Pharepa

Patient Information Leaflet

PHAREPA 5000 IU/1 ml solution for injection for subcutaneous and intravenous use, vials
PHAREPA 25000 IU/5 ml solution for injection for intravenous use, vials and bottles
Heparin sodium

Please read this leaflet carefully before using this medicine, as 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.
• This medicine has been prescribed for you only. Do not give it to others, even if they have the same symptoms as you, because it could be harmful.
• If you experience any side effects, including those not listed in this leaflet, consult your doctor, pharmacist, or nurse. See section 4.

Contents of this leaflet

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

1. What Pharepa is and what it is used for

This medicine contains the active substance heparin sodium, which belongs to a group of medicines called anticoagulants. These act by preventing the formation of blood clots (thrombi) in blood vessels. PHAREPA is used for the treatment and prevention of diseases in which blood clot formation occurs in both veins and arteries (venous and arterial thromboembolic disease), as well as in extracorporeal circulation and hemodialysis.

2. What you need to know before using Pharepa

Do not use Pharepa

• if you are allergic to sodium heparin or to any of the other ingredients of this medicine (see “What Pharepa contains”).
• if you suffer from:
  • severe thrombocytopenia or disorders associated with hemorrhagic diathesis;
  • severe hepatic, renal, or pancreatic diseases;
  • conditions for which coagulation tests cannot be performed at appropriate intervals (exclusively for therapeutic dosages);
  • disseminated intravascular coagulation (DIC) due to heparin-induced thrombocytopenia;
  • hemorrhagic cerebrovascular accidents;
  • organic lesions at risk of bleeding, such as gastric and/or intestinal ulcers, cerebral hemorrhage, aneurysm, or cerebral neoplasm;
  • trauma or surgical procedures involving the central nervous system, eyes, or ears;
  • retinopathy or vitreous hemorrhage;
  • infective endocarditis.

Regional anesthesia for elective surgical procedures is contraindicated in patients receiving heparin at anticoagulant doses.
In the presence of organic lesions at high risk of bleeding, the use of heparin should be evaluated on a case-by-case basis, considering the individual risk-benefit ratio.

Warnings and precautions
Talk to your doctor, pharmacist, or nurse before using Pharepa.

Traceability
To improve the traceability of biological medicines, the name and batch number of the administered medicine must be clearly recorded.

Special caution is required in the following cases:

• suspected neoplasms with a tendency to bleed;
• chronic alcoholism;
• elderly patients: dose reduction may be necessary, especially in women who are at higher risk of bleeding (see section 3);
• patients with a history of hypersensitivity reactions to low molecular weight heparins;
• patients at risk of bleeding (see “Do not use Pharepa”). Bleeding may occur in any part of the body. An unexplained drop in hematocrit, a fall in blood pressure, or any other sign or symptom not attributable to other causes should raise suspicion of a hemorrhagic event. Sodium heparin must be used with extreme caution in conditions associated with a risk of hemorrhage. Some such conditions include:

Cardiovascular:

• subacute bacterial endocarditis;
• uncontrolled hypertension despite antihypertensive therapy.

Hematological:

• hemophilic syndromes or deficiency of coagulation factors;
• thrombocytopenia;
• thrombopathies;
• certain hemorrhagic vascular purpuras (e.g., Rendu-Osler disease).

Gastrointestinal:

• peptic ulcer;
• esophagitis or erosive gastritis;
• active inflammatory bowel disease;
• continuous drainage of the stomach or small intestine.

Surgical:
during and immediately after:

• lumbar puncture or spinal anesthesia or
• major surgery involving the brain, spinal cord, or eye.

Hepatic:

• liver diseases with altered coagulation parameters and/or esophageal varices or portal hypertension-related gastropathy at high risk of hemorrhage.

Other:

• threatened abortion;
• during the menstrual cycle;
• postpartum period;
• concomitant treatment with fibrinolytic agents or oral anticoagulants, platelet aggregation inhibitors, non-steroidal anti-inflammatory drugs (NSAIDs), and/or glycoprotein IIb/IIIa receptor antagonists (see section 4.5).

In case of minor bleeding, heparin therapy should be discontinued; in case of major bleeding, circulating heparin should be neutralized by administration of protamine (see “If you use more Pharepa than you should”). Care should be taken to avoid injury in patients undergoing heparin therapy.

Hyperkalemia
Sodium heparin may suppress adrenal secretion of aldosterone, leading to hyperkalemia. Risk factors include diabetes mellitus, chronic renal failure, pre-existing metabolic acidosis, elevated potassium levels before treatment, concomitant therapy with drugs that increase plasma potassium levels, and long-term use of heparin (see “Other medicines and Pharepa”). In at-risk patients, plasma potassium levels should be measured before starting heparin therapy and at regular intervals during treatment, especially if therapy lasts longer than 7 days.

Coagulation tests
When administering sodium or calcium heparin at anticoagulant doses, dosing should be adjusted based on frequent coagulation tests. If test results exceed the therapeutic range or if bleeding occurs, the dose should be reduced or, if necessary, heparin should be suspended (see section 3).
Due to the transient action of sodium heparin, coagulation parameters typically return to normal within a few hours.

Heparin-induced thrombocytopenia (HIT)
Thrombocytopenia is a known complication of sodium heparin therapy and may occur 4 to 10 days after starting treatment, or earlier in case of previous HIT. In 10–20% of patients, mild thrombocytopenia (platelet count >100,000/mm³) may develop, which may remain stable or resolve even if heparin administration continues.
However, in some cases (0.3–3%), a more severe, immune-mediated form (Type II heparin-induced thrombocytopenia) may occur, characterized by the formation of antibodies against the heparin-platelet factor 4 complex. In these patients, new thromboses associated with thrombocytopenia (HITT) may develop due to irreversible platelet aggregation induced by heparin, known as the "white clot syndrome." This process may lead to serious thromboembolic complications such as skin necrosis, extremity gangrene (sometimes requiring amputation), myocardial infarction, pulmonary embolism, stroke, and even death.
Therefore, administration of sodium heparin must be discontinued not only in case of thrombocytopenia, but also if the patient develops new thrombosis or worsening of pre-existing thrombosis. After discontinuation of heparin, anticoagulant therapy for the thrombosis (for which treatment was initiated, worsened, or newly developed) should be continued with an alternative anticoagulant. In such cases, the use of low molecular weight heparins is risky due to possible cross-reactivity, as is the immediate initiation of oral anticoagulant therapy (cases of worsening thrombosis have been reported).
Thus, any thrombocytopenia must be closely monitored. If the platelet count drops below 100,000/mm³, or if recurrent thrombosis occurs, sodium heparin must be discontinued immediately.
Platelet counts should be monitored in patients receiving heparin for more than 5 days, and treatment must be stopped immediately if thrombocytopenia develops.
HIT or HITT may manifest several weeks after stopping therapy; therefore, patients who develop thrombocytopenia or thrombosis after discontinuation of treatment should be evaluated for possible HIT or HITT.
If these conditions are suspected or confirmed, discontinue therapy and use an alternative anticoagulant. Do not restart heparin therapy, particularly within 3–6 months of diagnosis and as long as the patient remains positive for anti-HIT antibodies.

Reduced sensitivity to heparin:
Reduced sensitivity to sodium heparin may occur in fever, thrombosis, thrombophlebitis, infections with thrombotic tendency, inflammatory states, sometimes during myocardial infarction, cancer, congenital or acquired antithrombin III deficiency, and in postoperative patients.

Heparin must not be administered intramuscularly due to the risk of hematomas (see section 4.8).
Due to the increased risk of bleeding, particular caution is required when administering intramuscular injections concomitantly.

Spinal or epidural anesthesia
In patients undergoing spinal or epidural anesthesia, epidural analgesia, or lumbar puncture, prophylaxis with unfractionated heparin may very rarely be associated with spinal or epidural hematomas, which may lead to prolonged or permanent paralysis. The risk is increased by the use of indwelling epidural catheters for continuous infusion, concomitant use of drugs affecting hemostasis (e.g., non-steroidal anti-inflammatory drugs (NSAIDs), platelet aggregation inhibitors, or anticoagulants), traumatic or repeated spinal punctures, underlying coagulation disorders, and advanced age. The presence of one or more of these risk factors should be carefully evaluated before proceeding with this type of anesthesia/analgesia during unfractionated heparin prophylaxis.
As a general rule, insertion of a spinal catheter should be performed at least 12 hours after the last prophylactic dose of low-dose unfractionated heparin. Subsequent doses should not be administered until at least 4 hours after catheter insertion or removal, or further delayed or withheld if bloody aspiration occurs during initial placement of the spinal or epidural needle. Removal of an indwelling epidural catheter should be performed as far as possible (approximately 12 hours) from the last prophylactic dose of heparin given during anesthesia.

If administration of unfractionated heparin is considered before or after epidural or spinal anesthesia, extreme caution and frequent monitoring for neurological signs and symptoms (e.g., back pain, sensory and motor deficits [numbness and weakness of the lower limbs], bladder or bowel dysfunction) must be exercised. Nursing staff should be trained to recognize these signs and symptoms. Patients should be instructed to immediately inform medical or nursing staff if any of these symptoms occur.
If signs or symptoms suggestive of epidural or spinal hematoma are suspected, immediate diagnosis and treatment including spinal cord decompression should be initiated.

Unlike therapy with dicoumarol, routine laboratory monitoring of heparin therapy is not strictly necessary. However, for monitoring purposes, the clotting time in a test tube (Lee-White) is sufficient, and prothrombin time measurement is not required.
Limited data from individual clinical cases have indicated a possible association between heparin use and altered thyroid function tests (e.g., falsely elevated T3 and T4 levels).
Due to the animal origin of heparin, in patients with a history of allergic reactions, it is advisable to perform a sensitivity test by injecting a test dose of 1,000 units of heparin.

Other medicines and Pharepa

Oral anticoagulants
Anticoagulant doses of sodium heparin may slightly prolong prothrombin time (increase of about 0.5 in INR). This should be taken into account when evaluating this parameter, especially during transition from heparin to oral anticoagulant therapy. Close clinical and laboratory monitoring (frequent assessment of PT and aPTT) is recommended when combining unfractionated heparin at anticoagulant doses with these drugs.

Antiplatelet agents, fibrinolytics, and other medicines associated with bleeding risk
Acetylsalicylic acid, non-steroidal anti-inflammatory drugs (NSAIDs) (phenylbutazone, ibuprofen, indomethacin, ketorolac, diclofenac), antiplatelet agents (ticlopidine, clopidogrel, sulfinpyrazone), cephalosporins (cefaclor, cefixime, ceftriaxone, cefamandole, cefoperazone), dextran, dipyridamole, hydroxychloroquine, fibrinolytic drugs (streptokinase, urokinase, alteplase), coumarin derivatives, glycoprotein IIb/IIIa receptor antagonists (eptifibatide, abciximab), epoprostenol, or other drugs interfering with platelet aggregation (which constitutes the main hemostatic defense in heparinized patients) may cause bleeding and should be used with great caution in patients treated with sodium heparin, especially at anticoagulant doses.

Nitroglycerin administered intravenously
Intravenous administration of nitroglycerin may significantly reduce the effect of heparin (shortening of activated partial thromboplastin time, aPTT). After discontinuation of nitroglycerin, a sudden increase in aPTT may occur. Close monitoring of aPTT and adjustment of heparin dosage are required in patients receiving concomitant nitroglycerin infusion.

Medicines that increase serum potassium levels
Particularly careful medical monitoring is required when using drugs that increase serum potassium levels (e.g., ACE inhibitors, sartans, potassium-sparing diuretics, potassium salts, beta-blockers) concomitantly with heparin (see section 4.4).

Other interactions
Digitalis, tetracyclines, nicotine, glucocorticoids, penicillins, phenothiazines, and antihistamines may partially reduce the anticoagulant effect of heparin.

Thyroid function tests
During heparin therapy, thyroid function tests may be altered (e.g., falsely elevated T3 and T4 levels) (see “Warnings and Precautions”).

Pregnancy, breastfeeding, and fertility

Pregnancy
Heparin does not cross the placental barrier. There have been no reports linking heparin administration during pregnancy to congenital malformations. Nevertheless, the safety of heparin 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 assessment of the individual risk-benefit ratio.

Breastfeeding
Heparin is not excreted in breast milk.

Fertility
There are no data available on the effect of heparin on human fertility.

Driving and using machines
Pharepa does not affect the ability to drive or operate machinery.

Pharepa contains sodium
Pharepa in vials contains 3.2 mg of sodium per ml of solution, less than 1 mmol (23 mg) of sodium per vial, i.e., essentially 'sodium-free'.
Pharepa in bottles contains 29.5 mg of sodium (main component of table salt) per bottle (5.9 mg/ml of solution). This corresponds to 1.48% of the maximum daily recommended dietary intake for an adult.

Pharepa contains methyl p-hydroxybenzoate and propyl p-hydroxybenzoate
Pharepa 25000 IU/5 ml solution for intravenous injection in bottles contains methyl p-hydroxybenzoate and propyl p-hydroxybenzoate, which may cause allergic reactions (including delayed-type) and, exceptionally, bronchospasm.

3. How to use Pharepa

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

If you use more Pharepa than you should
This medicine will be administered by a doctor or nurse, so it is unlikely that an excessive dose will be given.
If you think that 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 Pharepa
This medicine will be administered by a doctor or nurse, so it is unlikely that a dose will be missed.
Do not administer a double dose to make up for a forgotten dose.
If you have any doubts about the use of this medicine, consult your doctor, pharmacist, or nurse.

If you stop using Pharepa
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 everybody will experience them.
Summary of the safety profile
No specific toxicity of heparin has been demonstrated so far.
Frequency not known (frequency cannot be estimated from the available data):

• Non-immune heparin-induced thrombocytopenia (platelet count 100,000–150,000/µL) without thrombosis;
• Heparin-induced thrombocytopenia (platelet count < 100,000/µL or rapid decrease in platelet count by <50% of baseline value) with arterial and venous thrombosis or embolism;
• Disseminated intravascular coagulation;
• Bleeding;
• Increased platelet aggregation;
• Injection site irritation;
• Erythema;
• Mild pain;
• Haematoma or ulcer at injection site;
• Hypersensitivity (chills, pyrexia, urticaria, asthma, rhinitis, increased lacrimation, nausea and vomiting, itching and burning sensation in the feet, hypotension, vasospasm, shock);
• Osteoporosis (after therapeutic administration);
• Skin necrosis;
• Alopecia;
• Haematoma;
• Petechiae;
• Purpura;
• Hypoaldosteronism;
• Hyperkalemia;
• Metabolic acidosis (particularly in patients with renal impairment and diabetes mellitus);
• Hyperlipidemia (rebound after discontinuation of therapy);
• Amnesia;
• Cerebral hemorrhage;
• Extradural intracranial haematoma;
• Non-traumatic spinal subdural haematoma;
• Ventricular hemorrhage;
• Hepatotoxicity;
• Bronchospasm;
• Pulmonary edema;
• Hemopneumothorax;
• Melena;
• Increased transaminases;
• Increased FT3 and FT4 levels;
• Priapism.

Heparin-induced thrombocytopenia
In non-sensitized patients, reduction in platelet count usually begins 6–14 days after starting treatment. In sensitized patients, it occurs within a few hours.
The anticoagulant effect of heparin may be reduced (heparin resistance).

Bleeding
Bleeding has been reported, particularly from the skin, mucous membranes, wounds, and gastrointestinal and genitourinary tracts. Bleeding is the main complication that may occur during treatment with sodium heparin, especially at anticoagulant doses. Coagulation times above the therapeutic range or minor bleeding during therapy can generally be managed by reducing the dose or, if necessary, temporarily discontinuing the drug.
Gastrointestinal or urinary bleeding during anticoagulant therapy may indicate the presence of an underlying occult lesion. Bleeding may occur in any part of the body, but certain specific hemorrhagic complications may be difficult to recognize:
a) Adrenal hemorrhage, leading to acute adrenal insufficiency, has been described during anticoagulant therapy.
Therefore, treatment should be discontinued if the patient develops signs and symptoms of acute adrenal insufficiency;
b) Ovarian hemorrhage (corpus luteum) has occurred in women of reproductive age receiving short- or long-term anticoagulant therapy;
c) Retroperitoneal hemorrhage.
In any case of major bleeding, heparin therapy must be discontinued and circulating heparin should be neutralized by administration of protamine (see "If you use more Pharepa than you should").

Injection site reactions
Irritation at the injection site, erythema, mild pain, haematoma or ulcer may occur following subcutaneous administration of heparin. These complications are much more common after intramuscular administration, which must be absolutely avoided, even occasionally (see section "Warnings and Precautions").

Additional adverse effects in children
The frequency, type, and severity of adverse reactions in the pediatric population are expected to be the same as in adults.

Reporting of adverse effects
If you experience any adverse effect, including those not listed in this leaflet, talk to your doctor, pharmacist, or nurse. You can also report adverse effects directly via the national reporting system at the following website:
https://www.aifa.gov.it/content/segnalazionireazioni-avverse .
By reporting adverse effects, you can help provide more information on the safety of this medicine.

5. How to store Pharepa

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the label after EXP.
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 Pharepa contains
The active substance is sodium heparin. 1 ml of solution contains 5,000 IU of sodium heparin.
The excipients are:

• 5,000 IU/ml: water for injections.
• 25,000 IU/5 ml vials: water for injections.
• 25,000 IU/5 ml vials: methyl p-hydroxybenzoate; propyl p-hydroxybenzoate; sodium chloride; water for injections.

Description of the appearance of Pharepa and contents of the pack
PHAREPA 5000 IU/1 ml solution for injection for subcutaneous and intravenous use, vials
Pack of 10 vials of 1 ml.
PHAREPA 25000 IU/5 ml solution for injection for intravenous use, vials and bottles
Pack of 10 vials of 5 ml, 1 bottle of 5 ml, and 5 bottles of 5 ml.
Marketing Authorization Holder and Manufacturer
Marketing Authorization Holder:
Pharmatex Italia Srl, Via San Paolo 1, 20121 Milano – Italy
Manufacturer responsible for batch release:
Fisiopharma Srl, Nucleo Industriale 84020 Palomonte (SA) – Italy
________________________________________________________________________________

The following information is intended for healthcare professionals only:

Dosage and method of administration
Prophylaxis of arterial and venous thromboembolism

• Perioperative prophylaxis: Initial dose of 5,000 IU administered 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 choice between administration every 8 or 12 hours should take into account the individual patient's risk of thromboembolism and bleeding.

Extracorporeal circulation (cardiopulmonary bypass)
300 IU/kg administered intravenously, adjusted to maintain the Activated Clotting Time (ACT) within the range of 400–500 seconds.

Hemodialysis
Initial dose of 1,000–5,000 IU administered intravenously, followed by 1,000–2,000 IU/hour, adjusted according to clinical needs.

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 as an intravenous bolus followed by 5,000–10,000 IU intravenously every 4–6 hours.

Monitoring:
When sodium heparin is administered at anticoagulant doses, dosage must be determined 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 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 (see "Warnings and Precautions").

Use in children and adolescents
Prophylaxis of arterial and venous thromboembolism
Dosage recommendations are not 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 intravenously every 4 hours as intermittent injection

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

Use in the elderly
Lower doses may be required due to an increased risk of bleeding.
Monitoring:
When sodium heparin is administered at anticoagulant doses, dosing 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-acting, administration via 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, hematuria, melena, hematomas, petechiae). A drop in blood pressure or a reduction in hematocrit may indicate occult bleeding.

Treatment of overdose
Minor bleeding
Discontinue heparin therapy.

Severe hemorrhage
Protamine is used for the rapid neutralization of heparin activity in cases of significant bleeding. The amount required depends on the blood level of administered heparin and the time elapsed since injection. 1 mg of protamine administered intravenously neutralizes 100 IU of heparin present in the patient. The dose of protamine required to neutralize a heparin bolus decreases proportionally with the time elapsed 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 of heparin infused during the last 4 hours.

Protamine must be administered by slow intravenous infusion; the rate should not exceed 50 mg in 10 minutes.