Fluxum^® (Solution) Instructions for Use

Marketing Authorization Holder

Alfasigma S.p.A. (Italy)

Contact Information

ALFASIGMA RUS LLC (Russia)

ATC Code

B01AB07 (Parnaparin)

Active Substance

Parnaparin sodium (Rec.INN registered by WHO)

Dosage Forms

	Fluxum®	Solution for subcutaneous injection 3200 anti-Xa IU/0.3 ml: syringes 6 pcs. in a set with needles
		Solution for subcutaneous injection 4250 anti-Xa IU/0.4 ml: syringes 6 pcs. in a set with needles
		Solution for subcutaneous injection 6400 anti-Xa IU/0.6 ml: syringes 6 pcs. in a set with needles

Dosage Form, Packaging, and Composition

Solution for s.c. injection transparent, from colorless to light yellow.

Excipients : water for injections – up to 0.3 ml.

0.3 ml – glass syringes* (2) – blisters (3) – cardboard packs.

Solution for s.c. injection transparent, from colorless to light yellow.

Excipients : water for injections – up to 0.4 ml.

0.4 ml – glass syringes* (2) – blisters (3) – cardboard packs.

Solution for s.c. injection transparent, from colorless to light yellow.

Excipients : water for injections – up to 0.6 ml.

0.6 ml – glass syringes* (2) – blisters (3) – cardboard packs.

* syringe, complete with a needle in a case.

Clinical-Pharmacological Group

Direct-acting anticoagulant

Pharmacotherapeutic Group

Direct-acting anticoagulant agent

Pharmacological Action

Fluxum^® contains the active substance Parnaparin sodium – a low molecular weight glycosaminoglycan with a molecular weight from 4000 to 6000 Da (average molecular weight about 5000 Da), which is obtained using an original patented process of fragmentation and purification of heparin.

Parnaparin sodium has an antithrombotic effect. In vitro and in vivo it significantly inhibits factor Xa, has a small effect on factor IIa and on aPTT. Parnaparin is characterized by a more pronounced activity against factor Xa (anti-Xa) compared to factor IIa (anti-IIa). The ratio of anti-Xa/anti-IIa activity is greater than 4 (compared to heparin, for which this ratio is 1). This ratio can be considered as a therapeutic index or safety index. Parnaparin sodium does not have proaggregant platelet action.

Pharmacokinetics

Distribution, metabolism, excretion

On average, Fluxum^® reaches its peak activity against factor Xa 3 hours after s.c. administration; anti-Xa activity persists in the blood for about 20 hours after a single injection; these characteristics make it possible to use the drug once a day. The bioavailability of parnaparin sodium, assessed by anti-Xa activity, is close to 100%. AUC has a linear dependence on the dose.

Parnaparin sodium is distributed in the liver and kidneys.

With the s.c. route of administration, the pharmacokinetic profile of anti-Xa activity is more favorable compared to the profile with i.v. administration, as it is characterized by a smoother curve with fewer peaks and a slower decline in activity.

It is metabolized in the liver to inactive compounds and excreted from the body by the kidneys. T_1/2 is about 6 hours.

Indications

• Deep vein thrombosis (DVT);
• Post-thrombophlebitic syndrome;
• Chronic venous insufficiency;
• Acute superficial thrombophlebitis;
• Varicophlebitis.

Prevention of deep vein thrombosis (DVT)

• During general surgical and orthopedic operations;
• In patients at high risk of developing deep vein thrombosis.

ICD codes

Dosage Regimen

The drug is administered s.c.

Prevention of DVT

Prevention of DVT in general surgery 0.3 ml (3200 anti-Xa IU) 2 hours before surgery. Then once a day for at least 7 days. Blood coagulation tests are not necessary.

Prevention of DVT in patients undergoing orthopedic surgery and in patients at increased risk of DVT 0.4 ml (4250 anti-Xa IU) 12 hours before and after surgery, then once a day during the postoperative period, for at least 10 days.

Treatment of DVT, post-thrombophlebitic syndrome, chronic venous insufficiency, acute superficial thrombophlebitis and varicophlebitis

Treatment of DVT 0.6 ml (6400 anti-Xa IU) 2 times a day for at least 7-10 days. If necessary, treatment can be started with slow infusion administration of 1.2 ml (12800 anti-Xa IU) over 3-5 days. After the acute phase of the disease is relieved, it is recommended to continue s.c. administration of the drug at a dose of 0.6 ml (6400 anti-Xa IU) or 0.4 ml (4250 anti-Xa IU) for 10-20 days.

After the recommended period of treatment with Fluxum^®, oral anticoagulant therapy should be started when necessary (see “Transition from Fluxum^® to oral anticoagulants” in the “Special Instructions” section).

Treatment of post-thrombophlebitic syndrome and chronic venous insufficiency 0.6 ml (6400 anti-Xa IU) or 0.4 ml (4250 anti-Xa IU) or 0.3 ml (3200 anti-Xa IU) depending on the severity of the disease once a day for at least 30 days.

Treatment of acute superficial thrombophlebitis and varicophlebitis 0.6 ml (6400 anti-Xa IU) or 0.4 ml (4250 anti-Xa IU) or 0.3 ml (3200 anti-Xa IU) depending on the severity of the disease once a day for at least 20 days.

Technique of s.c. injection

The pre-filled disposable syringe is ready for immediate use. Air bubbles should not be expelled from the syringe before injection to avoid loss of the medicinal product when using pre-filled syringes. The injection is preferably given when the patient is lying down. The injection site should be alternated between the left and right anterolateral or posterolateral surfaces of the abdominal wall.

Fluxum^® is injected into the subcutaneous tissue of the abdomen, into the thickness of the skin fold. The needle is positioned perpendicular to the fold, between the thumb and forefinger. The skin fold is held until the end of the injection. The injection site must be changed.

Adverse Reactions

Clinical trial data

Adverse reactions were classified by system-organ class and distributed by frequency of occurrence in the following order: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10000 to <1/1000), very rare (<1/10000).

Blood and lymphatic system disorders rare – thrombocytopenia, sometimes severe (see section “Special Instructions”), limited hemorrhagic phenomena, mainly associated with pre-existing risk factors, such as organic diseases with a high risk of bleeding, or iatrogenic phenomena (see also section “Drug Interactions”).

Immune system disorders very rare – anaphylactic or anaphylactoid reactions.

Skin and subcutaneous tissue disorders rare – dermatitis, erythema, skin itching, roseola, skin rash and urticaria.

Other common – hematoma, bleeding, irritation, pain and discomfort at the injection site, rare – erythema (with plaques), roseola, necrosis at the injection site.

Laboratory test results uncommon – increased activity of liver transaminases.

Injury, poisoning and procedural complications very rare – spinal or epidural hematomas associated with the prophylactic use of heparin during spinal or epidural anesthesia, or lumbar puncture. Hematomas caused varying degrees of neurological changes, including long-term or permanent paralysis (see also section “Special Instructions”).

Post-marketing surveillance data

The following adverse events have been reported during post-marketing surveillance. The frequency of these events is unknown (cannot be calculated from the available data).

Hematopoietic system disorders anemia.

Nervous system disorders decreased level of consciousness.

Cardiovascular system disorders deep vein thrombosis, hot flushes.

Respiratory system disorders dyspnea, nosebleed, pharyngeal edema, pleural hemorrhage.

Digestive system disorders abdominal pain, diarrhea, lip edema, melena, nausea.

Hepatobiliary disorders cholestatic hepatitis, jaundice.

Skin and subcutaneous tissue disorders maculopapular rash, generalized pruritus.

Musculoskeletal and connective tissue disorders arthralgia, myalgia.

Reproductive system and breast disorders metrorrhagia.

Other asthenia.

Contraindications

• Hypersensitivity to parnaparin or other components of the drug, to heparin and pork products;
• Performance of regional anesthesia in patients receiving Fluxum^® for therapeutic purposes;
• Conditions or diseases complicated by bleeding, as well as an increased risk of bleeding or predisposition to bleeding in hemostasis disorders (except for consumption coagulopathy not caused by heparin), gastric and duodenal ulcer and erosive-ulcerative lesions of the gastrointestinal tract in the acute phase, angiodysplasia, chorioretinopathy, hemorrhagic stroke;
• Thrombocytopenia induced by parnaparin sodium, including in the anamnesis;
• Acute bacterial endocarditis (except for prosthetic endocarditis);
• Cerebral aneurysm;
• Severe uncontrolled arterial hypertension (BP ≥180/100 mm Hg);
• Severe traumatic brain injury (in the postoperative period);
• Severe diseases of the kidneys and pancreas;
• Concomitant use with vitamin K antagonists (after achieving the required INR), salicylates and other NSAIDs, antiplatelet drugs (including clopidogrel, dipyridamole), sulfinpyrazone and the combination of ticlopidine with parnaparin sodium in high doses;
• Children and adolescents under 18 years of age (efficacy and safety have not been established).

With caution renal and hepatic insufficiency; mild and moderate arterial hypertension; gastric and duodenal ulcer and erosive-ulcerative lesions of the gastrointestinal tract in the anamnesis; other diseases/conditions in the anamnesis that may be complicated by bleeding; heparin-induced thrombocytopenia and thrombocytopenia caused by other low molecular weight heparins, including in the anamnesis; chorioretinopathy in the anamnesis; diseases of the brain and spinal cord in the postoperative period; concomitant use with indirect anticoagulants, systemic corticosteroids, dextran (for parenteral use); combination of parnaparin sodium in low doses with ticlopidine.

Use in Pregnancy and Lactation

Studies conducted in animals have not shown teratogenic and embryotoxic effects of parnaparin sodium. There is no convincing data on penetration through the placental barrier and excretion with breast milk.

However, since the risk of toxic effects of parnaparin sodium on the fetus cannot be completely ruled out, the drug should be used during pregnancy only in case of extreme necessity and under direct medical supervision.

If it is necessary to use the drug during lactation, breastfeeding should be discontinued.

Use in Hepatic Impairment

The drug should be used with caution in hepatic insufficiency.

Use in Renal Impairment

The drug should be used with caution in renal insufficiency.

Pediatric Use

The use of the drug is contraindicated in children and adolescents under 18 years of age.

Geriatric Use

Elderly patients (especially over 80 years of age) may be at greater risk of bleeding complications, so careful clinical monitoring is recommended.

Special Precautions

Fluxum^® should not be administered i.m.

Parnaparin-induced thrombocytopenia

It is known that Fluxum^®, like heparin itself and other low molecular weight heparins, can cause thrombocytopenia. Heparin-induced thrombocytopenia usually develops 4-10 days after the start of treatment or earlier in repeated cases. In 10-20% of patients, early mild thrombocytopenia (platelets >100000/µl) occurs, which may persist or regress with continued treatment. As a result of the formation of antibodies to the heparin/platelet factor 4 complex, a more severe immune form, heparin-induced thrombocytopenia type 2, may develop in some cases, followed by thrombosis and thromboembolism in the arteries of the brain, lungs, lower extremities, often with a fatal outcome. These patients may develop a new thrombus associated with thrombocytopenia caused by irreversible heparin-induced platelet aggregation, the so-called white clot syndrome.

Patients should be carefully monitored during treatment with Fluxum^®. Therefore, in case of thrombocytopenia or the appearance of symptoms associated with a new thrombotic event, or in case of worsening of a previous case of thrombosis, the administration of low molecular weight heparin should be discontinued. Alternative anticoagulant therapy should be undertaken after heparin withdrawal. Immediate use of oral anticoagulant therapy should be avoided, as cases of thrombosis exacerbation have been observed.

During long-term treatment, the platelet count should be determined before starting therapy with Fluxum^® and 2 times a week during the first month, and then monitoring of the platelet count may be less frequent. Fluxum^® should be prescribed with particular caution to patients with a history of thrombocytopenia caused by heparin or another low molecular weight heparin; their platelet count should be determined daily. If thrombocytopenia occurs during heparin treatment, therapy with low molecular weight heparins may be an alternative treatment. In this case, the platelet count should be determined daily and, if thrombocytopenia persists, the low molecular weight heparin should be discontinued as soon as possible. In case of thrombocytopenia less than 100000/µl, in case of occurrence and progression of thrombosis, Fluxum^® must be discontinued and the patient transferred to another anticoagulant therapy. Switching to oral anticoagulant therapy in these cases is not recommended, as progression of thrombosis is known.

If heparin-induced thrombocytopenia is suspected, in vitro platelet aggregation tests are not of great diagnostic value; consultation with specialists is necessary.

Spinal/epidural anesthesia

Performing spinal or epidural anesthesia, spinal-epidural analgesia or lumbar puncture against the background of prophylactic use of Fluxum^®, as well as other low molecular weight heparins, may be complicated by spinal or epidural hematoma with the development of persistent or irreversible paralysis. The risk of these complications increases with the use of epidural catheters, with the concomitant use of NSAIDs, antiplatelet drugs or anticoagulants, with trauma or repeated spinal punctures, with pre-existing hemostasis disorders or in elderly patients. If it is necessary to perform anesthesia/analgesia of this type against the background of prophylactic use of Fluxum^®, the presence of these risk factors should be carefully checked before these interventions. Spinal catheters are usually placed no earlier than 8-12 hours after the last prophylactic dose of low molecular weight heparin. Fluxum^® should not be administered 2-4 hours before and after catheter placement/removal. The injection should be delayed or canceled if blood is aspirated from the spinal canal during spinal or epidural anesthesia. The catheter should be removed as late as possible after (8-12 hours) the last prophylactic administration of Fluxum^®.

Special attention should be paid to patients who received Fluxum^® before or after epidural or spinal anesthesia, checking for neurological symptoms such as back pain, sensory and motor disorders (numbness or weakness in the lower extremities), impaired bowel or bladder function. Patients should be informed of the need to immediately consult a doctor if these symptoms occur. If an epidural or spinal hematoma is suspected, immediate diagnosis and treatment, including spinal cord decompression, is required.

Non-interchangeability of parnaparin sodium with other low molecular weight heparins and unfractionated heparin

Parnaparin cannot be interchanged (unit for unit) with unfractionated heparin, other low molecular weight heparins or synthetic polysaccharides. Each of these drugs differs in its source material, manufacturing process, physicochemical, biological and clinical properties, leading to differences in biochemical identity, dosage and possibly clinical efficacy and safety. Each of these drugs is unique and has its own instructions for use. If skin necrosis occurs, treatment with Fluxum^® should be discontinued.

Transition from Fluxum^® to oral anticoagulants

– Transition from Fluxum^® to vitamin K antagonists (VKA) Since there is an interval before VKAs reach their maximum effect, treatment with Fluxum^® should not be discontinued until the required INR is achieved.

– Transition to direct oral anticoagulants (DOACs) These drugs should not be administered simultaneously with Fluxum^®. DOAC treatment should be initiated at the end of the recommended treatment period with parnaparin and precisely at the time when the next parnaparin injection would have been scheduled, had parnaparin treatment been continued.

Other precautions

There is no experience with the use of Fluxum^® in patients with mechanical prosthetic heart valves (including pregnant women).

Heparins may suppress adrenal aldosterone secretion, leading to hyperkalemia, especially in patients with diabetes mellitus, chronic renal failure, pre-existing metabolic acidosis, elevated plasma potassium levels, or those taking potassium-sparing drugs. The risk of hyperkalemia appears to increase with the duration of therapy but is usually reversible. Plasma potassium levels should be measured in at-risk patients before initiating heparin therapy and then monitored regularly, especially if treatment is extended beyond 7 days.

Use in pediatrics

The use of Fluxum^® in patients under 18 years of age is included in the “Contraindications” because efficacy and safety have not been established.

Elderly patients

Elderly patients (especially those over 80 years of age) may be at greater risk of bleeding complications, so careful clinical monitoring is recommended. However, there is no need to reduce the recommended doses of Fluxum^® unless renal function is severely impaired.

Renal impairment

As indicated in the “With caution” subsection of the “Contraindications” section, the use of Fluxum^® in patients with renal impairment should be conducted with caution. This is due to increased drug exposure, which increases the risk of bleeding, so careful clinical monitoring is recommended. In cases of severe renal impairment (CrCl <30 ml/min), an increased risk of bleeding may also be observed at recommended doses, so in these patients, a dose reduction of Fluxum^® may be required and monitoring of anti-Xa plasma activity is recommended.

Hepatic impairment

As reported in the “With caution” subsection of the “Contraindications” section, the use of Fluxum^® in patients with hepatic impairment should be conducted with caution due to an increased risk of bleeding; careful clinical monitoring is also recommended in this case.

Fluxum^® contains less than 1 mmol sodium (23 mg) per syringe, i.e., it is essentially sodium-free.

Effect on ability to drive and operate machinery

Fluxum^® does not affect the ability to drive vehicles and engage in activities requiring increased attention and speed of psychomotor reactions.

Overdose

Symptoms Accidental overdose may lead to bleeding, which is not observed when the drug is used at therapeutic doses.

Treatment To neutralize the drug’s effect, protamine sulfate should be administered intravenously at a ratio of 0.6 ml of protamine sulfate per 0.1 ml of Fluxum^®.

Drug Interactions

Not recommended combinations

Acetylsalicylic acid, other salicylates, NSAIDs increased risk of bleeding due to the antiplatelet effect and damaging effect on the gastrointestinal mucosa of these drugs.

Ticlopidine increased risk of bleeding due to antiplatelet action. Concomitant use with high therapeutic doses of parnaparin sodium is not recommended. When used concomitantly with low prophylactic doses of parnaparin sodium, careful clinical observation and monitoring of coagulation parameters is necessary.

Other antiplatelet drugs (e.g., clopidogrel, dipyridamole) increased risk of bleeding.

Sulfinpyrazone increased risk of bleeding.

Combinations requiring caution

Oral anticoagulants enhancement of the anticoagulant effect. When replacing parnaparin sodium with oral anticoagulants, careful patient monitoring is necessary. To assess the effect of these drugs on hemostasis, blood tests should be taken before prescribing parnaparin sodium.

Systemic corticosteroids increased risk of bleeding when taking corticosteroids in high doses for more than 10 days due to damage to the gastrointestinal mucosa and a direct effect on the vascular wall. The use of parnaparin sodium concomitantly with corticosteroids must be justified, and this therapy should be conducted under medical supervision.

Dextran (for parenteral use) increased risk of bleeding due to antiplatelet action. When used concomitantly, a dose adjustment of parnaparin sodium is necessary so that the reduction in blood coagulation parameters is no more than 1.5-fold. The effect of parnaparin sodium is reduced when used concomitantly with ascorbic acid, antihistamines, cardiac glycosides, penicillin (IV administration), tetracycline, phenothiazine derivatives.

Incompatibility

Fluxum^® is an acidic polysaccharide that forms insoluble complexes with bases. For this reason, the solution of Fluxum^® is incompatible with solutions of vitamin K, B vitamins, hydrocortisone, hyaluronidase, calcium gluconate, quaternary ammonium bases, chloramphenicol, tetracycline, and aminoglycosides.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 3 years. Do not use after the expiration date printed on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.