Cmax and AUC were decreased by 22% and 39%, respectively, in comparison with subjects with normal liver function. The lower plasma concentrations of fondaparinux have been attributed to the reduced binding to ATIII, which in turn is dependent on the lower plasma concentrations of ATIII in subjects with hepatic insufficiency which, therefore, results in an increase in the renal clearance of fondaparinux. therefore, free fondaparinux concentrations are expected to remain unchanged in patients with mild or moderate hepatic impairment and therefore no dose adjustment is required based on pharmacokinetics.
05.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and toxicity. Animal studies are insufficient with respect to reproductive toxicity effects due to limited exposure.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Sodium chloride
Water for injections
Hydrochloric acid
Sodium hydroxide
06.2 Incompatibility
In the absence of compatibility studies, this drug must not be mixed with other medicinal products.
06.3 Period of validity
3 years.
06.4 Special precautions for storage
Store below 25 ° C. Do not freeze.
06.5 Nature of the immediate packaging and contents of the package
Type I glass (1ml) fitted with a 27 gauge x 12.7mm needle and locked by a bromobutyl or chlorobutyl elastomer piston locking system.
Arixtra is available in packs of 2, 7, 10 and 20 pre-filled syringes. There are two types of syringes:
• syringe with yellow piston and with an automatic safety system
• syringe with a yellow plunger and a manual safety system.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
The subcutaneous injection is administered as with a conventional syringe.
Parenteral solutions should be visually examined prior to administration for abnormal particles and staining.
Instructions for self-administration are given in the package leaflet.
The needle protection system of Arixtra pre-filled syringes has been designed with a safety system to protect against accidental needle sticks following injection.
Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.
07.0 MARKETING AUTHORIZATION HOLDER
Aspen Pharma Trading Limited
3016 Lake Drive
Citywest Business Campus
Dublin 24
Ireland
08.0 MARKETING AUTHORIZATION NUMBER
EU / 1/02/206 / 005-008
035606060
035606072
EU / 1/02/206/024
EU / 1/02/206/025
035606223
EU / 1/02/206/026
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 21 March 2002
Date of last renewal: 21 March 2007
10.0 DATE OF REVISION OF THE TEXT
D.CCE August 2014
