Pharmacological properties of the drug Fraxiparine
Pharmacodynamics . Nadroparin, a low molecular weight heparin obtained from standard heparin by depolymerization, is a glycosaminoglycan with an average molecular weight of 4300 Da. Nadroparin exhibits a high level of binding to the blood plasma protein antithrombin III. This affinity causes accelerated inhibition of factor Xa and is the main reason for the high antithrombotic activity of nadroparin. Another mechanism of the antithrombotic activity of nadroparin is stimulation of tissue conduction factor inhibitor, activation of fibrinolysis by direct release of tissue plasminogen activator from epithelial cells, modification of hemorheological parameters (reduction of blood viscosity and fluidity of platelets and membrane granulocytes). Nadroparin has a high ratio between anti-Xa and anti-IIa activity. It has an immediate and prolonged antithrombotic effect. Compared with unfractionated heparin, nadroparin has a less effective effect on platelet function and aggregation and has very little effect on primary homeostasis. Pharmacokinetics is determined by measuring the anti-factor Xa activity of blood plasma. Bioavailability. After subcutaneous administration, the maximum concentration in the blood plasma is reached after 3–5 hours. Bioavailability is almost complete (about 98%). After intravenous administration, the maximum anti-Xa activity is achieved after 10 minutes with a half-life of 2 hours. Metabolism of nadroparin occurs mainly in the liver (desulfation, depolymerization). Excretion. After subcutaneous administration, the half-life is about 3.5 hours. Special groups of patients Elderly patients. Because the physiological function of the kidneys declines with age, the elimination process slows down. The possibility of developing renal failure in this group of patients should be taken into account and the dose of the drug should be adjusted accordingly. Kidney failure. Data from clinical observations on the study of the pharmacokinetic parameters of nadroparin when administered intravenously to patients with varying degrees of renal failure revealed a correlation between the clearance of nadroparin and creatinine clearance. The average AUC and half-life in moderate renal failure (creatinine clearance 36–43 ml/min) increased by 52 and 39%, respectively, the average plasma clearance decreased to 63% of normal. Wide individual variability was noted. In patients with severe renal failure (creatinine clearance 10–20 ml/min), with subcutaneous administration of nadroparin, the AUC and half-life increased to 95 and 112%, respectively, compared with those in healthy volunteers. Plasma clearance in severe renal failure was reduced by up to 50% compared to patients with normal renal function. In patients with severe renal impairment (creatinine clearance 3–6 ml/min) undergoing hemodialysis, AUC and half-life increased by 62 and 65%, respectively, compared with healthy volunteers. Plasma clearance in patients with severe renal failure on hemodialysis was reduced to 67% of that in patients with normal renal function.
Pharmacodynamics
Nadroparin calcium is characterized by higher anti-Xa factor compared to anti-IIa factor or antithrombotic activity. The ratio between the two activities for nadroparin is in the range of 2.5–4.
In prophylactic doses, nadroparin does not cause a significant decrease in activated partial thrombin time (aPTT).
During a course of treatment during the period of maximum activity, the aPTT can be extended to a value 1.4 times higher than the standard one. This prolongation reflects the residual antithrombotic effect of nadroparin calcium.
Indications for use of the drug Fraxiparine
Prevention of thromboembolic complications during general or orthopedic surgical interventions; in patients at high risk of thromboembolic complications (respiratory failure and/or infectious diseases of the respiratory tract, and/or heart failure) hospitalized in the intensive care unit; treatment of thromboembolic complications; prevention of blood clotting during hemodialysis; treatment of unstable angina and myocardial infarction without a pathological Q on the ECG.
Use of the drug Fraxiparine
Particular attention should be paid to the specific dosing recommendations for each individual low molecular weight heparin drug, since different units of measurement (IU or mg) are used to determine the doses of these drugs. Therefore, nadroparin should not be used as a replacement for other low molecular weight heparin during the course of treatment. Special care is required to follow the specific instructions for use of each drug. Fraxiparine is not used for intramuscular administration. The drug is intended for subcutaneous administration and use during hemodialysis in adults. Technique of subcutaneous administration. It is recommended to administer a subcutaneous injection of Fraxiparine with the patient lying down in the anterolateral abdominal wall, alternately on the right and left. The needle is inserted perpendicular to the surface of the body (and not at an angle), into a fold of skin, taken with the thumb and forefinger (hold while introducing the solution). Adults Prevention of thromboembolic complications General surgery. The recommended dose of nadroparin is 0.3 ml (2850 IU of anti-factor Xa activity), administered subcutaneously 2–4 hours before surgery. Further doses are administered once a day for the next at least 7 days and throughout the entire risk period until the patient is transferred to outpatient treatment. Orthopedic surgical interventions. The drug is administered subcutaneously in doses depending on the patient’s body weight (see table below). Doses are calculated based on the presence of 38 IU of anti-CA factor activity per 1 kg of patient body weight and are increased by 50% on the 4th postoperative day. The initial dose is administered 12 hours before surgery, the second dose is administered 12 hours after surgery. Subsequent doses are administered once a day throughout the entire risk period and until the patient is transferred to outpatient treatment. The minimum duration of treatment is 10 days.
Patient body weight kg) | Fraxiparine dose administered 12 hours before and after surgery and until the 3rd day after surgery | The dose of Fraxiparine, which is administered once a day, starting from the 4th day after surgery | ||
Administration volume (ml) | Amount of IU anti-Xa activity | Administration volume (ml) | Amount of IU anti-Xa activity | |
| ≤50 | 0,2 | 1900 | 0,3 | 2850 |
| 50–69 | 0,3 | 2850 | 0,4 | 3800 |
| ≥70 | 0,4 | 3850 | 0,6 | 5700 |
Patients with a high risk of thromboembolic complications (respiratory failure and/or infectious diseases of the respiratory tract, and/or heart failure) use Nadroparin subcutaneously once a day. The dose is calculated according to the patient's body weight, as presented in the table below. Treatment continues throughout the period of risk of thromboembolism.
Patient's body weight (kg) | 1 time per day | |
Administration volume (ml) | Amount of IU anti-Xa activity | |
| ≤70 | 0,4 | 3800 |
| 70 | 0,6 | 5700 |
Treatment of thromboembolic complications When treating thromboembolic complications, oral anticoagulants should be prescribed as early as possible, provided there are no contraindications for their use. Treatment with nadroparin should not be stopped before the appropriate international normalized ratio (INR) level is achieved. It is recommended to use nadroparin subcutaneously 2 times a day (every 12 hours), usually for 10 days. The dose is calculated according to the patient’s body weight, as indicated in the table, subject to the presence of 86 IU of anti-factor Xa activity per 1 kg of the patient’s body weight.
Patient's body weight (kg) | 2 times a day with the usual duration of treatment for 10 days | |
Administration volume (ml) | Amount of IU anti-Xa activity | |
| ≤50 | 0,4 | 3800 |
| 50–59 | 0,5 | 4750 |
| 60–69 | 0,6 | 5700 |
| 70–79 | 0,7 | 6650 |
| 80–89 | 0,8 | 7600 |
| ≥90 | 0,9 | 8550 |
Prevention of blood clotting during hemodialysis The dose of nadroparin is selected individually, also taking into account the technical conditions for hemodialysis. As a rule, nadroparin is used as a one-time intravascular injection of a hemodialysis loop into the arterial shunt at the beginning of each hemodialysis session. In patients without an increased risk of bleeding, the initial dose is calculated according to body weight and is sufficient for a hemodialysis session lasting up to 4 hours (see table).
Patient's body weight (kg) | Insertion into the arterial bypass at the start of dialysis | |
Administration volume (ml) | Amount of IU anti-Xa activity | |
| ≤50 | 0,3 | 2850 |
| 50–69 | 0,4 | 3800 |
| ≥70 | 0,6 | 5700 |
If there is an increased risk of bleeding, the dose should be reduced by half. If the hemodialysis session lasts 4 hours, the drug can be additionally administered at a lower dose. This dose is based on the individual response of the patient, who must be closely monitored at all times for signs of bleeding or clotting in the dialysis system. Treatment of unstable angina and myocardial infarction without a pathological Q wave on the ECG. It is recommended to use nadroparin subcutaneously 2 times a day (every 12 hours). The usual duration of treatment is 6 days. In clinical studies, for the treatment of patients with unstable angina and myocardial infarction without a Q on the ECG, nadroparin was used in combination with 325 mg of acetylsalicylic acid per day. The initial dose is administered as an intravenous bolus injection, subsequent doses are administered subcutaneously. The dose is calculated based on the patient’s body weight, subject to the presence of 86 IU of anti-factor Xa activity per 1 kg of the patient’s body weight (see table).
Patient's body weight (kg) | Initial IV dose (ml) | Next subcutaneous dose (every 12 hours, ml) | Amount of IU anti-Xa activity |
| ≤50 | 0,4 | 0,4 | 3800 |
| 50–59 | 0,5 | 0,5 | 4750 |
| 60–69 | 0,6 | 0,6 | 5700 |
| 70–79 | 0,7 | 0,7 | 6650 |
| 80–89 | 0,8 | 0,8 | 7600 |
| 90–99 | 0,9 | 0,9 | 8550 |
| ≥100 | 1,0 | 1,0 | 9500 |
Children and adolescents under the age of 18 Nadroparin is not recommended for the treatment of children and adolescents, since there is insufficient data regarding the safety and effectiveness of the drug and to determine the optimal dosage in this group of patients. Elderly patients There is no need to change the dose if there is no impairment of renal function. It is recommended to check your kidney function before starting treatment. Renal failure Prevention of thromboembolic complications . Do not change the dose in patients with mild renal failure (creatinine clearance ≥50 ml/min). In case of moderate or severe renal failure, the effect of nadroparin is increased, and the risk of thromboembolism and bleeding increases. If dose reduction is appropriate for moderate renal impairment (creatinine clearance ≥30 ml/min and ≤50 ml/min), the dose is reduced by 25–33%, taking into account individual risk factors for bleeding and thromboembolism. In severe renal failure (creatinine clearance ≤30 ml/min), the dose is reduced by 25–33%. Treatment of thromboembolic complications, unstable angina and myocardial infarction without a pathological Q wave on the ECG For the treatment of the above conditions in patients with mild renal failure (creatinine clearance ≥50 ml/min), the dose should not be changed. If dose reduction is appropriate for moderate renal impairment (creatinine clearance ≥30 ml/min and ≤50 ml/min), the dose is reduced by 25–33%, taking into account individual risk factors for bleeding and thromboembolism. For the treatment of these conditions in patients with severe renal failure, the use of nadroparin is contraindicated. Liver failure No clinical studies have been conducted in this group of patients.
Pharmacokinetics
Pharmacokinetic properties are determined based on changes in plasma anti-Xa factor activity. After subcutaneous administration, almost 100% of the drug is rapidly absorbed. Cmax in plasma is achieved between 3 and 4 hours if nadroparin calcium is used in a regimen of 2 injections per day. When using nadroparin calcium in a regimen of 1 injection per day, Cmax is achieved between 4 and 6 hours after administration. Metabolism occurs mainly in the liver (desulfation, depolymerization). After subcutaneous administration, T1/2 of anti-Xa factor activity of low molecular weight heparins is higher than in the case of unfractionated heparins and is 3–4 hours.
As for anti-factor IIa activity, when low molecular weight heparins are used, it disappears from the plasma faster than anti-factor Xa activity.
Excretion occurs primarily by the kidneys, in its original or slightly modified form.
At-risk groups
In elderly patients, since renal function is physiologically reduced, elimination slows down. This does not affect the dose and regimen of administration of the drug for prophylactic purposes as long as the renal function of these patients remains within acceptable limits, i.e. slightly damaged.
Before starting treatment with LMWH, renal function should be systematically assessed in elderly patients over 75 years of age using the Cockroft formula.
Mild to moderate renal failure (Cl >30 ml/min): in some cases it may be useful to monitor the level of anti-Xa factor activity in the blood to exclude the possibility of overdose during a course of drug use.
Hemodialysis: Low molecular weight heparin is injected into the arterial line of the dialysis loop in sufficiently high doses to prevent clotting in the loop. In principle, pharmacokinetic parameters do not change, except in the case of overdose, when the passage of the drug into the systemic circulation may lead to an increase in anti-Xa factor activity associated with end-phase renal failure.
Contraindications to the use of the drug Fraxiparine
Hypersensitivity to nadroparin or any component of the drug; thrombocytopenia associated with a history of nadroparin use; signs of bleeding or an increased risk of bleeding associated with impaired hemostasis, excluding DIC not caused by the use of heparin; organic lesions with a tendency to bleeding (for example, acute gastric or duodenal ulcer); hemorrhagic stroke; acute infective endocarditis; severe renal failure (creatinine clearance ≤30 ml/min) in patients during the treatment of thromboembolic complications, unstable angina and myocardial infarction without a pathological Q on the ECG.
Interaction
The development of hyperkalemia may depend on the simultaneous presence of several risk factors. Drugs that cause hyperkalemia: potassium salts, potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor blockers, NSAIDs, heparins (low molecular weight or unfractionated), cyclosporine and tacrolimus, trimethoprim. The risk of developing hyperkalemia increases when the above-mentioned drugs are combined with Fraxiparine.
The combined use of Fraxiparine with drugs that affect hemostasis, such as acetylsalicylic acid, NSAIDs, vitamin K antagonists, fibrinolytics and dextran, leads to a mutual enhancement of the effect.
In addition, it should be taken into account that platelet aggregation inhibitors (except for acetylsalicylic acid as an analgesic and antipyretic drug, i.e. in doses over 500 mg): NSAIDs, abciximab, acetylsalicylic acid in antiplatelet doses (50–300 mg) at Cardiological and neurological indications, beraprost, clopidogrel, eptifibatide, iloprost, ticlopidine, tirofiban increase the risk of bleeding.
Side effects of the drug Fraxiparine
The listed side effects are classified according to organs, systems and frequency of occurrence: very often (≥1/10), often (≥1/100 and ≤1/10), infrequently (≥1/1000 and ≤1/100), rarely (≥ 1/10,000 and ≤1/1000), very rare (≤1/10,000). From the blood and lymphatic system Very often: various bleedings, occurring more often in patients with risk factors. Rarely: thrombocytopenia (sometimes thrombogenic), thrombocytosis. Very rare: eosinophilia, reversible after cessation of treatment. From the immune system Very rare: hypersensitivity reactions (including angioedema and skin reactions), anaphylactoid reaction. Metabolism and digestive disorders Very rare: reversible hyperkalemia associated with heparin-induced aldosterone suppression, mainly in patients with risk factors. From the hepatobiliary system Often: increased levels of transaminases, usually reversible. From the reproductive system : Very rare: priapism. General disorders and local reactions Very common: small hematomas at the injection site. In some cases, hard nodules may appear and disappear within a few days. Common: reactions at the injection site. Rarely: calcification at the injection site. Calcification occurs more often in patients with altered calcium phosphate levels, such as chronic renal failure. Very rare: skin necrosis at the injection site, preceded by infiltration or painful and erymatous spots without general symptoms. In such cases, the use of the drug must be stopped immediately.
Side effects
The most common side effect is the formation of a subcutaneous hematoma at the injection site. In some cases, the appearance of dense nodules is observed, which does not indicate heparin encapsulation, which disappear after a few days.
Large doses of Fraxiparine can provoke bleeding of various localizations and mild thrombocytopenia (type I), which usually disappears with further therapy. A temporary moderate increase in the level of liver enzymes (ALT, AST) is possible.
Skin necrosis and allergic reactions occur rarely. Several cases of anaphylactic reactions and immune thrombocytopenia (type II) associated with arterial and/or venous thrombosis or thromboembolism have been reported.
Special instructions for the use of the drug Fraxiparine
Thrombocytopenia Due to the existing risk of heparin-induced thrombocytopenia, the platelet count should be monitored during the entire course of treatment with nadroparin. Isolated cases of severe thrombocytopenia accompanied by arterial or venous thrombosis have been reported. Such a diagnosis can be assumed in the following situations: thrombocytopenia; any significant decrease in platelet count (30 to 50% compared to baseline); negative dynamics of thrombosis for which treatment was prescribed; the appearance of thrombosis during treatment; ICE. If these conditions occur, treatment with nadroparin should be discontinued. The above-mentioned effects are of an immunoallergic nature, if treatment is carried out for the first time, and occur between the 5th and 21st day of treatment, but may occur much earlier if the patient has a history of thrombocytopenia associated with heparin treatment. In patients with a history of thrombocytopenia that occurred during treatment with heparin (both standard and low molecular weight), treatment with nadroparin can be prescribed if necessary. In this case, careful clinical observation and determination of the platelet count daily are necessary. If thrombocytopenia occurs, treatment with nadroparin should be discontinued immediately. If thrombocytopenia occurs during treatment with heparin (both standard and low molecular weight), it must be discontinued and treatment with a drug of another class of antithrombotic agents must be continued. If such a drug is not available, another low molecular weight heparin drug can be used if the use of heparin is necessary. The platelet count should be monitored at least once a day and treatment should be stopped as soon as possible if the initial thrombocytopenia persists even after changing the drug. in vitro platelet aggregation test is of limited value in establishing the diagnosis of heparin-induced thrombocytopenia. Elderly patients It is recommended to check renal function before starting treatment in this category of patients. Situations in which the risk of bleeding increases Nadroparin is used with caution in situations associated with an increased risk of bleeding, such as:
- liver failure;
- severe hypertension (arterial hypertension);
- a history of gastric or duodenal ulcers or other organic lesions with a tendency to bleeding;
- chorioretinitis;
- period after operations on the brain and spinal cord, on the eyes.
Renal failure It is known that nadroparin is excreted mainly by the kidneys, which leads to an increase in the effect of nadroparin in renal failure and an increased risk of bleeding, so nadroparin is used with caution in these patients. The decision to reduce the dose when the creatinine clearance is 30-50 ml/min should be based on a clinical assessment of individual risk factors for bleeding compared with the risk of thromboembolism. Hyperkalemia Heparin may inhibit adrenal aldosterone secretion and cause hyperkalemia, especially in patients with elevated plasma potassium levels or the risk of such increases, such as patients with diabetes mellitus, chronic renal failure, metabolic acidosis, or patients taking drugs that can lead to hyperkalemia (eg ACE inhibitors, NSAIDs). The risk of hyperkalemia increases with duration of treatment, but hyperkalemia is usually reversible. In patients with risk factors, it is necessary to regularly monitor the level of potassium in the blood plasma. Spinal/epidural anesthesia, lumbar puncture and concomitant medications The risk of developing a spinal/epidural hematoma increases with the use of an epidural catheter or with the concomitant use of other drugs that affect hemostasis, such as NSAIDs, platelet aggregation inhibitors and other anticoagulants. The risk of developing a hematoma may increase with traumatic or repeated epidural or spinal puncture. Therefore, the simultaneous use of spinal blockade and anticoagulants is possible only after a careful assessment of the benefits/risks in each individual case:
- in patients treated with anticoagulants, the benefits of spinal blockade must be carefully weighed against the possible risks;
- In patients preparing for elective surgery with a spinal block, the benefits of anticoagulants should be carefully weighed against the possible risks.
When performing a lumbar puncture, spinal or epidural anesthesia, a sufficient interval should be maintained between the injection of nadroparin and the insertion or removal of the spinal/epidural catheter or needle. Patients should be under close medical supervision to promptly identify symptoms of neurological disorders. If they occur, the patient must immediately undergo appropriate therapy. Salicylates, NSAIDs and platelet aggregation inhibitors For the prevention or treatment of venous thromboembolic complications and for the prevention of blood clotting during hemodialysis, the concomitant use of acetylsalicylic acid, other salicylates, NSAIDs and platelet aggregation inhibitors is not recommended as they increase the risk of bleeding. If it is necessary to use such a combination, careful clinical monitoring is necessary. During clinical studies in the treatment of patients with unstable angina and myocardial infarction without a pathological Q on the ECG, nadroparin was used in combination with acetylsalicylic acid at a dose of 325 mg/day. Latex allergy The protective cap on the needle of the pre-filled syringe contains natural latex rubber, which may cause an allergic reaction if you are hypersensitive to latex. Does not affect the ability to drive vehicles and perform work that requires increased attention. During pregnancy and breastfeeding. There are no clinical studies examining the effect of nadroparin on reproductive function. Animal studies have not shown a teratogenic or embryotoxic effect of Fraxiparine. However, clinical data regarding the transplacental passage of nadroparin in pregnant women are limited, so the use of the drug during pregnancy is not recommended, unless the expected benefit outweighs the possible risk. Data regarding the excretion of nadroparin into breast milk are limited, therefore the use of nadroparin during breastfeeding is not recommended.
Use during pregnancy and breastfeeding
Experiments on animals have not shown the teratogenic effect of nadroparin calcium; however, in the first trimester of pregnancy it is preferable to avoid prescribing Fraxiparine, both in a prophylactic dose and in the form of a course of treatment.
During the II and III trimesters of pregnancy, Fraxiparine can be used only in accordance with the doctor's recommendations for the prevention of venous thrombosis (when comparing the benefits to the mother with the risk to the fetus). Course treatment is not used during this period.
If the use of epidural anesthesia is considered, it is recommended, as far as possible, to withhold prophylactic heparin treatment at least 12 hours before anesthesia.
Since absorption of the drug in the gastrointestinal tract in newborns is, in principle, unlikely, treatment with Fraxiparine in nursing mothers is not contraindicated.
Fraxiparine overdose, symptoms and treatment
The main clinical sign of overdose with subcutaneous or intravenous administration is bleeding. In this case, it is necessary to determine the number of platelets and other indicators of blood clotting. Patients with minor bleeding very rarely require specific treatment measures. As a rule, it will be sufficient to reduce the dose or delay the administration of the next dose of nadroparin. In severe cases, the use of protamine sulfate is indicated. The drug largely neutralizes the anticoagulant effect of nadroparin, but some anti-Xa activity remains. When determining the amount of protamine sulfate required for administration, the following calculation is used: 0.6 ml of protamine sulfate neutralizes approximately 950 IU of the anti-factor Xa activity of nadroparin. In this case, it is necessary to take into account the time that has passed since the administration of heparin, since a reduction in the dose of the antidote may be necessary.
Composition and release form
| Injection | 1 syringe |
| nadroparin calcium ME anti-Xa | 2850 |
| excipients: calcium hydroxide solution - qs (or dilute hydrochloric acid) to pH 5.0–7.5; water for injection - qs up to 0.3 ml |
in a blister there are 2 disposable syringes of 0.3 ml each; There are 1 or 5 blisters in a cardboard box.
| Injection | 1 syringe |
| nadroparin calcium ME anti-Xa | 3800 |
| excipients: calcium hydroxide solution - qs (or dilute hydrochloric acid) to pH 5.0–7.5; water for injection - qs up to 0.4 ml |
in a blister there are 2 disposable syringes of 0.4 ml each; There are 1 or 5 blisters in a cardboard box.
| Injection | 1 syringe |
| nadroparin calcium, ME anti-Xa | 5700 |
| excipients: calcium hydroxide solution - qs (or dilute hydrochloric acid) to pH 5.0–7.5; water for injection - qs up to 0.6 ml |
in a blister there are 2 disposable syringes of 0.6 ml each; There are 1 or 5 blisters in a cardboard box.
| Injection | 1 syringe |
| nadroparin calcium, ME anti-Xa | 7600 |
| excipients: calcium hydroxide solution - qs (or dilute hydrochloric acid) to pH 5.0–7.5; water for injection - qs up to 0.8 ml |
in a blister there are 2 disposable syringes of 0.6 ml each; There are 1 or 5 blisters in a cardboard box.
| Injection | 1 syringe |
| nadroparin calcium, ME anti-Xa | 9500 |
| excipients: calcium hydroxide solution - qs (or dilute hydrochloric acid) to pH 5.0–7.5; water for injection – qs up to 1 ml |
in a blister there are 2 disposable syringes of 1 ml each; There are 1 or 5 blisters in a cardboard box.
