HEPARIN SODIUM 1 000 I.U./ML SOLUTION FOR INJECTION OR CONCENTRATE FOR SOLUTION FOR INFUSION

Active substance: HEPARIN

View full screen / Print PDF » Download PDF ⇩

Transcript
SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Monoparin 1,000 I.U./ml solution for injection or concentrate for solution for
injection.
Heparin sodium 1,000 I.U./ml solution for injection or concentrate for solution
for infusion.

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Heparin sodium 1,000 I.U./ml (1,000 I.U./ml in 1ml, 5,000 I.U. in 5ml, 10,000 I.U. in
10ml and 20,000 I.U. in 20ml)
For excipients see 6.1

3

PHARMACEUTICAL FORM
Solution for injection or concentrate for solution for infusion.
A colourless or straw-coloured liquid, free from turbidity and from matter that
deposits on standing.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Treatment of deep vein thrombosis, pulmonary embolism, unstable angina pectoris
and acute peripheral arterial occlusion.
In extracorporeal circulation and haemodialysis.

4.2

Posology and method of administration
Route of administration

By continuous intravenous infusion in 5% glucose or 0.9% sodium chloride or
by intermittent intravenous injection.
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:
Loading dose: 5,000 units intravenously (10,000 units may be required in severe
pulmonary embolism)
Maintenance: 1,000-2,000 units/hour by intravenous infusion,
or 5,000-10,000 units 4-hourly by intravenous injection.
Elderly:
Dosage reduction may be advisable.
Children and small adults:
Loading dose: 50 units/kg intravenously
Maintenance: 15-25 units/kg/hour by intravenous infusion,
or 100 units/kg 4-hourly by intravenous injection
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. Also refer to
section 4.4, Special warnings and precautions for use.

4.3

Contraindications
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 contraindicated 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 e.g.
hiatus hernia, peptic ulcer, neoplasm, bacterial endocarditis, retinopathy, bleeding
haemorrhoids, suspected intracranial haemorrhage, cerebral thrombosis or threatened
abortion.
Menstruation is not a contra-indication.

4.4

Special warnings and precautions for use
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.
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 IIIdependent 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: Drugs that interfere with platelet aggregation eg. aspirin and other
NSAIDs should be used with care. 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: Hyperkalaemia may occur with concomitant use.
Nitrates: Reduced activity of heparin has been reported with simultaneous
intravenous glyceryl trinitrate infusion.
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

Pregnancy and lactation
Heparin is not contraindicated in pregnancy. Heparin does not cross the placenta or
appear in breast milk. The decision to use heparin in pregnancy should be taken after
evaluation of the risk/benefit in any particular circumstances.
Reduced bone density has been reported with prolonged heparin treatment during
pregnancy.
Haemorrhage may be a problem during pregnancy or after delivery.

4.7

Effects on ability to drive and use machines
None stated.

4.8

Undesirable effects
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.
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.

4.9

Overdose
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 sulphate, at a dosage of 1 mg for every 100 I.U. of heparin to
be neutralised. The bolus dose of protamine sulphate 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.

5

PHARMACOLOGICAL PROPERTIES

5.1

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

5.2

Pharmacokinetic properties
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.

5.3

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

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Water for injections
Sodium hydroxide solution 3M

Hydrochloric acid 3M

6.2

Incompatibilities
Heparin is incompatible with many injectable preparations e.g. some antibiotics,
opioid analgesics and antihistamines.
The following drugs are incompatible with heparin;
Alteplase, amikacin sulphate, 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 sulphate, haloperidol lactate, hyaluronidase,
hydrocortisone sodium succinate, kanamycin sulphate, labetolol hydrochloride,
meticillin sodium, methotrimeprazine, netilmicin sulphate, nicardipine hydrochloride,
oxytetracycline hydrochloride, pethidine hydrochloride, polymyxin B sulphate,
promethazine hydrochloride, streptomycin sulphate, tobramycin sulphate,
triflupromazine hydrochloride, vancomycin hydrochloride and vinblastine sulphate.
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.

6.3

Shelf life
Unopened -36 months
From a microbiological point of view, unless the method of opening precludes the
risk of microbial contamination, the product should be used immediately.
If not used immediately, in-use storage times and conditions are the responsibility of
the user.

6.4

Special precautions for storage
Do not be store above 25°C.
Store in the original package.

6.5

Nature and contents of container
Neutral glass ampoules (Type I Ph Eur) of 1ml or 2ml, 5ml, 10ml and 20ml capacity
containing 1ml, 5ml, 10ml and 20ml of solution respectively. Cartons contain 10
ampoules.

6.6

Special precautions for disposal
Not applicable.

7

MARKETING AUTHORISATION HOLDER
Wockhardt UK Ltd
Ash Road North
Wrexham
LL13 9UF
UK

8

MARKETING AUTHORISATION NUMBER(S)
PL 29831/0105

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
05/07/1991 / 20/09/2006

10

DATE OF REVISION OF THE TEXT
18/09/2009

Expand view ⇕

Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

Hide
(web2)