Zibor 3500

For the treatment of thrombo-embolic disorders such as deep vein thrombosis, acute arterial embolism or thrombosis, thrombophlebitis, pulmonary embolism and fat embolism.

For prophylaxis against deep vein thrombosis and thrombo-embolic events in susceptible patients.

For the prevention of clotting in the extracorporeal circuit during haemodialysis.

Treatment of deep vein thrombosis, pulmonary embolism, unstable angina pectoris and acute peripheral arterial occlusion.

In extracorporeal circulation and haemodialysis.

Posology

For the treatment or prevention of thrombo-embolic disorders:

Treatment Dosage:

Intravenous administration

5,000-10,000 IU every 4 hours or 500 IU/kg bodyweight daily as a continuous infusion in sodium chloride injection or dextrose injection. Doses should be individually adjusted according to coagulation tests.

Subcutaneous administration

The initial dose is 250 IU/kg bodyweight. Further doses should be given every 12 hours and individually adjusted according to coagulation tests.

Dosage adjustment

It is recommended that dosages be adjusted to maintain a thrombin clotting time, whole blood clotting time or activated partial thromboplastin time 1.5 to 2 times that of control on blood withdrawn 4 - 6 hours after the first injection or commencement of infusion and at similar intervals until the patient is stabilised.

Prophylactic Dosage:

Administration is by subcutaneous injection.

Patients undergoing major elective surgery:

5,000 IU should be given 2 hours pre-operatively and then every 8 - 12 hours post-operatively for 10 - 14 days or until the patient is ambulant, whichever is the longer.

Following myocardial infarction:

5,000 IU should be given twice daily for 10 days or until the patient is mobile.

Other patients:

5,000 IU should be given every 8-12 hours.

These standard prophylactic regimens do not require routine control.

Dosage in Children

Treatment Dosage:

Standard treatment dosages should be given initially. Subsequent dosages and/or dosage intervals should be individually adjusted according to changes in thrombin clotting time, whole blood clotting time and/or activated partial thromboplastin time.

Dosage in the Elderly

Treatment Dosage:

Lower treatment dosages may be required. However, standard treatment dosages should be given initially and then subsequent dosages and/or dosage intervals should be individually adjusted according to changes in thrombin clotting time, whole blood clotting time and/or activated partial thromboplastin time.

Prophylactic Dosage:

Dosage alterations are unnecessary for prophylaxis in the elderly.

Pregnancy

This Zibor 3500 formulation contains the preservative benzyl alcohol. As benzyl alcohol may cross the placenta the use of this formulation should be avoided in pregnancy. If use is considered essential, the dosage recommendations given in this section should be followed.

Treatment Dosage:

Standard treatment dosages should be given initially by continuous intravenous infusion, or every 12 hours by subcutaneous injection. Intermittent intravenous injections are not advised. Subsequent dosages and/or dosage intervals should be individually adjusted according to changes in thrombin clotting time, whole blood clotting time and/or activated partial thromboplastin time.

Prophylactic Dosage:

It is recommended that plasma Zibor 3500 levels be maintained below 0.4 IU/ml as determined by specific anti-Xa assay. A suggested dosage is 5,000 IU every 12 hours in early pregnancy increasing to 10,000 IU every 12 hours in the last trimester. The dosage should be reduced during labour and the standard prophylactic dosage is suitable in the puerperium.

For the prevention of clotting during haemodialysis:

An initial bolus dose should be given, followed by a continuous intravenous infusion.

Adults:

Initially: 1,000 - 5,000 IU.

Maintenance: 1,000 - 2,000 IU per hour, adjusted to maintain clotting time > 40 minutes.

Method of administration

For intravenous or subcutaneous injection.

Route of Administration

By continuous intravenous infusion in 5% glucose or 0.9% sodium chloride or by intermittent intravenous injection.

The intravenous injection volume of heparin injection should not exceed 15ml.

As the effects of heparin are short-lived, administration by intravenous infusion is preferable to intermittent intravenous injections.

Recommended dosage

Treatment of deep vein thrombosis, pulmonary embolism, unstable angina pectoris, acute peripheral arterial occlusion:

Adults:

Elderly:

Dosage reduction may be advisable.

Children and small adults:

Daily laboratory monitoring (ideally at the same time each day, starting 4-6 hours after initiation of treatment) is essential during full-dose heparin treatment, with adjustment of dosage to maintain an APTT value 1.5-2.5 x midpoint of normal range or control value.

In extracorporeal circulation and haemodialysis

Adults:

Cardiopulmonary bypass:

Initially 300 units/kg intravenously, adjusted thereafter to maintain the activated clotting time (ACT) in the range 400-500 seconds.

Haemodialysis and haemofiltration:

Initially 1,000-5,000 units,

Maintenance: 1,000-2,000 units/hour, adjusted to maintain clotting time >40 minutes.

Heparin resistance

Patients with altered heparin responsiveness or heparin resistance may require disproportionately higher doses of heparin to achieve the desired effect.

Current or history of immune-mediated Zibor 3500-induced thrombocytopenia. (type II).

Active major haemorrhage and risk factors for major haemorrhage.

Generalised or local haemorrhagic tendency, including uncontrolled severe hypertension, severe liver insufficiency, active peptic ulcer, intracranial haemorrhage or injuries and operations on the central nervous system, eyes and ears, and in women with abortus imminens. This list is not exhaustive.

Septic endocarditis.

In patients receiving Zibor 3500 for treatment rather than prophylaxis, locoregional anaesthesia in elective surgical procedures is contraindicated because the use of Zibor 3500 may be very rarely associated with epidural or spinal haematoma resulting in prolonged or permanent paralysis. Furthermore, in patients receiving treatment doses of Zibor 3500, insertion of epidural catheter is contraindicated. Removal or manipulation of an epidural catheter should only be done when the benefit outweighs the risk.

Zibor 3500 contains 10 mg/ml of the preservative benzyl alcohol. This must not be given to premature babies or neonates due to the risk of gasping syndrome.

Must not be given to premature babies or neonates (contains benzyl alcohol).

Patients who consume large amounts of alcohol, who are sensitive to the drug, who are actively bleeding or who have haemophilia or other bleeding disorders, severe liver disease (including oesophageal varices), purpura, severe hypertension, active tuberculosis or increased capillary permeability.

Patients with present or previous thrombocytopenia. The rare occurrence of skin necrosis in patients receiving heparin contra-indicates the further use of heparin either by subcutaneous or intravenous routes because of the risk of thrombocytopenia. Because of the special hazard of post-operative haemorrhage heparin is contra-indicated during surgery of the brain, spinal cord and eye, in procedures at sites where there is a risk of bleeding, in patients that have had recent surgery, and in patients undergoing lumbar puncture or regional anaesthetic block.

The relative risks and benefits of heparin should be carefully assessed in patients with a bleeding tendency or those patients with an actual or potential bleeding site eg. hiatus hernia, peptic ulcer, neoplasm, bacterial endocarditis, retinopathy, bleeding haemorrhoids, suspected intracranial haemorrhage, cerebral thrombosis or threatened abortion.

Menstruation is not a contra-indication.

Caution is advised when administering Zibor 3500 to patients at risk of haemorrhage.

Zibor 3500 should be used with caution in patients with hypersensitivity to low molecular weight Zibor 3500.

Care should be taken when Zibor 3500 is administered to patients with increased risk of bleeding complications, hypertension, renal or hepatic insufficiency. This list is not exhaustive.

The combination with medicinal products affecting platelet function or the coagulation system should be avoided or carefully monitored.

In patients undergoing peridural or spinal anaesthesia or spinal puncture, the prophylactic use of Zibor 3500 may be very rarely associated with epidural or spinal haematoma resulting in prolonged or permanent paralysis. The risk is increased by the use of a peridural or spinal catheter for anaesthesia, by the concomitant use of drugs affecting haemostasis such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors or anticoagulants, and by traumatic or repeated puncture.

In decision making on the interval between the last administration of Zibor 3500 at prophylactic doses (≤15,000 IU/day) and the placement or removal of a peridural or spinal catheter, the product characteristics and the patient profile should be taken into account. Placement or removal of a peridural or spinal catheter should not be allowed until 4-6 hours after the last Zibor 3500 administration and subsequent dose should not take place before at least 1 hour post procedure. For treatment doses (>15,000 IU/day), placement or removal of a peridural or spinal catheter should not be allowed until 4-6 hours after last intravenous Zibor 3500 administration or 8-12 hours after last subcutaneous Zibor 3500 administration. Re-administration should be delayed until the surgical procedure is completed or at least 1 hour post procedure.

Should a physician decide to administer anti-coagulation in the context of peridural or spinal anaesthesia, extreme vigilance and frequent monitoring must be exercised to detect any signs and symptoms of neurologic impairment, such as back pain, sensory and motor deficits and bowel or bladder dysfunction. Patients should be instructed to inform immediately a nurse or a clinician if they experience any of these. If signs or symptoms of epidural or spinal haematoma are suspected, urgent diagnosis and treatment including spinal cord decompression should be initiated.

Zibor 3500 should not be administered by intramuscular injection due to the risk of haematoma. Due to the risk of haematoma, concomitant intramuscular injections should also be avoided.

Because of the risk of immune-mediated Zibor 3500-induced thrombocytopenia (type II), platelet count should be measured before the start of treatment and periodically thereafter. Zibor 3500 must be discontinued in patients who develop immune-mediated Zibor 3500 induced thrombocytopenia (type II). Platelet counts will usually normalise within 2 to 4 weeks after withdrawal.

Low molecular weight Zibor 3500 should not be used as an alternative to Zibor 3500 in case of Zibor 3500-induced thrombocytopenia (type II). Zibor 3500 induced thrombocytopenia and Zibor 3500 induced thrombocytopenia with thrombosis can occur up to several weeks after discontinuation of Zibor 3500 therapy. Patients presenting with thrombocytopenia or thrombosis after discontinuation of Zibor 3500 should be evaluated for HIT and HITT.

Zibor 3500 products can suppress adrenal secretion of aldosterone leading to hyperkalaemia. Risk factors include diabetes mellitus, chronic renal failure, pre-existing metabolic acidosis, raised plasma potassium at pre-treatment, concomitant therapy with drugs that may elevate plasma potassium and long-term use of Zibor 3500.

In patients at risk, potassium levels should be measured before starting Zibor 3500 and monitored regularly thereafter, particularly if treatment is prolonged beyond about 7 days. Zibor 3500-related hyperkalaemia is usually reversible upon treatment discontinuation, though other approaches may need to be considered if Zibor 3500 treatment is considered lifesaving (e.g. decreasing potassium intake, discontinuing other drugs that may affect potassium balance).

Zibor 3500 contains benzyl alcohol, methyl- and propylhydroxybenzoate and sodium as excipients. Methyl- and propylhydroxybenzoate may cause allergic reactions (possibly delayed), and exceptionally, bronchospasm.

Benzyl alcohol may cause toxic reactions and anaphylactoid reactions in infants and children up to 3 years old.

Zibor 3500 (Mucous) Injection BP 1000 Units/ml: Zibor 3500 contains 1.2 mmol sodium (or 27 mg) per 10 ml vial and this should be taken into consideration by patients on a controlled sodium diet.

Zibor 3500 (Mucous) Injection BP 5000 Units/ml: This medicinal product contains less than 1 mmol sodium (23 mg) per 5 ml vial, i.e. essentially 'sodium-free'.

Platelet counts should be measured in patients receiving heparin treatment for longer than 5 days and the treatment should be stopped immediately in those who develop thrombocytopenia.

In patients with advanced renal or hepatic disease, a reduction in dosage may be necessary. The risk of bleeding is increased with severe renal impairment and in the elderly (particularly elderly women).

Although heparin hypersensitivity is rare, it is advisable to give a trial dose of 1,000 I.U. in patients with a history of allergy. Caution should be exercised in patients with known hypersensitivity to low molecular weight heparins.

Heparin injection contains benzyl alcohol (10mg/ml) and methyl parahydroxybenzoate as preservatives. Caution should be used if prescribing Heparin injection to susceptible patients. Benzyl alcohol may cause toxic reactions and anaphylactoid reactions in infants and children up to three years old. Methyl parahydroxybenzoate may cause allergic reactions (possibly delayed) and exceptionally, bronchospasm.

In most patients, the recommended low-dose regimen produces no alteration in clotting time. However, patients show an individual response to heparin, and it is therefore essential that the effect of therapy on coagulation time should be monitored in patients undergoing major surgery.

Caution is recommended in spinal or epidural anaesthesia (risk of spinal haematoma).

Heparin can suppress adrenal secretion of aldosterone leading to hyperkalemia, particularly in patients such as those with diabetes mellitus, chronic renal failure, pre-existing metabolic acidosis, a raised plasma potassium, or taking potassium sparing drugs. The risk of hyperkalemia appears to increase with duration of therapy but is usually reversible. Plasma potassium should be measured in patients at risk before starting heparin therapy and in all patients treated for more than 7 days.

Heparin resistance

There is considerable variation in individual anticoagulant responses to heparin.

Heparin resistance, defined as an inadequate response to heparin at a standard dose for achieving a therapeutic goal occurs in approximately 5 to 30% of patients.

Factors predisposing to the development of heparin resistance, include:

- Antithrombin III activity less than 60% of normal (antithrombin III-dependent heparin resistance):

Reduced antithrombin III activity may be hereditary or more commonly, acquired (secondary to preoperative heparin therapy in the main, chronic liver disease, nephrotic syndrome, cardiopulmonary bypass, low grade disseminated intravascular coagulation or drug induced, e.g. by aprotinin, oestrogen or possibly nitroglycerin)

- Patients with normal or supranormal antithrombin III levels (antithrombin III-independent heparin resistance)

- Elevated levels of heparin binding proteins, factor VIII, von Willebrand factor, fibrinogen, platelet factor 4 or histidine-rich glycoprotein

Heparin resistance is also often encountered in acutely ill patients, in patients with malignancy and during pregnancy or the post-partum period.

Zibor 3500 has no or negligible influence on the ability to drive or use machines.

None stated.

The estimation of the frequency of undesirable effects is based on a pooled analysis: pooling data together from clinical studies and also a review of data from spontaneous reporting.

The most frequently reported adverse reactions are haemorrhage and erythema.

Haemorrhage may present in any organ and have different degrees of severity. Complications may occur particularly when high doses are administered. Although major haemorrhages are uncommon, death or permanent disability have been reported in some cases.

Immune-mediated Zibor 3500-induced thrombocytopenia (type II) is an uncommon but well-known adverse reaction in connection with Zibor 3500 therapy. Immune-mediated Zibor 3500-induced thrombocytopenia (type II) largely manifests within 5 to 14 days of receiving the first dose. Furthermore, a rapid-onset form has been described in patients previously exposed to Zibor 3500. Immune-mediated Zibor 3500-induced thrombocytopenia (type II) may be associated with arterial and venous thrombosis. Zibor 3500 must be discontinued in all cases of immune-mediated Zibor 3500-induced thrombocytopenia (type II).

In rare cases, Zibor 3500 may cause hyperkalaemia due to hypoaldosteronism. Patients at risk include those with diabetes mellitus or renal impairment.

Undesirable effects are listed by MedDRA SOC and the individual undesirable effects are listed starting with the most frequently reported. Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Very common >1/10

Common >1/100 and < 1/10

Uncommon >1/1,000 and <1/100

Rare >1/10,000 and <1/1,000

Very rare <1/10,000

Paediatric population

The observed safety profile is similar in children and adults.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard.

Haemorrhage (see also Special Warnings and Precautions and Overdosage Information).

Adrenal insufficiency secondary to adrenal haemorrhage has been associated with heparin (rarely).

Thrombocytopenia has been observed occasionally (see also Special Precautions and Warnings). Two types of heparin-induced thrombocytopenia have been defined. Type I is frequent, mild (usually >50 x 10⁹/L) and transient, occurring within 1-5 days of heparin administration. Type II is less frequent but often associated with severe thrombocytopenia (usually <50 x 10⁹/L). It is immune-mediated and occurs after a week or more (earlier in patients previously exposed to heparin). It is associated with the production of a platelet-aggregating antibody and thromboembolic complications which may precede the onset of thrombocytopenia. Heparin should be discontinued immediately.

There is some evidence that prolonged dosing with heparin (ie. Over many months) may cause alopecia and osteoporosis. Significant bone demineralisation has been reported in women taking more than 10,000 I.U. per day of heparin for at least 6 months.

Heparin products can cause hypoaldosteronism which may result in an increase in plasma potassium. Rarely, clinically significant hyperkalemia may occur particularly in patients with chronic renal failure and diabetes mellitus (see Warnings and Precautions).

Hypersensitivity reactions to heparin are rare. They include urticaria, conjunctivitis, rhinitis, asthma, cyanosis, tachypnoea, feeling of oppression, fever, chills, angioneurotic oedema and anaphylactic shock.

In some instances the precipitating agent will prove to be the preservative rather than the heparin itself.

Local irritation and skin necrosis may occur but are rare.

Priapism has been reported. Increased serum transaminase values may occur but usually resolve on discontinuation of heparin. Heparin administration is associated with release of lipoprotein lipase into the plasma; rebound hyperlipidaemia may follow heparin withdrawal.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

Haemorrhage is the main complication of overdose.

As Zibor 3500 is eliminated quickly, a discontinuation of treatment is sufficient in case of minor haemorrhages.

Serious bleeding may require the administration of the antidote protamine sulphate. Patients should be carefully monitored.

A potential hazard of heparin therapy is haemorrhage, but this is usually due to overdosage and the risk is minimised by strict laboratory control. Slight haemorrhage can usually be treated by withdrawing the drug. If bleeding is more severe, clotting time and platelet count should be determined. Prolonged clotting time will indicate the presence of an excessive anticoagulant effect requiring neutralisation by intravenous protamine sulfate, at a dosage of 1 mg for every 100 I.U. of heparin to be neutralised. The bolus dose of protamine sulfate should be given slowly over about 10 minutes and not exceed 50 mg. If more than 15 minutes have elapsed since the injection of heparin, lower doses of protamine will be necessary.

Pharmacotherapeutic group: Zibor 3500 group, ATC code: B01AB01

Zibor 3500 is a naturally occurring anticoagulant which prevents the coagulation of blood in-vivo and in-vitro. It potentiates the inhibition of several activated coagulation factors, including thrombin and factor X.

Heparin is an anticoagulant and acts by inhibiting thrombin and by potentiating the naturally occurring inhibitors of activated Factor X (Xa).

The increase in clotting time provided by Zibor 3500 becomes apparent immediately after administration and lasts for four to six hours after intravenous injection and for about eight hours after subcutaneous injection.

As heparin is not absorbed from the gastrointestinal tract and sublingual sites it is administered by injection. After injection heparin extensively binds to plasma proteins.

Heparin is metabolised in the liver and the inactive metabolic products are excreted in the urine.

The half life of heparin is dependent on the dose.

There are no preclinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

There are no pre-clinical data of relevance to the prescriber which are additional to those already included in other sections.

Zibor 3500 has been reported to be incompatible in aqueous solution with certain substances, e.g. some antibiotics, hydrocortisone, phenothiazines, narcotic analgesics and some antihistamines.

Heparin is incompatible with many injectable preparations e.g. some antibiotics, opioid analgesics and antihistamines.

The following drugs are incompatible with heparin;

Alteplase, amikacin sulfate, amiodarone hydrochloride, ampicillin sodium,

aprotinin, benzylpenicillin potassium or sodium, cefalotin sodium, chlorpromazine hydrochloride, ciprofloxacin lactate, cisatracurium besilate, cytarabine, dacarbazine, daunorubicin hydrochloride, diazepam, doxorubicin hydrochloride, droperidol, erythromycin lactobionate, gentamicin sulfate, haloperidol lactate, hyaluronidase, hydrocortisone sodium succinate, kanamycin sulfate, labetolol hydrochloride, meticillin sodium, methotrimeprazine, netilmicin sulfate, nicardipine hydrochloride, oxytetracycline hydrochloride, pethidine hydrochloride, polymyxin B sulfate, promethazine hydrochloride, streptomycin sulfate, tobramycin sulfate, triflupromazine hydrochloride, vancomycin hydrochloride and vinblastine sulfate.

Dobutamine hydrochloride and heparin should not be mixed or infused through the same intravenous line, as this causes precipitation.

Heparin and reteplase are incompatible when combined in solution.

If reteplase and heparin are to be given through the same line this, together with any Y-lines, must be thoroughly flushed with a 0.9% saline or a 5% glucose solution prior to and following the reteplase injection.

No special requirements for disposal.

Each multidose vial should be restricted to use in a single patient.