Epsoclar

Patient Information Leaflet: Instructions for the User

EPSOCLAR 5,000 IU/1 ml solution for subcutaneous or intravenous injection, 25,000 IU/5 ml solution for intravenous infusion, 25,000 IU/5 ml solution for intravenous infusion

Heparin sodium
Please read all of 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, ask your doctor, pharmacist, or nurse.
• If you experience any side effects, including those not listed in this leaflet, contact your doctor, pharmacist, or nurse. See section 4.

Contents of this leaflet:

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

1. What EPSOCLAR is and what it is used for

This medicinal product contains the active substance sodium heparin (derived from porcine intestinal mucosa),
which belongs to a group of medicines called antithrombotics that work by preventing the formation of
blood clots (thrombi) in blood vessels. EPSOCLAR is used for the treatment and prevention of diseases
in which blood clot formation occurs in veins or arteries (venous and arterial thromboembolic disease).
It is also used in patients undergoing haemodialysis or surgical procedures requiring extracorporeal circulation.

2. What you need to know before using EPSOCLAR

Do not use EPSOCLAR:

• if you are allergic to sodium heparin or to other substances closely related chemically, or to any of the other components of this medicine (listed in section 6);
• if you have severe reduction in platelet levels in the blood (severe thrombocytopenia);
• if you have active or uncontrolled bleeding, except when due to disseminated intravascular coagulation (DIC);
• if you suffer from severe liver, kidney, or pancreatic diseases;
• if you have been prescribed heparin at anticoagulant doses and cannot undergo specific blood coagulation tests (whole blood clotting time and activated partial thromboplastin time);
• 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 have a history of heparin-induced thrombocytopenia (HIT);
• if you suffer from (or have suffered from) cerebral hemorrhages;
• 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 suffer from infective endocarditis (an infection of the inner lining of the heart);
• if you are scheduled to undergo loco-regional anesthesia for elective surgical procedures.

In case of organ injuries with high risk of bleeding, your doctor will need to evaluate the use of heparin, considering the risk-benefit ratio in your specific case.

Warnings and precautions

Talk to your doctor, pharmacist, or nurse before using EPSOCLAR.

Heparin must not be administered intramuscularly due to the risk of hematoma formation.

During treatment with EPSOCLAR, particular caution is required if other medications are administered intramuscularly, due to the risk of hematoma.

Pay special attention to avoiding injury during treatment with EPSOCLAR.

Before this medicine is administered to you, inform your doctor if:

• you suffer from suspected neoplasia with a tendency to bleeding;
• you suffer from chronic alcoholism;
• you are elderly: in elderly patients (age 65 years or older), particularly in women, an increased risk of bleeding has been observed during heparin treatment. These patients should be closely monitored and dose reduction may be necessary;
• you have previously experienced allergic reactions to low molecular weight heparins;
• you have previously experienced allergic reactions to products of porcine origin;
• you are at risk of bleeding, especially:
  • if you suffer from uncontrolled high blood pressure (uncontrolled hypertension);
  • if you suffer from inflammation of the membrane lining the heart cavity (subacute bacterial endocarditis);
  • if you suffer from blood disorders with increased tendency to bleeding (hemophilic syndromes, 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 history of stomach and/or intestinal ulcer (peptic ulcer);
  • if you suffer from esophagitis or erosive gastritis;
  • if you suffer from active inflammatory bowel disease;
  • if you have continuous drainage of the stomach or intestine;
  • if you have recently undergone lumbar puncture or spinal anesthesia;
  • if you have recently undergone surgery on the brain, spine, or eye;
  • if you suffer from liver diseases associated with coagulation disorders and/or esophageal varices;
  • if you suffer from stomach diseases caused by increased blood pressure in the liver circulation (portal hypertension 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 you have other organ lesions at risk of bleeding.

In all cases of bleeding, even minor, discontinue treatment with EPSOCLAR and contact your doctor immediately. If you are being treated with heparin, your doctor will perform frequent coagulation tests to adjust the dosage.

Spinal or epidural anesthesia

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 may 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 medications 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.

Skin necrosis

Cases of skin necrosis have been reported with heparin administration, sometimes preceded by painful erythematous lesions. In such cases, immediate discontinuation of treatment is recommended.

Hyperkalemia

EPSOCLAR may cause an increase in potassium levels in the blood (hyperkalemia). If you suffer from or have previously suffered from hyperkalemia, a condition characterized by elevated blood potassium levels, your doctor will perform blood potassium tests before starting therapy and at regular intervals during treatment, especially if treatment lasts longer than 7 days. The risk of hyperkalemia is generally reversible upon discontinuation of therapy.

Use during pregnancy

Long-term use of therapeutic doses of heparin during pregnancy may increase the risk of osteoporosis and vertebral fractures.

Although heparin does not cross the placental barrier, it should be administered with caution during pregnancy, especially in the third trimester. Your doctor will determine when to discontinue sodium heparin before labor induction or cesarean section.

Heparin-induced thrombocytopenia (HIT)

If platelet levels in the blood decrease (thrombocytopenia), treatment must be discontinued, and continuation of anticoagulant therapy for the thrombosis for which treatment was initiated, or for worsening of the condition or the appearance of a new thrombotic event, must be managed after heparin discontinuation with an alternative anticoagulant. 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 must carefully monitor your platelet count throughout the course of treatment with sodium heparin.

Reduced sensitivity to heparin

If you experience fever, thrombosis, thrombophlebitis, infections with thrombotic tendency, inflammatory states, sometimes during myocardial infarction, cancer, congenital antithrombin III deficiency, or deficiency developed after surgery, you may have reduced sensitivity to heparin; your doctor will evaluate these conditions.

Monitoring of the response to heparin therapy by laboratory tests may be necessary.

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.

Laboratory tests

Unlike therapy with dicoumarol, strict laboratory monitoring of heparin therapy is not strictly necessary; however, your doctor will monitor your treatment with appropriate diagnostic tests (measurement of activated partial thromboplastin time – aPTT or anti-Xa activity).

The use of heparin may alter your thyroid function tests (e.g., falsely elevated T3 and T4 levels).

Since heparin is an animal-derived substance, 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 EPSOCLAR

Inform your doctor, nurse, or pharmacist if you are taking, have recently taken, or might take any other medicines.

Be especially careful and inform your doctor if you are taking:

• oral anticoagulants, as concomitant administration may increase the anticoagulant effect;
• platelet aggregation inhibitors, fibrinolytics, or other medications that interfere with platelet aggregation and may increase the risk of bleeding, such as acetylsalicylic acid, non-steroidal anti-inflammatory drugs (e.g., acetylsalicylic acid, dextran, phenylbutazone, ibuprofen, indomethacin, ketorolac, or diclofenac), drugs with antiplatelet effects (e.g., thienopyridines such as ticlopidine and clopidogrel or sulfinpyrazone), certain cephalosporin antibiotics (e.g., cefaclor, cefixime, ceftriaxone, cefamandole, cefoperazone), dextran, dipyridamole, hydroxychloroquine, fibrinolytic drugs (e.g., streptokinase, urokinase, alteplase), coumarin derivatives, glycoprotein IIb/IIIa receptor antagonists (e.g., eptifibatide, abciximab), epoprostenol;
• concomitant use of certain contrast media may also affect the coagulation process and increase the risk of bleeding;
• excessive alcohol consumption, which poses a particularly high risk of severe bleeding associated with heparin;
• intravenous nitroglycerin, as it may reduce the effect of heparin;
• heparin may enhance the effect of oral antidiabetic agents such as sulfonylureas, as well as benzodiazepines (chlordiazepoxide, diazepam, oxazepam) and propranolol;
• drugs that increase potassium levels in the blood, such as ACE inhibitors, sartans, potassium-sparing diuretics, potassium salts, or beta-blockers (medications used in the treatment of cardiovascular conditions);
• other drugs that may reduce the anticoagulant effect of heparin, such as digitalis, tetracyclines, nicotine, glucocorticoids, penicillins, phenothiazines, antihistamines, and andexanet alfa (a drug used to reverse the effects of certain anticoagulants such as apixaban or rivaroxaban). In addition, heparin may alter the results of thyroid function tests, leading to falsely elevated levels of certain thyroid hormones (T3 and T4).

Fertility, pregnancy, and breastfeeding

Pregnancy

If you are pregnant, suspect you may be pregnant, are planning a pregnancy, or are breastfeeding, consult your doctor, pharmacist, or nurse before using this medicine. The safety of use during pregnancy has not been fully established. Therefore, the decision to use heparin during pregnancy must be made after careful evaluation of the risk-benefit ratio in individual circumstances.

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

EPSOCLAR does not affect or has a negligible effect on the ability to drive vehicles and use machinery.

EPSOCLAR contains sodium

This medicine contains less than 1 mmol (23 mg) of sodium per vial and bottle, i.e., it is essentially "sodium-free".

EPSOCLAR 25,000 IU/5 ml (vials) contains chlorocresol.

EPSOCLAR 25,000 IU/5 ml solution for intravenous infusion (vials with perforated cap) and EPSOCLAR 25,000 IU/5 ml injectable solution for intravenous infusion (vials with perforated cap) contain chlorocresol, which may cause allergic reactions.

3. How to use EPSOCLAR

This medicine will be administered to you by healthcare professionals. If you have any doubts, consult your doctor or nurse.
Your doctor will determine the necessary dose according to your condition. If you are being given this medicine in anticoagulant doses, the dose must be established based on frequent coagulation tests.

If you use more EPSOCLAR than you should
Since this medicine will be administered by a doctor or nurse, it is unlikely that you will receive an excessive dose.
If you think you have been given too much, contact medical or nursing staff immediately.
In case of overdose, bleeding may occur.
In the event of severe bleeding, protamine must be administered to counteract the effect of this medicine.

If you forget to use EPSOCLAR
Since this medicine will be administered by a doctor or nurse, it is unlikely that a dose will be missed. Do not administer a double dose to make up for a missed dose.

If you have any doubts about the use of this medicine, consult your doctor, pharmacist, or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone will experience them.
The most common adverse effect of heparin is bleeding.
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 lacrimation, nausea and vomiting, itching and burning in the feet, hypotension, vasospasm, anaphylactic shock);
• Severe skin lesions with inflammation (skin necrosis), subcutaneous haematomas, more or less extensive purplish or reddish spots (purpura or petechiae);
• Reduction in the number of platelets in the blood (thrombocytopenia);
• Haematomas or ulcers, inflammatory lesions at the injection site;
• Liver toxicity (hepatotoxicity);
• Breathing difficulties or chest pain (may be symptoms of pulmonary oedema or haemopneumothorax);
• Blood in the stools (melena).

Other side effects
Other side effects that may occur, with unknown frequency (frequency cannot be estimated from the available data), are listed below:

• Disseminated Intravascular Coagulation (DIC);
• Reactions at the administration site (local irritation, erythema, pain, haematoma, ulcer);
• Amnesia;
• Cerebral haemorrhage, intracranial extradural haematoma, non-traumatic spinal epidural and subdural haematoma, intraventricular haemorrhage;
• Osteoporosis after therapeutic administration;
• Alopecia (hair loss);
• Hypoaldosteronism (reduced aldosterone production);
• Hyperkalaemia (increased potassium levels in the blood);
• Metabolic acidosis (particularly in patients with renal impairment and diabetes mellitus);
• Adrenal haemorrhage;
• Adrenal insufficiency;
• Rebound hyperlipidaemia (increase in blood lipids upon discontinuation of therapy);
• Bronchospasm (difficulty breathing);
• Retroperitoneal haemorrhage;
• Ovarian haemorrhage;
• Increased transaminase levels (enzymes produced by the liver);
• Increased platelet aggregation;
• 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, please contact your doctor or pharmacist. You may also report side effects directly via the Italian Medicines Agency (Agenzia Italiana del Farmaco) – 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 EPSOCLAR

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the 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 EPSOCLAR Contains
EPSOCLAR 5,000 IU/1 ml solution for injection for subcutaneous or intravenous use (vials)

• The active substance is sodium heparin. Each vial contains 5,000 IU of sodium heparin.
• The other component is water for injections (1 ml).

EPSOCLAR 25,000 IU/5 ml solution for intravenous infusion (vials)

• The active substance is sodium heparin. Each vial contains 25,000 IU of sodium heparin.
• The other component is water for injections (5 ml).

EPSOCLAR 25,000 IU/5 ml solution for intravenous infusion (vials with perforated stopper)

• The active substance is sodium heparin. Each vial contains 25,000 IU of sodium heparin.
• The other components are chlorocresol and water for injections (5 ml).

EPSOCLAR 25,000 IU/5 ml solution for intravenous infusion (vials with perforated stopper)

• The active substance is sodium heparin. Each vial contains 25,000 IU of sodium heparin.
• The other components are chlorocresol and water for injections (5 ml).

Description of the Appearance of EPSOCLAR and Contents of the Package
EPSOCLAR 5,000 IU/1 ml solution for injection for subcutaneous or intravenous use
EPSOCLAR is a clear, colourless or pale yellow solution.
Pack: 10 vials of 1 ml.

EPSOCLAR 25,000 IU/5 ml for intravenous infusion
EPSOCLAR is a clear, colourless or pale yellow solution.
Pack: 10 vials of 5 ml or 1 vial of 5 ml.

EPSOCLAR 25,000 IU/5 ml solution for intravenous infusion
EPSOCLAR is a clear, colourless or pale yellow solution.
Pack: 10 vials of 5 ml.

Marketing Authorisation 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 given patient, the prescriber must be familiar with the complete content of the Summary of Product Characteristics.

Dosage and Method of Administration
Dosage
Prophylaxis of arterial and venous thromboembolism

• Perioperative prophylaxis: Initial dose of 5,000 IU subcutaneously, 2 hours before surgery, followed by 5,000 IU every 8–12 hours for at least 7 days or until the patient resumes ambulation.
• Prophylaxis in non-surgical patients: The same dose is used for prophylaxis in high-risk non-surgical patients. The decision to administer every 8 or 12 hours should take into account the individual patient's thromboembolic and bleeding risks.
• Extracorporeal circulation (cardiopulmonary bypass): 300 IU/kg intravenously, adjusted to maintain the Activated Clotting Time (ACT) within the range of 400–500 seconds.
• Haemodialysis: Initial dose of 1,000–5,000 IU intravenously, followed by 1,000–2,000 IU/hour, adjusted according to clinical need.

Monitoring:
Routine monitoring is not required.

Treatment of arterial and venous thromboembolism
Initial dose:
80 IU/kg as an intravenous bolus, or
5,000 IU as an intravenous bolus injection (10,000 IU in cases of severe pulmonary embolism)

• Maintenance dose: 18 IU/kg/hour as a continuous intravenous infusion (range between 1,000 and 2,000 IU/hour), adjusted according to response, or 1,000 IU/hour as a continuous infusion.
• Alternative treatment regimens:
  • Intermittent intravenous injection: 10,000 IU IV bolus followed by 5,000–10,000 IU IV every 4–6 hours.
  • Intermittent subcutaneous injection: Initial dose of 333 IU/kg, followed by 250 IU/kg every 12 hours (range 10,000–20,000 IU) or 8,000–10,000 IU every 8 hours.

Monitoring:
When sodium heparin is administered at anticoagulant doses, dosage must be based on coagulation tests. The most commonly used test is the activated partial thromboplastin time (aPTT). The aPTT of treated patients should be maintained at 1.5 to 2.5 times the normal control value. Regular monitoring of aPTT values is recommended, preferably on a daily basis.
If coagulation tests exceed the therapeutic range or if bleeding occurs, the dose should be reduced or, if necessary, heparin should be discontinued.

Special Populations
Paediatric population
Prophylaxis of arterial and venous thromboembolism
No dosage recommendations are available.

Treatment of arterial and venous thromboembolism:
Initial dose: 50 IU/kg as an intravenous bolus injection
Maintenance dose: 15–25 IU/kg/hour as a continuous intravenous infusion,
or 100 IU/kg IV every 4 hours as intermittent injection,
or 250 IU/kg subcutaneously every 12 hours.

Monitoring:
When sodium heparin is administered at anticoagulant doses, dosage should be adjusted based on aPTT values.
Smaller children may require higher doses and infusion rates to achieve anticoagulant levels and aPTT prolongation comparable to older children.

Elderly
Lower doses may be required due to an increased risk of bleeding.

Monitoring:
When sodium heparin is administered at anticoagulant doses, doses should be adjusted according to aPTT values.

Method of Administration
Intravenous administration via continuous infusion or intermittent injection, or subcutaneous injection.
Because the effects of sodium heparin are short-term, administration by continuous intravenous infusion or subcutaneous injection is preferred over intermittent intravenous bolus injection.

Overdose
Symptoms of overdose
Bleeding, primarily from the skin and mucous membranes, wounds, gastrointestinal or genitourinary tract (epistaxis, haematuria, melena, haematomas, petechiae). A drop in blood pressure or a reduction in haematocrit may indicate occult bleeding.

Treatment of overdose
Minor bleeding:
Discontinue heparin therapy.

Major haemorrhage:
Administration of protamine sulfate intravenously may be required to rapidly neutralize heparin activity in cases of significant bleeding. The amount required depends on the dose of heparin administered and the time elapsed since injection. 1 mg IV neutralizes 100 IU of heparin present in the patient. The dose of protamine required to neutralize a heparin bolus decreases proportionally with the time since bolus administration (100% of the dose immediately after bolus, 50% after 30 minutes). The dose of protamine to be administered in cases of continuous heparin infusion corresponds to the amount needed to neutralize the heparin units infused in the last 4 hours.
Protamine must be administered by slow intravenous infusion; the rate must not exceed 50 mg in 10 minutes.