DBL™ Heparin Sodium Injection BP

New Zealand - English - Medsafe (Medicines Safety Authority)

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Active ingredient:
Heparin sodium 25000 IU/mL
Available from:
Pfizer New Zealand Limited
INN (International Name):
Heparin sodium 25000 IU/mL
Dosage:
25000 IU/mL
Pharmaceutical form:
Solution for injection
Composition:
Active: Heparin sodium 25000 IU/mL Excipient: Hydrochloric acid Sodium hydroxide Water for injection
Units in package:
Ampoule, glass, 5 x 0.2mL, 5 dose units
Class:
Prescription
Prescription type:
Prescription
Manufactured by:
New Zealand Pharmaceuticals Ltd
Product summary:
Package - Contents - Shelf Life: Ampoule, glass, 5 x 0.2mL - 5 dose units - 36 months from date of manufacture stored at or below 25°C - Ampoule, glass, 50 x 0.2mL - 50 dose units - 36 months from date of manufacture stored at or below 25°C
Authorization number:
TT50-3052
Authorization date:
1980-03-06

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NEW ZEALAND DATA SHEET

1.

PRODUCT NAME

DBL™ Heparin Sodium Injection BP

Solution for Injection, 1,000 IU/mL, 5,000 IU/mL and 25,000 IU/mL.

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Heparin Sodium Injection 1,000 IU/mL, 5,000 IU/mL and 25,000 IU/mL is prepared from

porcine intestinal mucosa and is free from pyrogenic substances.

Excipient(s) with known effect

Benzyl alcohol (vials only)

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

DBL Heparin Sodium Injection is a colourless or straw coloured sterile solution for injection:

available as ampoules (1,000 IU/mL, 5,000 IU/mL and 25,000 IU/mL) or vials (1,000 IU/mL

only). The pH of the injection ranges between 5.0 and 8.0.

4.

CLINICAL PARTICULARS

4.1 Therapeutic indications

Heparin is indicated for the prophylaxis and treatment of thromboembolic disorders such as

thrombophlebitis, pulmonary embolism and occlusive vascular disease. It is also used to

prevent thromboembolic complications arising from cardiac and vascular surgery, frostbite,

dialysis and other perfusion procedures. Heparin is also used as an anticoagulant in blood

transfusions.

4.2 Dose and method of administration

Heparin may be given by intermittent intravenous injection, intravenous infusion or deep

subcutaneous injection. It should not be given intramuscularly because of the danger of

haematoma formation.

Low dose prophylaxis against postoperative venous thromboembolism: The usual dose is

5,000 units by deep subcutaneous injection 2 hours before surgery and repeated every 8 to 12

hours for 7 days or longer until the patient is fully ambulatory.

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Adults

Treatment of established venous thrombosis or pulmonary embolism. Treatment may be

given by the following routes:

Continuous intravenous infusion: a bolus dose of 5,000 units may be given initially

followed by an infusion of 20,000 to 40,000 units over 24 hours.

Intermittent intravenous injection: an initial dose of 10,000 units followed by 5,000 to

10,000 units every 4 to 6 hours may be given.

Deep subcutaneous injection: the usual dose is 5,000 units injected intravenously

followed by subcutaneous injection of 10,000 units 8 hourly or 15,000 units 12

hourly.

concentrated

form

heparin

injection

should

used

(eg.

25,000

units/mL).

Paediatric population

A suggested dosage is 50 units/kg bodyweight initially by I.V. infusion followed by 100

units/kg bodyweight every 4 hours according to the clotting time.

For single patient use. Use once only and discard any residue.

4.3 Contraindications

Heparin therapy is contraindicated in patients who are hypersensitive to the drug.

It should not be used in the following cases:

in the presence of actual or potential haemorrhagic states, eg. haemophilia, ascorbic

acid deficiency, increased capillary fragility, hiatus hernia, neoplasms, retinopathy,

bleeding haemorrhoids or other organic lesions likely to bleed;

haemorrhagic vascular accident;

threatened abortion;

immediate postpartum period;

subacute bacterial endocarditis or acute infectious endocarditis;

severe hypertension;

gastric or duodenal ulcers or other ulcerative conditions which may have a tendency

to haemorrhage, eg. ulcerative colitis;

advanced renal or hepatic disease;

during and immediately after spinal or major surgery, especially those involving the

brain, eye or spinal cord;

shock;

severe thrombocytopenia or a history of thrombocytopenia with any kind of heparin

or with pentosan polysulfate;

patients in whom suitable blood coagulation tests, eg whole blood clotting time,

partial thromboplastin time, etc, cannot be performed at appropriate intervals (this

contraindication refers to full-dose heparin; there is usually no need to monitor

coagulation parameters in patients receiving low-dose heparin).

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Heparin

Injection

vials

contain

benzyl

alcohol

preservative,

should

administered to premature or low birth-weight neonates. Benzyl alcohol has been associated

with deaths in these patients. Heparin Injection ampoules do not contain benzyl alcohol.

4.4 Special warnings and precautions for use

Heparin should not be given by intramuscular injection, due to the risk of haematoma

formation.

When neuraxial anaesthesia (epidural/spinal anaesthesia) or spinal puncture is employed,

patients anticoagulated or scheduled to be anticoagulated with unfractionated heparin or low

molecular weight heparins/heparinoids for prevention of thromboembolic complications are

at risk of developing an epidural or spinal haematoma which can result in long term or

permanent paralysis.

The risk of these

events is increased by the

use of indwelling epidural catheters

administration of analgesia or by concomitant use of drugs affecting haemostasis such as

non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, or other anticoagulants.

The risk also appears to be increased by traumatic or repeated epidural or spinal puncture.

Patients should be frequently monitored for signs and symptoms of neurological impairment.

If neurological compromise is noted, urgent treatment is necessary.

The physician should consider the potential benefit versus risk before neuraxial intervention

in patients anticoagulated or to be anticoagulated for thromboprophylaxis.

As heparin is derived from animal tissue, it should be used with caution in patients with a

history of allergy or asthma. Before a therapeutic dose is given to such a patient, a trial dose

of 1,000 units may be advisable.

Heparin should be used with extreme caution in patients with continuous tube drainage of the

stomach or small intestine.

Any action which may cause vascular injury, with the exception of necessary intravenous or

subcutaneous injections, should be avoided where possible.

Outpatients should be warned of the haemorrhagic risks in case of possible trauma.

Heparin should be administered with caution to patients with hepatic or renal disease,

hypertension, a history of ulcers, or with vascular diseases of the chorio-retina. Dosage

reduction may be necessary in patients with advanced renal or hepatic disease.

Increased

resistance

heparin

frequently

encountered

with

fever,

thrombosis,

thrombophlebitis, infections with thrombosing tendencies, myocardial infarction, cancer and

in post-surgical patients.

Heparin therapy increases the risk of localised haemorrhage during and following oral

surgical

(dental)

procedures.

Temporary

heparin

dosage

reduction

withdrawal

therefore be advisable prior to oral surgery.

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Heparin therapy should be monitored carefully. Adequate monitoring of therapy reduces the

risk of overdosage and consequent risk of haemorrhage and is an important guide to the

development of serious adverse reactions such as delayed onset thrombocytopenia.

Platelet counts should be monitored in patients receiving heparin for more than a few days,

since heparin may cause thrombocytopenia with severe thromboembolic complications.

Heparin should be discontinued if thrombocytopenia develops.

Patients on heparin may rarely develop Heparin-induced Thrombosis-Thrombocytopenia

Syndrome (HITTS or “white clot syndrome”): new thrombus formation in association with

thrombocytopenia, as a result of irreversible platelet aggregation. This may lead to severe

thromboembolic complications such as skin necrosis, gangrene of the extremities, myocardial

infarction, pulmonary embolism and stroke. Heparin administration should therefore be

discontinued if a patient develops new thrombosis in association with thrombocytopenia.

These effects are probably of immuno-allergic nature, and occur mostly between the 5th and

21st day of treatment in patients being treated with heparin for the first time.

Delayed Onset of HIT and HITT

Heparin-induced

Thrombocytopenia

Heparin-induced

Thrombocytopenia

Thrombosis can occur up to several weeks after the discontinuation of heparin therapy.

Patients presenting with thrombocytopenia or thrombosis after discontinuation of heparin

should be evaluated for HIT and HITT.

Use in geriatrics

Dosage should be reduced in elderly people. Patients aged 60 years or over, especially

women, may be more susceptible to haemorrhage during heparin therapy.

Paediatric population

DBL Heparin Sodium Injection BP vials contain benzyl alcohol as a preservative, and should

not be administered to premature or low birth-weight neonates (see section 4.3). DBL

Heparin Sodium Injection ampoules do not contain benzyl alcohol.

Effects on laboratory tests

Significant elevations of AST and ALT levels have occurred in a high percentage of patients

(and healthy subjects) who have received heparin. Since AST determinations are important in

the differential diagnosis of myocardial infarction, liver disease and pulmonary embolism,

rises that might be caused by drugs (like heparin) should be interpreted with caution.

4.5 Interaction with other medicines and other forms of interaction

Heparin may prolong the one-stage prothrombin time. Therefore, when heparin is given with

oral anticoagulants such as warfarin, a period of at least 5 hours after the last intravenous

dose, or 24 hours after the last subcutaneous dose of heparin, should elapse before blood is

drawn for a valid prothrombin time to be obtained.

Drugs which affect platelet function, eg aspirin, other salicylates and other non-steroidal anti-

inflammatory agents, dextran, dipyridamole and systemic corticosteroids, may increase the

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risk of haemorrhage and should be used with caution in patients receiving heparin. Where

concomitant use cannot be avoided, careful clinical and biological monitoring should be

undertaken.

Other

drugs

which

potentiate

effect

heparin

include

hydroxychloroquine,

probenecid, vitamin K antagonists, cytostatic agents, cephamandole, valproic acid and. High

doses of penicillins, some contrast media, asparaginase and epoprostenol may also affect the

coagulation process and increase the risk of haemorrhage.

Concomitant use of thrombolytic agents such as alteplase, streptokinase or may also increase

the risk of haemorrhage.

Antihistamines, digitalis glycosides, tetracyclines, nicotine, ascorbic acid and quinine may

reduce the anticoagulant effect of heparin.

Glyceryl trinitrate has been reported to reduce the activity of heparin when both drugs are

administered simultaneously intravenously. This effect may be due to the presence of

propylene

glycol

solvent

many

glyceryl

trinitrate

parenteral

preparations.

interaction has been reported when the glyceryl trinitrate was administered immediately after

heparin.

Adjustment

heparin

dosage

during

following

administration

intravenous glyceryl trinitrate may be required.

Heavy alcohol drinkers are at greater risk of major heparin-associated bleeding than moderate

or non drinkers.

Experimental

evidence

suggests

that

heparin

antagonise

actions

ACTH,

corticosteroids and insulin.

Heparin is incompatible with certain substances in aqueous solution. Reference to specialised

literature should be made to verify in which solution the incompatibility was noted. The

following

incompatibilities

have

been

reported:

hydrocortisone;

hyaluronidase;

some

antihistamines, narcotic analgesics, phenothiazines and antibiotics.

4.6 Fertility, pregnancy and lactation

Fertility

No data available.

Pregnancy

Category C. The use of heparin in pregnancy has the usual risks for the mother, in particular

osteoporosis and thrombocytopenia. Although heparin does not cause malformations, an

increased incidence of human foetal loss and prematurity associated with haemorrhage has

been reported.

Lactation

Heparin is not distributed into milk and heparin therapy is therefore not contraindicated in

women who are breast-feeding. However, administration to breast-feeding women has rarely

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been reported to cause rapid (within 2 to 4 weeks) development of severe osteoporosis and

vertebral collapse.

4.7 Effects on ability to drive and use machines

No data available.

4.8 Undesirable effects

Haemorrhage

major

risk

heparin

therapy

range

from

minor

local

ecchymoses to major haemorrhagic complications. An overly prolonged clotting time or

minor bleeding can usually be controlled by discontinuing the heparin (see section 4.9). The

occurrence of significant gastrointestinal or urinary tract bleeding during heparin therapy may

indicate the presence of an underlying occult lesion.

Bleeding can occur at any site, but some specific haemorrhagic complications can be difficult

to detect.

a) Adrenal haemorrhage with resultant acute adrenal insufficiency has occurred during

anticoagulant therapy. Anticoagulant treatment should be discontinued in patients who

develop signs and symptoms of acute adrenal haemorrhage and insufficiency. Plasma

cortisol

levels

should

measured

immediately.

Corticosteroid

therapy

should

initiated promptly, before laboratory confirmation of the diagnosis, as any delay in

treatment may result in the patient’s death.

b) Ovarian (corpus luteum) haemorrhage may be fatal if unrecognised.

c) Retroperitoneal haemorrhage.

Thrombocytopenia has been reported to occur in up to 30% of patients receiving heparin.

Although the thrombocytopenia is often mild and of no obvious clinical significance, it may

be accompanied by severe thromboembolic complications such as skin necrosis, gangrene of

the extremities, myocardial infarction, pulmonary embolism and stroke (see section 4.4).

Certain episodes of painful, ischaemic and cyanosed limbs have in the past been attributed to

allergic vasospastic reactions; however these reactions may instead be complications of

thrombocytopenia.

Delayed onset thrombocytopenia is also a possible complication of heparin therapy. If this

occurs, the drug should be withdrawn immediately.

Skin necrosis has infrequently been reported at injection sites. It is thought to be a localised

manifestation of heparin-induced platelet aggregation and thrombosis, and should be taken as

a warning sign in patients who develop it. Heparin should be discontinued immediately.

Local irritation, erythema, mild pain, haematoma or ulceration may follow deep subcutaneous

injection. The emergence of firm nodules may be noted in some cases; however, these

nodules usually disappear after a few days.

Allergic reactions to heparin occur rarely. Hypersensitivity may be manifested by pruritus,

urticaria,

chills,

fever,

asthma-like

symptoms,

rhinitis,

lacrimation,

headache,

nausea,

vomiting and anaphylactoid reactions, including angioedema and shock. The most common

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manifestations are urticaria, chills and fever. Itching and burning, especially on the plantar

side of the feet, may occur.

Osteoporosis complicated by spontaneous bone fracture has been reported with prolonged use

of large doses of heparin.

Alopecia and priapism have occurred rarely in patients treated with heparin.

Suppression of aldosterone synthesis with hyperkalaemia and/or metabolic acidosis have

been noted in patients at risk (eg. diabetes, renal failure).

Suppression of renal functions has occurred following long-term, high dose administration of

heparin.

Significant elevations of AST and ALT levels have occurred in a high percentage of subjects

who have received heparin (see section 4.4).

Hypereosinophilia, which is reversible on discontinuation of heparin treatment, has occurred.

Rebound hyperlipidaemia has been reported following discontinuation of heparin therapy has

also been reported.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It

allows

continued

monitoring

benefit/risk

balance

medicine.

Healthcare

professionals

asked

report

suspected

adverse

reactions

https://nzphvc.otago.ac.nz/reporting/.

4.9 Overdose

Symptoms

main

complication

associated

with

heparin

overdose

over-anticoagulation

haemorrhage. Examples of types of bleeding observed in patients receiving heparin sodium

following

subcutaneous

administration

include

melanemia,

haematoma,

haematuria,

ecchymoses, epistaxis, haematemesis, intracranial haemorrhages, pulmonary haemorrhage

and other haemorrhage.

Treatment

Slight haemorrhage due to overdosage can usually be treated by withdrawing the drug.

Severe bleeding may be reduced by the administration of protamine sulphate. Protamine

sulphate should be administered intravenously. To avoid circulatory side effects, the injection

should be given slowly at a rate of 5 mL over a period of about 10 minutes. Not more than

50 mg should be given at any one time. The dose of protamine sulphate required is governed

by the amount of heparin that has to be neutralised; approximately 1mg of protamine sulphate

neutralises 110 units of heparin (mucous) that has been injected in the previous 15 minutes.

Since heparin is being continuously excreted, the dose should be reduced as more time

elapses after the heparin injection. Ideally, the dose of protamine sulphate required should be

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accurately determined by titration methods as the antagonist itself, in gross excess, acts as an

anticoagulant.

For advice on the management of overdose please contact the National Poisons Centre on

0800 POISON (0800 764766).

5.

PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Mechanism of action

Heparin is a naturally occurring mucopolysaccharide which inhibits the clotting of blood in

vitro and in vivo. It enhances the rate at which antithrombin III neutralises thrombin and

activated factor X (X

). Antithrombin III also neutralises other activated coagulation factors,

e.g. factors IX, XI, XII and plasmin.

With low-dose heparin therapy, anticoagulation appears to result from neutralisation of X

which prevents the conversion of prothrombin to thrombin. With full dose heparin therapy,

anticoagulation appears to result primarily from neutralisation of thrombin which prevents

the conversion of fibrinogen to fibrin. Full-dose heparin therapy also prevents the formation

of a stable fibrin clot by inhibiting activation of fibrin stabilising factor.

5.2 Pharmacokinetic properties

Heparin is not absorbed from the gastrointestinal tract and must be administered parenterally.

Its onset of action is immediate following I.V. administration. There may be considerable

variation among patients in the extent of absorption following deep subcutaneous injection of

heparin; however, the onset of activity usually occurs within 20-60 minutes.

Heparin is extensively bound to plasma proteins. It does not cross the placenta and is not

distributed into milk.

The metabolic fate of heparin is not fully understood. No biotransformation in plasma or

liver, nor any renal excretory mechanism has been identified as primarily responsible for

elimination

drug.

been

suggested

that

transfer

storage

reticuloendothelial system may play a role, or that heparin may be partially metabolised in

the liver. After administration of large doses intravenously, a small fraction of unchanged

drug is excreted in the urine.

5.3 Preclinical safety data

Genotoxicity

No data available.

Carcinogenicity

No data available.

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Reproductive and developmental toxicity

No data available.

6.

PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Ampoules

Hydrochloric acid

Sodium hydroxide

Water for injections

Vials

Benzyl alcohol

Hydrochloric acid

Sodium hydroxide

Water for injections

6.2 Incompatibilities

Incompatibility

been

reported

between

heparin

alteplase,

amikacin

sulphate,

amiodarone, ampicillin sodium, benzylpenicillin sodium, cephalothin sodium, ciprofloxacin

lactate,

cytarabine,

dacarbazine,

daunorubicin

hydrochloride,

diazepam,

dobutamine

hydrochloride, doxorubicin hydrochloride, droperidol, erythromycin lactobionate, gentamicin

sulphate, haloperidol lactate, hyaluronidase, hydrocortisone sodium succinate, kanamycin

sulphate,

methicillin

sodium,

netilimicin

sulphate,

opioid

analgesics,

oxytetracycline

hydrochloride, polymyxin B sulphate, promazine hydrochloride, promethazine hydrochloride,

streptomycin

sulphate,

sulphafurazole

diethanolamine,

tetracycline

hydrochloride,

tobramycin sulphate, vancomycin hydrochloride and vinblastine sulphate. Heparin sodium

also

been

reported

incompatible

with

cisatracurium

besylate,

labetalol

hydrochloride and nicardipine hydrochloride. Admixture with glucose can have variable

effects. Incompatibility has been reported between heparin and fat emulsion.

6.3 Shelf life

Ampoules: 36 months

Vials: 24 months

6.4 Special precautions for storage

Store below 25°C.

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6.5 Nature and contents of container

Ampoules, glass (bacteriostat free)

DBL Heparin Sodium Injection BP

Strength

Pack

1,000 IU/1 mL

5's and 50's

5,000 IU/0.2 mL

5's and 50's

5,000 IU/1 mL

5's and 50's

5,000 IU/5 mL

5's and 50's

25,000 IU/5 mL

50's

Not all pack sizes may be marketed

Vials, glass (with 1.0% v/v benzyl alcohol as bacteriostat)

DBL Heparin Sodium Injection BP

Strength

Pack

35,000 IU/35 mL

6.6 Special precautions for disposal

Any unused medicine or waste material should be disposed of in accordance with local

requirements.

7.

MEDICINE SCHEDULE

Prescription Medicine

8.

SPONSOR

Pfizer New Zealand Limited

P O Box 3998

Auckland, New Zealand, 1140

Toll Free Number: 0800 736 363

9.

DATE OF FIRST APPROVAL

06 March 1980

10. DATE OF REVISION OF THE TEXT

22 November 2019

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Summary table of changes

Section changed

Summary of new information

Included statement regarding use in one patient on one occasion only

Addition of hypersentivity information

Included information about neuraxial intervention

= Trademark

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