This information is intended for use by health professionals

1. Name of the medicinal product

Heparin sodium 1000 IU/ml ampoule, solution for infusion

2. Qualitative and quantitative composition

Heparin sodium 1,000 IU/ml

3. Pharmaceutical form

Solution for infusion.

4. Clinical particulars
4.1 Therapeutic indications

Treatment of thrombo-embolic disorders such as: deep vein thrombosis, acute arterial embolism or thrombosis, thrombophlebitis, pulmonary embolism, fat embolism.

Prevention of clotting in the extracorporeal circuit during haemodialysis.

4.2 Posology and method of administration

Treatment of thrombo-embolic disorders: This product may be used when heparin is being administered intravenously as an alternative to diluting heparin taken from multidose vials.

Method of administration

500 IU/kg bodyweight daily or 5,000 - 10,000 IU every 4 hours as a continuous infusion in sodium chloride injection or dextrose injection. The dose should be 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time, whole blood clotting time or activated partial thromboplastin time 1.5 to 2 times that of control on blood withdrawn 4-6 hours after commencement of infusion and at similar intervals until the patient is stabilised.

Dosage in the elderly: Lower dosages may be required, however, standard 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.

Pregnancy: See Section 4.6, Pregnancy and Lactation. If treatment is considered appropriate, standard dosages should be given initially.

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.

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.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the other excipients listed in section 6.1.

.

Patients who consume large amounts of alcohol, who are sensitive to the drug, generalised or local haemorrhagic tendency, are actively bleeding, have haemophilia or other bleeding disorders, including uncontrolled severe hypertension, severe liverdisease (including oesophageal varices), purpura, , active tuberculosis or increased capillary permeability,

Current or history of heparin-induced thrombocytopenia. The rare occurance 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.

An epidural anaesthesia during birth in pregnant women treated with heparin is contraindicated (see Section 4.6).

In patients receiving heparin for treatment rather than prophylaxis, locoregional anaesthesia in elective surgical procedures is contra-indicated because the use of heparin may be very rarely associated with epidural or spinal haematoma resulting in prolonged or permanent paralysis.

Menstruation is not a contraindication.

4.4 Special warnings and precautions for use

As there is a risk of antibody-mediated heparin-induced thrombocytopenia, 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. Heparin should be used with caution in patients with hypersensitivity to low molecular weight heparin

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.

Care should be taken when heparin is administered to patients with increased risk of bleeding complications, hypertension, renal or hepatic insufficiency.

Heparin can suppress adrenal secretion of aldosterone leading to hyperkalaemia, 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 hyperkalaemia 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 monitored regularly thereafter particularly if treatment is prolonged beyond about 7 days.

Drugs affecting platelet function or the coagulation system should in general not be given concomitantly with heparin (see Section 4.5).

In patients undergoing peridural or spinal anaesthesia or spinal puncture, the prophylactic use of heparin 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 heparin at prophylactic doses and the placement or removal of a peridural or spinal catheter, the product characteristics and the patient profile should be taken into account.

Subsequent dose should not take place before at least four hours have elapsed. Re-administration should be delayed until the surgical procedure is completed.

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.

Heparin should not be administered by intramuscular injection due to the risk of haematoma.

Due to increased bleeding risk, care should be taken when giving concomitant intramuscular injections, lumbar puncture and similar procedures.

.

Heparin induced thrombocytopenia and heparin induced thrombocytopenia with thrombosis can occur up to several weeks after discontinuation of heparin therapy. Patients presenting with thrombocytopenia or thrombosis after discontinuation of heparin should be evaluated for HIT and HITT.

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)

● Thromboembolic disorders

● Increased heparin clearance

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

● Active Infection (sepsis or endocarditis)

● Preoperative intra-aortic balloon counterpulsation

● Thrombocytopenia

● Thrombocytosis

● Advanced age

● Plasma albumin concentration ≤ 35g/dl

● Relative hypovolaemia

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

4.5 Interaction with other medicinal products and other forms of interaction

Analgesics: The anticoagulant effect of heparin may be enhanced by concomitant medication with other drugs affecting platelet function or the coagulation system, e.g. platelet aggregation inhibitors, thrombolytic agents, salicylates, non-steroidal anti-inflammatory drugs, vitamin K antagonists, dextrans, activated protein C. Where such combination cannot be avoided, careful clinical and biological monitoring is required. Increased risk of haemorrhage with ketorolac (avoid concomitant use even with low-dose heparin).

Anticoagulants, platelet inhibitors, etc: Increased risk of bleeding with oral anticoagulants, epoprostenol, clopidogrel, ticlopidine, streptokinase, dipyridamole, dextran solutions, or any other drug which may interfere with coagulation.

Cephalosporins: Some cephalosporins, e.g. cefaclor, cefixime and ceftriaxone, can affect the coagulation process and may therefore increase the risk of haemorrhage when used concurrently with heparin.

ACE inhibitors: Combined use with ACE inhibitors or angiotensin II antagonists may increase the risk of hyperkalaemia.

Nitrates: Use of glyceryl trinitrate infusion may reduce the anticoagulant effect of heparin.

Probenecid: May increase the anticoagulant effects of heparin

Tobacco smoke: Nicotine may partially counteract the anticoagulant effect of heparin. Increased heparin dosage may be required in smokers.

Interference with diagnostic tests may be associated with pseudo-hypocalcaemia (in haemodialysis patients), artefactual increases in total thyroxine and triiodothyronine, simulated metabolic acidosis and inhibition of the chromogenic lysate assay for endotoxin. Heparin may interfere with the determination of aminoglycosides by immunoassays.

4.6 Fertility, pregnancy and lactation

Because of the known haemorrhagic effect, heparin should be used with caution in pregnant women and only if the benefits outweigh the risks according to the physician's judgement. Precaution is particularly required because of uteroplacental haemorrhage, especially at the time of delivery. If epidural anaesthesia is envisaged, heparin treatment should be suspended, whenever possible.

The use of heparin in women with abortus imminens is contraindicated (see Section 4.3).

Reduced bone density has been reported with prolonged heparin treatment during pregnancy.

Heparin does not cross the placental barrier and is not excreted in breast milk.

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Frequency estimate: Very common ( ≥1/10), common ( ≥1/100 to <1/10), uncommon ( ≥1/1,000 to <1/100), rare ( ≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

The most frequently reported undesirable effects are bleeding events, reversible increase in liver enzymes, reversible thrombocytopenia and various skin reactions. Isolated reports of generalised allergic reactions, skin necrosis and priapism have been reported.

Blood and lymphatic system disorders

Heparin can cause thrombocytopenia either through a direct effect or through an immune effect producing a platelet-aggregating antibody (see Section 4.4). Reversible after drug withdrawal.

Common: Thrombocytopenia type I

Rare: Thrombocytopenia type II, probably of an immunoallergic nature (see section 4.4)

In some cases thrombocytopenia type II has been accompanied by venous or arterial thrombi. 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.

Immune system disorders

Rare: Allergic reactions of all types and severities, with various manifestations. They include urticarial, conjunctivitis, rhinitis, asthma, cyanosis, tachypnoea, feeling of oppression, fever, chills, angioneurotic oedema and anaphylactic shock.

Very rare: Anaphylactoid reactions

Metabolism and nutrition disorders

Rare: Hypoaldosteronism. Heparin products can cause hypoaldosteronism which may result in an increase in plasma potassium. Rarely, clinically significant hyperkalaemia may occur particularly in patients with chronic renal failure and diabetes mellitus (see Section 4.4).

Vascular disorders

Common: Haemorrhage

Haemorrhages may affect any organ, particularly in connection with high doses.

In some cases haemorrhage has resulted in death or permanent disability.

Very rare cases of epidural and spinal haematoma have been reported in patients receiving heparin for prophylaxis undergoing spinal or epidural anaesthesia or spinal puncture (see Section 4.4).

Hepatobiliary disorders

Common: Raised transaminases, gamma-GT, LDH and lipase levels. They are reversible after drug withdrawal.

Endocrine disorders

Rare: Adrenal insufficiency secondary to adrenal haemorrhage has been associated with heparin

Skin and subcutaneous tissue disorder

Uncommon: Rash (various types of rash such as erythematous and maculopapular), urticaria, pruritus, Alopecia (with prolonged dosing with heparin)

Rare: Local irritation and Skin necrosis. If this occurs treatment must be withdrawn immediately.

One case of erythema multiforme was also reported.

Musculoskeletal and connective tissue disorders

Uncommon: Osteoporosis has been reported in connection with long- term heparin treatment (i.e. over many months).

Significant bone demineralisation has been reported in women taking more than 10,000 I.U. per day of heparin for at least 6 months.

Reproductive system and breast disorders

Very rare: Priapism

General disorders and administration site conditions

Common: Injection site reactions; local irritation may occur when injected subcutaneously

Reporting of suspected adverse reactions

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed on this leaflet. You can also report side effects directly 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. By reporting side effects, you can help provide more information on the safety of this medicine.

4.9 Overdose

Bleeding is the main sign of overdose with heparin and the risk is minimised by strict laboratory control. As heparin is eliminated quickly, a discontinuation of treatment is sufficient in case of minor haemorrhages. In case of severe haemorrhages clotting time and platelet count should be determined.

Prolonged clotting time will indicate the presence of an excessive anticoagulant effect requiring neutralisation with protamine sulphate injected slowly intravenously over about 10 minutes. One mg of protamine sulphate neutralises approximately 100 IU of heparin. Nevertheless, the required protamine sulphate dose varies according to the time of heparin administration and the dose administered. . If more than 15 minutes have elapsed since the injection of heparin, lower doses of protamine will be necessary.

It is important to avoid overdosage of protamine sulphate because protamine itself has anticoagulant properties. A single dose of protamine sulphate should never exceed 50 mg. Intravenous injection of protamine may cause a sudden fall in blood pressure, bradycardia, dyspnoea and transitory flushing, but these may be avoided or diminished by slow and careful administration

5. Pharmacological properties
5.1 Pharmacodynamic properties

Heparin 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.

5.2 Pharmacokinetic properties

The anticoagulant effect of heparin after intravenous infusion becomes apparent immediately.

5.3 Preclinical safety data

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

6. Pharmaceutical particulars
6.1 List of excipients

Sodium chloride

Sodium citrate

Water for Injections

6.2 Incompatibilities

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

6.3 Shelf life

3 years.

6.4 Special precautions for storage

Store below 25°C.

6.5 Nature and contents of container

Ph. Eur. Type I glass ampoules

10 x 5ml ampoules, 50 x 5ml ampoules

10 x 10ml ampoules, 50x 10ml ampoules 10 x 20ml ampoules, 50 x 20ml ampoules

6.6 Special precautions for disposal and other handling

Contains no preservative, any portion of the contents not used at once should be discarded.

7. Marketing authorisation holder

Fannin (UK) Ltd.

DCC Vital

Westminster Industrial Estate

Repton Road, Measham

Swadlincote,

Derbyshire,

England

DE127DT

8. Marketing authorisation number(s)

PL 20417/0109

9. Date of first authorisation/renewal of the authorisation

16 May 1996

10. Date of revision of the text

11 june 2019