SOSEFLUSS 12,500 IU/0.5 ml solution for injection s.c.
Calcium Heparin

COMPOSITION
SOSEFLUSS 12,500 IU/0.5 ml
Each pre-filled syringe contains:
Active substance: Calcium heparin (purified from EDTA) 12,500 IU
Excipient: Water for injections

PHARMACEUTICAL FORM AND CONTENT
Solution for subcutaneous injection.
Pack of 10 pre-filled syringes of 0.5 ml, each containing 12,500 IU/syringe

THERAPEUTIC PHARMACOLOGICAL CATEGORY
Antithrombotic

MARKETING AUTHORISATION HOLDER
So.Se.PHARM S.r.l. – Via dei Castelli Romani, 22 – 00040 Pomezia (RM)

MANUFACTURER AND FINAL CONTROLLER
Special Product’s Line S.p.A. - Via Campobello, 15 – 00040 Pomezia (RM)

THERAPEUTIC INDICATIONS
Prophylaxis and treatment of venous and arterial thromboembolic disease.

CONTRAINDICATIONS
Hypersensitivity to heparin or other substances closely related in chemical structure.
Hemorrhagic disorders (except in the initial phase of consumption coagulopathies).
Therapeutic period of antivitamin K agents.
Severe hypertension.
Hemorrhagic lesions: peptic ulcer, retinopathies, hemorrhoidal syndromes, recent trauma—especially involving the Central Nervous System—or threat of abortion.

Heparin sodium or calcium must not be used in patients:

with confirmed hypersensitivity to the drug or any of the excipients;
with severe thrombocytopenia;
in whom appropriate coagulation tests—such as whole blood clotting time and activated partial thromboplastin time (APTT)—cannot be performed at appropriate intervals. This contraindication applies to heparin sodium or calcium administered at anticoagulant doses; generally, there is no need to monitor coagulation parameters in patients receiving low-dose prophylactic heparin (≤ 0.2 ml three times daily for calcium heparin or ≤ 15,000 IU daily for sodium heparin);
with uncontrolled bleeding: if associated with disseminated intravascular coagulation (DIC), the use of heparin should be evaluated on a case-by-case clinical basis;
regional or spinal anesthesia for elective surgical procedures is contraindicated in patients receiving heparin at anticoagulant doses;
hemorrhagic cerebrovascular accidents;
in the presence of organic lesions with high bleeding risk, the use of heparin should be evaluated on a case-by-case clinical basis, considering the individual risk-benefit ratio.

PRECAUTIONS FOR USE
Due to the nature of the drug, the risk of bleeding must always be considered in patients undergoing heparin therapy, particularly as complications are mostly due to overdosage or the presence of predisposing factors (see contraindications). Special monitoring is required in elderly patients, individuals with allergies, hepatic or renal insufficiency, and patients with indwelling catheters.

In patients with a history of allergic reactions, it is advisable to test reactivity by administering a test dose of 1,000 IU of heparin.

This recommendation also applies to patients with acute myocardial infarction receiving concomitant therapy with SOSEFLUSS and acetylsalicylic acid.

SOSEFLUSS should be used with caution during pregnancy, especially in the third trimester and the immediate postpartum period (no effects on the infant are expected, as the product does not cross the placental barrier and is not excreted in breast milk). Its use is contraindicated in cases of threatened abortion.

Before using SOSEFLUSS in combination with other drugs dissolved in the same infusion solution, compatibility must be verified (see warnings).

In patients undergoing anticoagulant-dose heparin therapy, intramuscular administration of drugs should be avoided.

In patients undergoing spinal or epidural anesthesia, epidural analgesia, or lumbar puncture, prophylaxis with low-dose 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—such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet aggregation inhibitors, or anticoagulants—by trauma 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 prophylaxis with unfractionated heparins.

As a rule, insertion of a spinal catheter should be performed at least 8–12 hours after the last administration of low-dose prophylactic unfractionated heparin (usually calcium heparin). Subsequent doses should not be administered until at least 2–4 hours after catheter insertion or removal, or further delayed or withheld if blood is aspirated during initial placement of the spinal or epidural needle.

Removal of a “permanent” epidural catheter should be performed as far as possible (approximately 8–12 hours) from the last prophylactic dose of heparin administered during anesthesia.

If unfractionated heparin is to be administered before or after epidural or spinal anesthesia, extreme caution must be exercised, and frequent monitoring for signs and symptoms of neurological impairment—such as lower back pain, sensory and motor deficits (numbness and weakness of the lower limbs), or disturbances in bladder or bowel function—should be performed. 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 of epidural or spinal hematoma are suspected, immediate diagnosis must be established and treatment initiated, including spinal cord decompression.

INTERACTIONS
Resistance to the effect of heparin has been reported during nitroglycerin infusion in coronary care units (approximately 50% reduction in effect on coagulation tests). Combined use of heparin with drugs affecting platelet aggregation (especially acetylsalicylic acid and ticlopidine) and blood coagulability should be undertaken with extreme caution, as they mutually potentiate antiplatelet and anticoagulant effects.

Oral anticoagulants
Anticoagulant-dose sodium or calcium heparin may slightly prolong prothrombin time (increase of approximately 0.5 in INR). This should be considered when evaluating this parameter, particularly during the transition from heparin to oral anticoagulant therapy. Close clinical and laboratory monitoring (frequent assessment of PT and PTT) is recommended when unfractionated heparin at anticoagulant doses is used concomitantly with these drugs.

Antiplatelet agents
Drugs such as acetylsalicylic acid, dextran, phenylbutazone, ibuprofen, indomethacin, dipyridamole, hydroxychloroquine, or other drugs interfering with platelet aggregation (which constitutes the main hemostatic defense in heparinized patients) may induce bleeding and should be used with great caution in patients treated with sodium or calcium heparin, especially at anticoagulant doses.

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

SPECIAL WARNINGS
Mixtures of calcium heparin with solutions of other drugs may result in precipitates and loss of activity. Heparin should not be administered in the same infusion bottles containing antibiotics such as penicillin, tetracycline, or erythromycin; psychotropic substances such as chlordiazepoxide or chlorpromazine; or fat emulsions.

Bleeding
Bleeding may occur in any part of the body in patients receiving sodium or calcium heparin. 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 or calcium heparin should be used with extreme caution in conditions associated with a risk of bleeding.

Some such conditions include:

Cardiovascular: subacute bacterial endocarditis, severe uncontrolled hypertension despite antihypertensive therapy;
Hematological: conditions associated with increased bleeding tendency such as hemophilic syndromes or coagulation factor deficiencies, thrombocytopenia, thrombocytopathies, and certain hemorrhagic vascular purpuras (e.g., Rendu-Osler disease);
Gastrointestinal: peptic ulcer, esophagitis or erosive gastritis, active-phase inflammatory bowel disease, other gastrointestinal conditions at risk of bleeding, continuous gastric or small intestine drainage;
Surgical: during and immediately after: a) lumbar puncture or spinal anesthesia b) major surgery on the brain, spinal column, or eye;
Other: liver disease with coagulation abnormalities and/or esophageal varices or portal hypertension-related gastropathy at high bleeding risk, threat of abortion.

Coagulation tests
When administering sodium or calcium heparin at anticoagulant doses, dosage should be adjusted based on frequent coagulation tests.
If coagulation tests exceed the therapeutic range or if bleeding occurs, the dose should be reduced or, if necessary, heparin should be suspended (see special warnings and precautions for use).
Due to the transient action of sodium heparin, coagulation parameters typically return to normal within a few hours; for calcium heparin, longer times may be required.

Heparin-induced thrombocytopenia
Thrombocytopenia is a well-known complication of sodium or calcium heparin therapy and may occur 4 to 10 days after treatment initiation, or earlier if there is a history of previous heparin-induced thrombocytopenia.
In 10–20% of patients, mild thrombocytopenia (platelet count > 100,000/mm³) may occur, which may remain stable or resolve even if heparin administration continues.

However, in some cases (0.3–3%), a more severe form (type II heparin-induced thrombocytopenia), immune-mediated, may develop, characterized by the formation of antibodies against the heparin–platelet factor 4 complex. In these patients, new thromboses associated with thrombocytopenia may develop due to irreversible platelet aggregation induced by heparin, known as the “white clot syndrome.” This process may lead to severe thromboembolic complications such as skin necrosis, limb gangrene (sometimes requiring amputation), myocardial infarction, pulmonary embolism, stroke, and occasionally death. Therefore, administration of sodium or calcium heparin should be discontinued not only upon onset of thrombocytopenia but also if new thrombosis or worsening of pre-existing thrombosis occurs. Continued anticoagulant therapy—either for the thrombosis that prompted treatment or for new or worsening thrombosis—should be initiated after heparin discontinuation using an alternative anticoagulant. The use of low-molecular-weight heparins in these cases is risky due to possible cross-reactivity, as is immediate initiation of oral anticoagulant therapy (cases of worsening thrombosis have been reported).

Therefore, any form of thrombocytopenia must be closely monitored. If platelet count falls below 100,000/mm³ or recurrent thrombosis occurs, sodium or calcium heparin must be discontinued.
Platelet count should be assessed before treatment and subsequently twice weekly during the first month of prolonged administration.

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

DOSAGE, METHOD, AND DURATION OF ADMINISTRATION
Dosage
As prescribed by the physician.

Instructions for using the pre-filled syringe
Remove the needle protective cap.
Proceed with injection.

Injection technique
The injection, using the 1 ml graduated syringe, should be administered into the subcutaneous tissue, preferably in the gluteal region or over the iliac crest, either on the right or left side. The needle should be inserted fully, perpendicularly (not tangentially), into the thickness of a skin fold created between the operator’s thumb and index finger. The skin fold should be maintained throughout the entire injection. After injection, do not rub the site; apply gentle pressure instead.

Do not administer the injection if insertion of the needle causes sharp pain, indicating vessel injury.
In such cases, withdraw the needle and administer the injection on the opposite side.

When administering sodium or calcium heparin at anticoagulant doses, dosage should be determined based on frequent coagulation tests. If coagulation tests exceed the therapeutic range or if bleeding occurs, the dose should be reduced or, if necessary, heparin should be suspended (see special warnings and precautions for use).

Antagonist action of protamine
Protamine is used for rapid neutralization of heparin activity in cases of significant bleeding.
The required amount depends on the blood level of administered heparin and the time elapsed since injection.
Protamine should be administered by slow intravenous infusion; 50 mg of protamine neutralizes 5,000 IU of heparin. The dose of protamine required to neutralize a heparin bolus decreases proportionally with time since bolus administration (100% immediately after bolus, 50% after 1 hour, 25% after 2 hours).
The dose of protamine required during continuous heparin infusion corresponds to the amount needed to neutralize the heparin infused over the last 4 hours.

OVERDOSE
In case of overdose, a hemorrhagic event may occur. If this occurs within 6 hours of the last SOSEFLUSS injection, administer intravenously 3 ml of 1% protamine sulfate (equivalent to 30 mg). Since protamine neutralizes only circulating heparin and not heparin deposited at the injection site, it is advisable to repeat the intravenous injection of 2 ml between the 8th and 12th hour.

If the hemorrhagic event occurs more than 6 hours after SOSEFLUSS injection, it is sufficient to administer intravenously 2 ml of 1% protamine sulfate (equivalent to 20 mg).

See section “Antagonist action of protamine”

UNDESIRABLE EFFECTS
Bleeding
Bleeding is the main complication that may occur during treatment with sodium or calcium heparin, particularly at anticoagulant doses. Coagulation times above the therapeutic range or minor bleeding during therapy can usually be managed by reducing the dose or, if necessary, temporarily suspending the drug. Gastrointestinal or urinary bleeding during anticoagulant therapy may indicate an underlying occult lesion. Bleeding may occur in any part of the body, but certain specific hemorrhagic complications may be difficult to detect:
a) Adrenal hemorrhage, leading to acute adrenal insufficiency, has been reported 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 undergoing short- or long-term anticoagulant therapy;
c) Retroperitoneal hemorrhages.

In any case of significant bleeding, heparin therapy should be discontinued, and circulating heparin should be neutralized by protamine administration (see overdose).

Local reactions
Local irritation, erythema, mild pain, hematoma, or ulceration may follow subcutaneous administration of heparin. These complications are much more common after intramuscular administration, which must be strictly avoided, even occasionally.

Hypersensitivity
The most commonly reported manifestations include generalized hypersensitivity reactions such as chills, fever, urticaria, and, less frequently, mild asthma, lacrimation, nausea, and vomiting, or shock.

Thrombocytopenia
Cases of thrombocytopenia have been reported in patients receiving sodium or calcium heparin (see special warnings). Although often mild and clinically insignificant, it may occasionally be associated with severe thrombotic and/or embolic complications.

Cases of osteoporosis have been reported after long-term, high-dose therapy.

Rarely reported: skin necrosis, suppression of aldosterone synthesis, transient delayed alopecia, priapism, rebound hyperlipidemia upon discontinuation of therapy.
Rare cases of increased transaminases have also been reported.

Adherence to the instructions in the package leaflet reduces the risk of adverse effects.
It is important to inform your doctor or pharmacist of any adverse effect, even if not described in this leaflet.

KEEP THIS MEDICINE OUT OF REACH OF CHILDREN.

EXPIRY DATE AND STORAGE:
Expiry date: see date on the packaging.
The shelf life applies to the product kept in its original, undamaged packaging and stored correctly.

CAUTION: do not use the product after the expiry date stated on the packaging.

Revision of the Package Leaflet by the Ministry of Health
June 2007

Sosefluss