Epsodilave

Patient Information Leaflet: Instructions for the User

EPSODILAVE 250 U.I./5 ml solution for catheter patency, 300 U.I./3 ml solution for catheter patency, 500 U.I./2 ml solution for catheter patency

Heparin sodium
Please read this leaflet carefully before using this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, consult your doctor or nurse.
• If you experience any side effects, including those not listed in this leaflet, consult your doctor or nurse. See section 4.

Contents of this leaflet:

1. What EPSODILAVE is and what it is used for
2. What you need to know before using EPSODILAVE
3. How to use EPSODILAVE
4. Possible side effects
5. How to store EPSODILAVE
6. Contents of the pack and other information

1. What EPSODILAVE is and what it is used for

EPSODILAVE contains the active substance sodium heparin, which belongs to a group of medicines called anticoagulants that work by preventing the formation of blood clots (thrombi).
This medicine is used to keep medical devices inserted into veins (venous catheters and cannulae) clean and unobstructed. These devices are used for the administration of medicines by intravenous route, either intermittently or continuously (by infusion), or for repeated blood sampling.
This medicine may be used at rest, after each administration or after each blood draw, in order to prevent the formation of blood clots within the devices themselves, which could interfere with the passage of medicines to be administered. The dose of EPSODILAVE used is sufficient to achieve an anticoagulant effect without causing systemic effects in the patient.

2. What you need to know before using EPSODILAVE

Do not use EPSODILAVE

• If you are allergic to sodium heparin or to other substances closely related from a chemical point of view, or to any of the other components of this medicine (listed in section 6);
• If you have low levels of platelets in the blood (severe thrombocytopenia);
• If you suffer from severe liver, kidney, or pancreatic diseases;
• If coagulation tests cannot be performed at appropriate intervals (exclusively for therapeutic dosages);
• If you suffer from disseminated intravascular coagulation (DIC) (a serious syndrome causing blood clotting in many blood vessels) attributable to heparin-induced thrombocytopenia;
• If you currently have (or have previously had) cerebral hemorrhage;
• If you have lesions at risk of bleeding, such as gastric and/or intestinal ulcers, aneurysm, or cerebral neoplasm;
• If you have experienced trauma or undergone surgery involving the central nervous system, eyes, or ears;
• If you suffer from retinopathy or vitreous hemorrhage;
• If you have infective endocarditis (an infection affecting the inner lining of the heart).
• If you are scheduled to undergo loco-regional anesthesia for elective surgical procedures. Additionally, if you have organic lesions with high risk of bleeding, your doctor will need to evaluate the use of heparin by considering the risk-benefit ratio in your specific case.

Warnings and precautions
Talk to your doctor or nurse before using EPSODILAVE.
This medicine must not be injected and must not be used for anticoagulant therapy.
Before being administered this medicine, inform your doctor if:

• You suffer from suspected neoplasm with a tendency to bleed;
• You suffer from chronic alcoholism;
• You are elderly; a dose reduction may be necessary, especially in women who are at higher risk of bleeding;
• You are at risk of bleeding, particularly:
  • if you have uncontrolled high blood pressure (uncontrolled hypertension);
  • if you suffer from inflammation of the membrane lining the heart cavities (subacute bacterial endocarditis);
  • if you have blood disorders with increased tendency to bleed (hemophilic syndromes or deficiency of coagulation factors);
  • if you have a reduced number of platelets in the blood (thrombocytopenia) or impaired platelet function (thrombocytopathy);
  • if you suffer from certain hemorrhagic vascular purpuras (such as Rendu-Osler disease);
  • if you have a stomach and/or intestinal ulcer;
  • if you suffer from esophagitis or erosive gastritis;
  • if you have active inflammatory bowel disease;
  • if you have a continuous drainage of the stomach or small intestine;
  • if you have recently undergone lumbar puncture or spinal anesthesia;
  • if you have recently undergone brain, spinal cord, or eye surgery;
  • if you suffer from liver diseases with altered coagulation parameters and/or esophageal vein problems (esophageal varices);
  • if you suffer from stomach diseases caused by increased blood pressure in the liver circulation (portal hypertensive gastropathy);
  • in case of threatened abortion;
  • during the menstrual cycle;
  • in the postpartum period;
  • if you are receiving concomitant treatment with fibrinolytic agents or oral anticoagulants, platelet aggregation inhibitors, non-steroidal anti-inflammatory drugs (NSAIDs), and/or glycoprotein IIb/IIIa receptor antagonists.

If this medicine is administered during spinal or epidural anesthesia, epidural analgesia, or lumbar puncture, the use of low molecular weight heparin may rarely be associated with spinal or epidural hematomas, which could lead to prolonged or permanent paralysis of the lower limbs. You should therefore be frequently monitored for signs and symptoms of neurological impairment, such as back pain, sensory and motor deficits (numbness and weakness in the lower limbs), and intestinal and/or bladder dysfunction. Inform your doctor or nurse immediately if you experience any of these symptoms. The risk of spinal/epidural hematomas is increased by the following conditions:

• Placement of catheters in the spinal canal (indwelling epidural catheter for continuous infusion);
• Concomitant use of other medicines that may affect coagulation, such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet aggregation inhibitors, or other anticoagulants;
• Trauma or repeated lumbar punctures;
• Coagulation disorders;
• Advanced age.

In all cases of bleeding, even minor, discontinue treatment with EPSODILAVE and contact your doctor immediately.
EPSODILAVE may cause an increase in potassium levels in the blood (hyperkalemia). If you currently have or have previously had hyperkalemia, a condition characterized by elevated potassium levels in the blood, your doctor will perform blood tests to measure potassium levels before starting treatment and at regular intervals during treatment, especially if treatment lasts longer than 7 days.
If platelet levels in the blood decrease (thrombocytopenia), treatment must be discontinued.
This effect may be associated with clot formation (arterial or venous thrombosis), may be of allergic origin, or may occur following accidental intravenous administration of the medicine.
Your doctor should closely monitor your platelet count throughout the course of treatment with sodium heparin.
If you develop fever, thrombosis, thrombophlebitis, infections with thrombotic tendency, inflammatory conditions, sometimes occurring during myocardial infarction, cancer, congenital or post-surgical antithrombin III deficiency, you may have reduced sensitivity to heparin; your doctor will evaluate these conditions.
Interaction with andexanet alfa
Andexanet alfa may reduce the anticoagulant effect of heparin. The use of heparin after andexanet alfa should be avoided. Inform your doctor if you have been administered andexanet alfa.
During treatment with EPSODILAVE, avoid intramuscular administration of other medicines due to the risk of hematoma.

• Unlike treatment with dicoumarol, routine laboratory monitoring of heparin therapy is not strictly necessary; however, your doctor will monitor your treatment with appropriate diagnostic tests (measurement of clotting time in test tube – Lee White).
• The use of heparin may alter your thyroid function tests (e.g., falsely elevated T3 and T4 levels).
• Since heparin is a substance of animal origin, if you have had previous allergic reactions, your doctor may administer a reduced dose of heparin to test for possible reactions.

Children and adolescents
Sodium heparin is not recommended in children and adolescents under 18 years of age.
Other medicines and EPSODILAVE
Inform your doctor or nurse if you are taking, have recently taken, or might take any other medicines.
Even though accidental intravenous administration of this medicine at recommended doses does not usually cause effects, inform your doctor if you are taking:

• Oral anticoagulants, as concomitant administration may increase the anticoagulant effect;
• Platelet aggregation inhibitors, fibrinolytics, or other medicines that interfere with platelet aggregation and may induce bleeding, such as acetylsalicylic acid, non-steroidal anti-inflammatory drugs (e.g., acetylsalicylic acid, dextran, phenylbutazone, ibuprofen, indomethacin, ketorolac, or diclofenac), medicines with antiplatelet effects (e.g., ticlopidine, clopidogrel, or sulfinpyrazone), certain cephalosporin antibiotics (e.g., cefaclor, cefixime, ceftriaxone, cefamandole, cefoperazone), dextran, dipyridamole, hydroxychloroquine, fibrinolytic agents (e.g., streptokinase, urokinase, alteplase), coumarin derivatives, glycoprotein IIb/IIIa receptor antagonists (e.g., eptifibatide, abciximab), epoprostenol.
• Intravenous nitroglycerin, as it may cause a reduction in heparin's effect;
• Medicines that increase potassium levels in the blood, such as ACE inhibitors, sartans, potassium-sparing diuretics, potassium salts, or beta-blockers (medicines used in the treatment of cardiovascular conditions);
• Other medicines that may reduce the anticoagulant effect of heparin, such as digitalis, tetracyclines, nicotine, glucocorticoids, penicillins, phenothiazines, antihistamines, and andexanet alfa (a medicine used to reverse the effects of certain anticoagulants such as apixaban or rivaroxaban). In addition, heparin may alter the results of tests assessing thyroid function, leading to a false increase in certain thyroid hormones (T3 and T4).

Fertility, pregnancy, and breastfeeding
Pregnancy
If you are pregnant, think you may be pregnant, are planning to become pregnant, or are breastfeeding, consult your doctor or pharmacist before using this medicine. The safety of use during pregnancy has not been fully established. In the absence of reliable data, the decision to use heparin during pregnancy should be made after careful evaluation of the risk-benefit ratio in individual cases.
Breastfeeding
Heparin is not excreted in breast milk.
Fertility
There are no available data on the effect of heparin on human fertility.
Driving and using machines
This medicine does not affect the ability to drive or operate machinery.
EPSODILAVE contains sodium
This medicine contains less than 1 millimole (23 mg) of sodium per vial and bottle, i.e., it is essentially “sodium-free”.

3. How to use EPSODILAVE

This medicine will be administered by a doctor or other healthcare professional, observing sterile conditions. If you have any doubts, consult your doctor or nurse.
Each time the catheter or another intravenous drug administration device is used, the amount of EPSODILAVE to be used corresponds to the intraluminal volume of the circuit.
It is recommended to change the solution each time the catheter or infusion device is used.
Before each new use of the device, the intraluminal heparin solution must be withdrawn prior to administering a medicinal product (infusion therapy) or performing a blood draw.
The concentration to be used is determined by the doctor, taking into account the catheter usage procedures.
If you use more EPSODILAVE than you should
If an excessive dose of EPSODILAVE is administered, bleeding (haemorrhage) may occur.
In case of accidental ingestion/overdose of this medicine, contact your doctor or the nearest hospital immediately.
If you have any doubts about how to use this medicine, consult your doctor or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone will experience them.
If any of the side effects worsen, or if you notice any side effects not listed in this leaflet, inform your doctor or nurse.
If you experience any of the following serious reactions, contact your doctor immediately:

• Bleeding (haemorrhage), in any part of the body
• Severe allergic reactions (may include chills, high fever, urticaria, asthma, rhinitis, increased tearing, nausea and vomiting, itching and burning in the feet, hypotension, vasospasm, anaphylactic shock)
• Severe skin lesions with inflammation (skin necrosis), bruising, more or less extensive purplish or reddish spots (purpura or petechiae)
• Thrombocytopenia (reduced number of platelets in the blood)
• Disseminated intravascular coagulation (DIC)
• Bruising or ulcers at the injection site
• Liver damage (hepatotoxicity)
• Breathing difficulties or chest pain (may be symptoms of pulmonary oedema or haemopneumothorax)
• Blood in the stools (melena)

Other side effects that may occur, with unknown frequency (frequency cannot be estimated from the available data), are listed below:
Reactions at the administration site (local irritation, erythema, mild pain)
Amnesia
Cerebral haemorrhage, extradural intracranial haematoma, non-traumatic spinal subdural haematoma, ventricular haemorrhage
Osteoporosis
Alopecia (hair loss)
Hypoaldosteronism (reduced production of aldosterone)
Hyperkalaemia (increased blood potassium levels)
Metabolic acidosis (particularly in patients with renal impairment and type 2 diabetes)
Rebound hyperlipidaemia (increased blood lipid levels) upon discontinuation of therapy
Bronchospasm (difficulty breathing)
Increased transaminases (enzymes produced by the liver)
Increased FT3 and FT4 levels (thyroid hormones)
Priapism (persistent and painful erection not associated with sexual stimulation)

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor or pharmacist. You can also report side effects directly via the Italian Medicines Agency - Website: http://www.aifa.gov.it/content/segnalazioni-reazioni-avverse. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store EPSODILAVE

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the packaging after "Exp".
The expiry date refers to the last day of that month.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of
medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What EPSODILAVE 250 U.I./5 ml solution for catheter patency contains

• The active substance is sodium heparin. 1 ml of solution contains 50 I.U. of sodium heparin.
• The other components are sodium chloride, water for injections.

What EPSODILAVE 300 U.I./3 ml solution for catheter patency contains

• The active substance is sodium heparin. 1 ml of solution contains 100 I.U. of sodium heparin.
• The other components are sodium chloride, water for injections.

What EPSODILAVE 500 U.I./2 ml solution for catheter patency contains

• The active substance is sodium heparin. 1 ml of solution contains 250 I.U. of sodium heparin.
• The other components are sodium chloride, water for injections.

Description of the appearance of EPSODILAVE and contents of the pack
EPSODILAVE 250 U.I./5 ml solution for catheter patency
Pack of 10 vials containing 5 ml of solution.
EPSODILAVE 300 U.I./3 ml solution for catheter patency
Pack of 10 vials containing 3 ml of solution.
EPSODILAVE 500 U.I./2 ml solution for catheter patency
Pack of 10 vials containing 2 ml of solution.

Marketing Authorization Holder
Pfizer Italia S.r.l.
Via Isonzo, 71
04100 Latina
Italy

Manufacturer
Biologici Italia Laboratories S.r.l.
Via Filippo Serpero, 2
20060 Masate (MI)
Italy

The following information is intended exclusively for physicians or healthcare professionals

To determine the appropriateness of use in a specific patient, the prescriber must be
fully aware of the entire content of the Summary of Product Characteristics.
Dosage and method of administration
At each use of the catheter or infusion device, inject a volume of EPSODILAVE corresponding to the intraluminal volume of the circuit. The solution should be changed every time the catheter or infusion device is used.
Before each new use of the circuit, it is recommended to aspirate the intraluminal heparin solution prior to initiating infusion therapy or blood sampling.
The concentration to be used is left to the physician's discretion, taking into account the specific catheter usage procedures.

Special warnings
Heparin may, in rare cases, cause thrombocytopenia, sometimes associated with arterial or venous thrombosis.
These effects, which are probably immune-mediated, may occur even after accidental systemic passage of EPSODILAVE, and require immediate discontinuation of the medicinal product. Immunoallergic reactions to heparin typically occur between the 5th and 21st day of treatment.
Therefore, platelet counts must be monitored in patients receiving EPSODILAVE: perform a baseline platelet count before starting treatment, followed by two counts per week after initiation. If prolonged use is required, this monitoring schedule should be maintained for at least the first month; thereafter, monitoring may be less frequent.

Sodium heparin suppresses adrenal aldosterone secretion, potentially leading to hyperkalemia, particularly in patients with diabetes mellitus, chronic renal failure, a history of metabolic acidosis, elevated plasma potassium levels, or those receiving potassium-sparing medications. The risk of hyperkalemia appears to increase with the duration of treatment but is usually reversible. Serum electrolytes should be measured in at-risk patients before initiating heparin therapy and monitored regularly thereafter, especially when treatment lasts longer than 7 days.

Cases of skin necrosis, sometimes preceded by purpura or painful erythematous lesions, have been reported when heparin is administered subcutaneously. In such cases, immediate discontinuation of treatment is advised.

In patients undergoing epidural or spinal anesthesia or lumbar puncture, the prophylactic use of heparin has very rarely been associated with epidural or spinal hematomas resulting in prolonged or permanent paralysis. The risk increases with the use of epidural or spinal catheters for anesthesia, concomitant use of drugs affecting coagulation (e.g., non-steroidal anti-inflammatory drugs [NSAIDs], platelet aggregation inhibitors, or anticoagulants), and in cases of traumatic or repeated punctures.
When determining the interval between prophylactic-dose heparin administration and placement or removal of a spinal or epidural catheter, both the pharmacological characteristics of the medicinal product and the patient’s clinical condition should be taken into account. For unfractionated heparin, it is recommended that the preoperative dose of heparin be administered no sooner than 1 hour after catheter placement for anesthesia, that the catheter be removed no sooner than 4 hours after the last heparin dose, and that the first postoperative dose of heparin be administered no sooner than 1 hour after catheter removal.

If anticoagulant treatment is administered during spinal or epidural anesthesia, careful monitoring is required to detect early signs or symptoms of neurological impairment such as back pain, sensory and motor deficits (numbness and weakness of the lower limbs), or bowel or bladder dysfunction. Healthcare personnel must be prepared to recognize these signs and symptoms. Furthermore, patients should be warned to immediately inform their physician or nurse if they experience any of the symptoms listed above.

At the onset of signs or symptoms suggestive of suspected spinal or epidural hematoma, urgent diagnostic investigations must be performed, and, if indicated, spinal decompression (laminectomy) should be performed promptly (within 6–12 hours).

Overdose
The main clinical symptom of overdose is bleeding. At the onset of bleeding, treatment with sodium heparin must be immediately discontinued. Mild bleeding episodes rarely require specific treatment. In cases of severe bleeding, slow intravenous infusion of protamine sulfate may be necessary. The dose of protamine sulfate depends on the time elapsed between heparin injection and the need to neutralize its effects (100% of the dose immediately after bolus, 50% after 30 minutes) and on the dose administered. Each mg of protamine sulfate neutralizes approximately the activity of 100 IU of heparin.
Vitamin K does not reverse heparin activity.

Incompatibilities
Protamine sulfate (heparin antidote).
In general, it is not recommended to mix EPSODILAVE with other medicinal products.

In aqueous solution, heparin is incompatible with the following drugs: lactate of haloperidol, amikacin sulfate, amiodarone hydrochloride, aprotinin, chlorpromazine hydrochloride, ciprofloxacin lactate, cephaloridine, cisatracurium besylate, cytarabine, dacarbazine, daunorubicin hydrochloride, diazepam, doxorubicin hydrochloride, droperidol, erythromycin, gentamicin sulfate, hyaluronidase, hydroxyzine hydrochloride, hydrocortisone sodium succinate, kanamycin sulfate, labetalol hydrochloride, levofloxacin, metotrimeprazine, narcotic analgesics, netilmicin sulfate, nicardipine hydrochloride, novobiocin sodium, pethidine hydrochloride, polymyxin B sulfate, prochlorperazine, promazine hydrochloride, promethazine hydrochloride, streptomycin sulfate, tobramycin sulfate, triflupromazine hydrochloride, vinblastine sulfate, vinorelbine tartrate, viomycin sulfate, and, depending on the diluent, cephalothin sodium and vancomycin hydrochloride.
Conflicting results have been reported with ampicillin sodium, benzylpenicillin, dimenhydrinate, methicillin sodium, oxytetracycline hydrochloride, sulfafurazole diethanolamine, and tetracycline hydrochloride.

Dobutamine hydrochloride and heparin must not be mixed or infused through the same intravenous line due to the risk of precipitation.
Heparin and rTPA (reteplase) are incompatible when combined in solution.