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DANAPAROID SODIUM 750 ANTI-XA UNITS/0.6ML SOLUTION FOR INJECTION

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Mock up

Assessed against UK PIL dated April 2004
By whitneya at 7:36 am, Oct 27, 2008

Orgaran® Solution for injection/
Danaparoid Sodium 750 Anti-Xa Units/0.6ml
solution for injection
(danaparoid sodium)

Patient Information Leaflet
Your medicine is available using either of the above names but will
be referred to as Orgaran throughout this leaflet.
Read all of this leaflet carefully before you are given this medicine.




Keep this leaflet. You may need to read it again.
If you have further questions, please ask your doctor or your
pharmacist.
This medicine has been prescribed for you personally and you
should not pass it on to others. It may harm them, even if their
symptoms are the same as yours.

In this leaflet:
1.
2.
3.
4.
5.



What Orgaran is and what it is used for
Before you are given Orgaran
How Orgaran is given
Possible side effects
Storing Orgaran

The active substance is danaparoid sodium.
The other ingredients are sodium sulphite, sodium chloride and
water for injection.

Manufacturer:
Manufactured by: N.V. Organon, 5340 BH Oss, The Netherlands.
Procured from within the EU and repackaged by: Doncaster
Pharmaceuticals Group Ltd, Kirk Sandall, Doncaster, DN3 1QR.
Product Licence holder: Doncaster Pharmaceuticals Group Ltd, Kirk
Sandall, Doncaster, DN3 1QR.
POM

1.

PL No: 04423/0597

What Orgaran is and what it is used for

Orgaran is a clear, colourless, sterile, isotonic solution for injection
which is available in packs containing 10 or 20 ampoules.
Orgaran prevents the formation of blood clots in blood vessels
(thrombosis) and is used in patients who have an increased risk of
blood clot formation. Orgaran is supplied in glass ampoules.
Each ampoule contains 750 anti-Xa units of danaparoid sodium in
0.6ml.

2. Before you are given Orgaran
You should not be given Orgaran

If you suffer from or have ever had any of the following:
if you bleed easily
if you have had a stroke
if you are bleeding and it can’t be stopped
if you are allergic to Orgaran
if you are allergic to sulphite as this may rarely cause severe
hypersensitivity reactions and bronchospasm
if you have liver or kidney disease
if you have high blood pressure
if you have an active gastroduodenal ulcer
if you have damage to the retina of the eye due to diabetes
if you have an acute infection of the inner lining and valves of
the heart (acute bacterial endocarditis)
if you are pregnant or breast-feeding
if previous treatment with heparins (a group of medicines often
used for blood clots) caused a large drop in the number of blood
platelets (thrombocytopenia) and if a blood test showed that a
similar effect may happen with Orgaran.
Even so, your doctor may still decide to give you this medicine.
If you are receiving Orgaran to treat blood clots you should
not have a spinal or epidural anaesthetic.
You should tell your doctor before you are given Orgaran if you have
now or ever have had:
kidney or liver disease
peptic ulcer
a history of asthma or allergy (sodium sulphite may rarely
cause severe reactions and bronchospasm. Symptoms include:
tightening of the chest, swelling, itching or rash) as extra
supervision may be necessary.
Special care is also needed if you are receiving Orgaran for
the prevention of blood clots and you have to have a spinal or
epidural anaesthetic.

Pregnancy and breast-feeding

If you are pregnant, or suspect that you are pregnant or if you are
breast-feeding then tell your doctor. Your doctor will decide whether
Orgaran can be given to you.

Driving and using machines:

Orgaran is not known to have any effects on the ability to drive and
use machines.

Using other medicines

Other medicines may effect how Orgaran works or Orgaran may
affect how they work. Tell your doctor if you are taking (or intend to
take) other medicines, such as:
oral anticoagulants
aspirin or anti-rheumatics
steroids.

3. How Orgaran is given

The medicine is given as an injection under the skin or as an infusion
by your doctor or nurse. The normal dose is 750 units, twice-a-day,
for 7 to 10 days. Higher doses may be necessary in some patients.

If too much Orgaran is given:

When too much Orgaran is given unusual blood loss may occur.
This may be shown by:
nosebleeds, bleeding gums;
blackened stools (may indicate blood loss from stomach or
intestines);
blood in the urine;
unusually severe menstruation.

4. Possible side effects

Like all medicines, Orgaran can have side-effects.
Sometimes:
increased bleeding or swelling composed of blood at the
operation site (haematoma)
bruises and / or pain around the injection site.
Rarely:
Allergic reaction
rash
a large drop in the number of blood platelets
(thrombocytopenia)
change in liver blood tests
If you have any of these or any other side effects, tell your doctor.

Very rarely:

When Orgaran is used at the same time as spinal anaesthesia
or puncture, bruising of the spine may occur.
If you notice any of the following symptoms you should tell
your doctor or nurse IMMEDIATELY as you may require
treatment:
back pain
tingling, numbness or weakness in the legs
bowel or bladder problems

5. Storing Orgaran
Do not store above 30°C.
Do not freeze.
Keep the ampoules in the outer carton to protect from light.
Keep out of the reach and sight of children.
Do not use after the expiry date printed on the carton and
ampoule label.
Return any unused medicines to your pharmacist for safe
disposal.

6. More information about Orgaran

Orgaran contains a natural substance, derived from pig-intestine,
which prevents the formation of blood clots in blood-vessels
(thrombosis). It belongs to the group of medicines called antithrombotics. Blood clots which form in veins may restrict the blood
flow causing tissue to die. Parts of the clot are liable to break off
and may block the blood circulation in the lungs. A blood clot in the
lungs may be very serious.
Patients who are bedridden have an increased risk of clot formation
in the veins of the legs, especially if they have undergone an
operation.
These patients receive Orgaran to prevent the formation of blood
clots.
Orgaran® is a registered trademark of N.V. Organon.
Leaflet revision & issue date (Ref): 24.10.08

Mock up

Assessed against UK PIL dated December 2001

INFORMATION FOR THE DOCTOR

1. Trade name of the medicinal product
Orgaran® Solution for injection/
Danaparoid Sodium 750 Anti-Xa Units/0.6ml solution for injection
This medicine is available using the names Orgaran® Solution for
injection/ Danaparoid Sodium 750 Anti-Xa Units/0.6ml solution for
injection, but will be referred to as Orgaran throughout the leaflet.

2. Qualitative and Quantitative Composition
Orgaran contains danaparoid sodium, which is a mixture of low
molecular weight sulphated glycosaminoglycuronans derived from
animal mucosa, comprising heparan sulphate, dermatan sulphate and
a minor amount of chondroitin sulphate. One ml contains 1250
amidolytic anti-factor Xa units danaparoid sodium and 0.15% (w/v)
sodium sulphite.
The anti-Xa unit is derived from the international heparin standard in
an antithrombin-III containing buffer system.

3. Pharmaceutical form
Orgaran is supplied in ampoules containing 750 anti-Xa units (0.6ml),
as a sterile, isotonic solution of pH7 in water for injections.
Orgaran is administered by subcutaneous injection.

4. Clinical Particulars
4.1 Therapeutic indications

Prevention of deep vein thrombosis and its possible
consequences in patients undergoing general or
orthopaedic surgery.
Treatment of thrombo-embolic disorders in patients who
require urgent parenteral anti-coagulation because of the
development or history of heparin-induced
thrombocytopenia (HIT)

4.2 Posology and method of administration
a) Non-HIT patients (DVT prophylaxis)

In general Orgaran should be administered by
subcutaneous injection at a dose of 750 anti-factor Xa
units, twice daily for 7 to 10 days or until the risk of
thromboembolism has diminished.
In surgical patients it is recommended to start this dosing
pre-operatively and to give the last pre-operative dose 1 –
4 hours before surgery.
Plasma anti-Xa activity is linearly related to the dose of
Orgaran given. If it is necessary to monitor anticoagulant
activity, and for individual dose setting, a functional antifactor Xa test using a chromogenic peptide substrate
should be used. In this test Orgaran should be used as
standard for constructing the reference curve.

b)

HIT patients

The diagnosis of HIT should as a minimum be based on:
1) Thrombocytopenia (platelet count < 100 x 109/L)
occurring during heparin administration and
2) Exclusion of all other causes of thrombocytopenia
In general monitoring of plasma anti-Xa activity is
not necessary. However, in patient suffering from
renal insufficiency and/or patients weighing over
90kg, monitoring (using an amidolytic assay) is
recommended.
Orgaran should be administered intravenously as a
bolus of 2500 anti-Xa units (for patient less than
55kg 1250 units, if over 90kg, 3750 units) followed
by an intravenous infusion of 400 units/h for 2 hours,
then 300 units/h for 2 hours, then a maintenance
infusion of 200 units/h for 5 days.
The expected plasma anti-Xa levels are
0.5 - 0.7 units/ml, 5 – 10 minutes after the bolus,
not higher than 1.0 units/ml during the adjustment
phase of maintenance infusion and 0.5 – 0.8 units/ml
during the maintenance infusion.

Dosage in the elderly:

Clearance of anti-factor Xa activity has not been shown to be
markedly reduced in the elderly and the usual dosage is
recommended.

Children:

There is insufficient experience with the use of Orgaran in children to
suggest a dosage regimen for this group of patients.

Dosage in patients with moderately impaired renal
and/or liver function:

Orgaran should be used with caution in patients with moderately
impaired renal and/or liver function with impaired haemostasis.
Conversion to anticoagulants is possible, however it is advisable only
to start such a therapy once there is adequate antithrombotic control
with Orgaran.

By whitneya at 7:37 am, Oct 27, 2008

Oral anticoagulants can be given with the infusion (maximum rate
300 units/h) which can then be stopped when the international
normalised ratio is ≥ 1.5.
If the bleeding risk is high then either:
a)
Stop the infusion and start Orgaran 750 anti-Xa units
subcutaneously twice a day, then 24 hours later start
anticoagulants 48 – 72 hours before Orgaran is withdrawn to
give time for the prothrombin time, Thrombotest and
international normalised ratio to reach therapeutic levels
(measurement of these parameters is not reliable within 5 hours
of Orgaran injection (See interactions with other medicaments
and other forms of interactions)) or
b) Stop the infusion, give no further Orgaran then start the
anticoagulants 12 hours later.

4.3 Contra-indications

As with heparins, in patients receiving Orgaran for treatment
rather than for prophylaxis, locoregional anaesthesia in elective
surgical procedures is contraindicated.
severe haemorrhagic diathesis, e.g. haemophilia and idiopathic
thrombocytopenia purpura, unless the patient also has HIT and
no alternative anti-thrombotic treatment is available.
haemorrhagic stroke in the acute phase
uncontrollable active bleeding state
severe renal – and/or hepatic insufficiency, unless the patient
also has HIT and no alternative anti-thrombotic treatment is
available
severe hypertension
active gastroduodenal ulcer, unless it is the reason for operation
diabetic retinopathy
acute bacterial endocarditis
hypersensitivity to Orgaran
a positive invitro aggregation test for the heparin-induced
antibody in the presence of Orgaran in patients with a history of
thrombocytopenia induced by heparin or heparin-like
anticoagulants
hypersensitivity to sulphite.

4.4 Special Warnings and Special precautions for use

Orgaran should be used with caution in patients with moderately
impaired renal, and/or liver function with impaired haemostasis,
ulcerative lesions of the gastro-intestinal tract or other diseases which
may lead to an increased danger of haemorrhage into a vital organ or
site.
Orgaran contains sodium sulphite. In asthma patients
hypersensitive to sulphite the latter can result in bronchospasm
and/or anaphylactic shock.
Since Orgaran has been shown to have a low incidence (< 10%)
of (platelet) cross-reactivity with plasma from patients sensitised
by heparin, Orgaran can be used for these patients but it is
advisable to rule out cross-reactivity by an in vitro test. Because
the risk of antibody-induced thrombocytopenia is very small, it is
advisable to check the number of platelets regularly. If antibodyinduced thrombocytopenia occurs, one should stop the use of
Orgaran and consider alternative treatment.
Orgaran should not be given by the intramuscular route.
The safety and efficacy of Orgaran in patients with nonhaemorrhagic stroke remains to be confirmed.
No incidence of osteoporosis have been reported in patients
treated with the recommended dose of Orgaran. However, as for
heparin, treatment with glycosaminoglycuronan may result in
osteoporosis if the dosage is inappropriate.
It should be noted that the anti-Xa of Orgaran have a different
relationship to clinical efficacy than those of heparin and low
molecular weight heparins.
As with heparins, in patients undergoing peridural or spinal
anaesthesia or spinal puncture, the prophylactic use of Orgaran
may theoretically be associated with epidural or spinal
haematoma resulting in prolonged or permanent paralysis. The
risk is increased by the prolonged use of a peridural or spinal
catheter for analgesia, by the concomitant use of drugs affecting
haemostasis such as nonsteroidal anti-inflammatory drugs
(NSAIDs), and by traumatic or repeated puncture.
In decision-making on the interval between the last
administration of Orgaran 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 Orgaran 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 (numbness and weakness in lower limbs) and bowel or
bladder dysfunction. Nurses should be trained to detect such
signs and symptoms. 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.

4.5 Interactions with other Medicaments and other
forms of Interaction
In clinical studies no clinically significant interactions with other
medications have been found.

Orgaran may be used together with oral anticoagulants, drugs which
interfere with platelet function (such as aspirin and non-steroidal antiinflammatory drugs) or potentially ulcerogenic drugs (such as
corticosteroids), but caution remains necessary. This is particularly
important in patients undergoing peridural or spinal anaesthesia or
spinal puncture see section 4.4.
Monitoring of anticoagulant activity of oral anticoagulants by
prothrombin time and thrombotest is unreliable within 5 hours after
Orgaran administration.
There is no data available on the effect of Orgaran on thyroid function
tests.

4.6

Pregnancy and Lactation

Animal studies have not demonstrated any teratogenic effect or
placental transfer. There is no data available about Orgaran secretion
into breast milk.
In the few cases in which human umbilical cord blood was tested for
the presence of anti-Xa activity, no activity was found.
Although Orgaran has been used with success in a small number of
pregnancies, the available information is still considered to be
insufficient to assess whether deleterious effects may occur in
pregnancy during the use of Orgaran. Therefore Orgaran cannot be
recommended during pregnancy and lactation.

4.7

Effects on Ability to Drive and Use Machines

4.8

Undesirable Effects

Orgaran is not known to have any effect on the ability to drive and
use machines.
Enhanced bleeding or haematoma may occur at the operation site.
Bruising and/or pain may occur at injection sites.
Skin rashes and other local or generalised hypersensitivity reactions
have occasionally been observed.
Antibody induced thrombocytopenia, as can be caused by (low
molecular weight) heparin, was observed in rare cases during the use
of Orgaran, but only in patients who were already sensitised to either
heparin or low molecular weight heparin (see section 4.4)
Liver abnormalities such as changes in transaminase and alkaline
phosphatase have been observed, but no clinical significance has
been demonstrated.
Very rarely, cases of epidural and spinal haematomas were reported
in association with prophylactic use of heparins in the context of
peridural or spinal anaesthesia and of spinal puncture. These
haematomas have caused various degrees of neurological
impairment, including prolonged or permanent paralysis (see Section
4.4 ‘Special warnings and precautions for use’).

4.9 Overdosage

In the event of serious bleeding other than caused by a surgical error,
Orgaran should be stopped and a blood transfusion should be
considered. Although protamine partially neutralises the
anticoagulant activity of Orgaran the relevance for the reversal of the
bleeding is not clear and therefore cannot be recommended.

5

Pharmacological Properties

5.1 Pharmacodynamic Properties

Danaparoid sodium has been shown both in animal models and in
human studies to be an effective antithrombotic substance. At
therapeutic doses danaparoid sodium has no or only a minor effect on
haemostatic plug formation, platelet function and platelet
aggregability with no significant effect on bleeding time at the
recommended doses. Occasionally, after high intravenous or
subcutaneous doses, a prolonged bleeding time has been observed.
The anticoagulant activity of danaparoid sodium in clotting assays
such as prothrombin time, activated partial thromboplastin time,
kaolin cephalin clotting time and prothrombin time is small, and
characterised by a very flat dose-response curve up to relatively high
doses.
The ultimate step in blood coagulation, the fibrinogen-fibrin
conversion, is critically dependent on prothrombin generation to
which Factor Xa and thrombin contribute substantially. The
anticoagulant profile of danaparoid sodium is characterised by a high
ratio of anti-factor Xa/antithrombin activities, resulting in an effective
inhibition of thrombin generation and thrombus formation. The antiXa activity is mediated by antithrombin-lll and is not inactivated by
endogenous heparin-neutralising factors. The small antithrombin
activity is mediated by heparin co-factor ll and antithrombin-lll. The
heparan sulphate fraction with low affinity for antithrombin-lll, lacking
significant effects on coagulation factors Xa and lla in vitro, has been
shown in animal studies to contribute substantially to the
antithrombotic activity by an as yet unexplained mechanism.
Orgaran shows low cross-reactivity (< 10%) with the heparin induced
antibody. This can be explained by the absence of heparin in Orgaran
and its low degree of sulphation (see section 4.4).

5.2 Pharmacokinetic Properties

Pharmacokinetic studies have primarily been based on the kinetics of
relevant anticoagulant activities of danaparoid sodium, because no
specific chemical assay methods are available. In animal models the
time courses of the long-lasting anti-Xa and antithrombotic activities
of danaparoid sodium were strongly related.
The absolute bioavailability of danaparoid sodium after subcutaneous
administration approaches 100%. In humans the time to reach peak
plasma anti-Xa activity levels is approximately 4-5 hours.
The half-lives of elimination of anti-Xa and thrombin generation
inhibiting activities of approximately 25 hours and 7 hours
respectively, after both subcutaneous and intravenous administration
are independent of the dose. Steady-state levels of plasma anti-Xa
activity are usually reached within 4-5 days of dosing. Measured by
thrombin generation inhibiting activity steady-state levels are reached
earlier, i.e. within 1-2 days.
Danaparoid sodium is mainly eliminated by renal excretion and
animal experiments indicate that the liver is not involved in its
metabolism. In patients with severely impaired renal function the
half-life of elimination of plasma anti-factor Xa activity may be
prolonged.

5.3 Preclinical Safety Data

The results of pre-clinical studies do not add to the information
included in the outer sections of the SmPC.

6.

Pharmaceutical Particulars.

6.1 List of Excipients
Sodium sulphite
Sodium chloride
Water for injection

6.2 Incompatabilities

When administered as an intravenous bolus or infusion, Orgaran
should be given separately and not mixed with other drugs.
However, Orgaran is compatible with, and therefore can be added to,
infusions of saline, dextrose or dextrose-saline.

6.3 Shelf Life

See expiry date on packaging.

6.4 Special Precautions for Storage

Do not store above 30°C. Do not freeze.
Keep the ampoules in the outer carton to protect from light.

6.5 Nature and Contents of Container

1-ml glass ampoules containing 750 anti-factor Xa units (0.6ml)
danaparoid sodium per ampoule (1250 anti-factor Xa units/ml) in
packs of 10 or 20 ampoules.

6.6 Instructions for Use/Handling
See section 4.2

This product is manufactured by: N.V. Organon, 5340 BH Oss,
The Netherlands.
Procured from within the EU and repackaged by: Doncaster
Pharmaceuticals Group Ltd, Kirk Sandall, Doncaster, DN3 1QR.
Product Licence holder: Doncaster Pharmaceuticals Group Ltd,
Kirk Sandall, Doncaster, DN3 1QR.
PL No: 04423/0597
Orgaran® is a registered trademark of N.V. Organon.
Leaflet revision & issue date (Ref): 24.10.08

Final draft

Assessed against UK PIL dated April 2004
By whitneya at 7:38 am, Oct 27, 2008

Orgaran® Solution for injection/
Danaparoid Sodium 750 Anti-Xa Units/0.6ml
solution for injection
(danaparoid sodium)

Patient Information Leaflet
Your medicine is available using either of the above names but will
be referred to as Orgaran throughout this leaflet.
Read all of this leaflet carefully before you are given this medicine.




Keep this leaflet. You may need to read it again.
If you have further questions, please ask your doctor or your
pharmacist.
This medicine has been prescribed for you personally and you
should not pass it on to others. It may harm them, even if their
symptoms are the same as yours.

In this leaflet:
1.
2.
3.
4.
5.



What Orgaran is and what it is used for
Before you are given Orgaran
How Orgaran is given
Possible side effects
Storing Orgaran

The active substance is danaparoid sodium.
The other ingredients are sodium sulphite, sodium chloride and
water for injection.

Manufacturer:
Manufactured by: N.V. Organon, 5340 BH Oss, The Netherlands.
Procured from within the EU and repackaged by: Doncaster
Pharmaceuticals Group Ltd, Kirk Sandall, Doncaster, DN3 1QR.
Product Licence holder: Doncaster Pharmaceuticals Group Ltd, Kirk
Sandall, Doncaster, DN3 1QR.
POM

1.

PL No: 04423/0597

What Orgaran is and what it is used for

Orgaran is a clear, colourless, sterile, isotonic solution for injection
which is available in packs containing 10 or 20 ampoules.
Orgaran prevents the formation of blood clots in blood vessels
(thrombosis) and is used in patients who have an increased risk of
blood clot formation. Orgaran is supplied in glass ampoules.
Each ampoule contains 750 anti-Xa units of danaparoid sodium in
0.6ml.

2. Before you are given Orgaran
You should not be given Orgaran

If you suffer from or have ever had any of the following:
if you bleed easily
if you have had a stroke
if you are bleeding and it can’t be stopped
if you are allergic to Orgaran
if you are allergic to sulphite as this may rarely cause severe
hypersensitivity reactions and bronchospasm
if you have liver or kidney disease
if you have high blood pressure
if you have an active gastroduodenal ulcer
if you have damage to the retina of the eye due to diabetes
if you have an acute infection of the inner lining and valves of
the heart (acute bacterial endocarditis)
if you are pregnant or breast-feeding
if previous treatment with heparins (a group of medicines often
used for blood clots) caused a large drop in the number of blood
platelets (thrombocytopenia) and if a blood test showed that a
similar effect may happen with Orgaran.
Even so, your doctor may still decide to give you this medicine.
If you are receiving Orgaran to treat blood clots you should
not have a spinal or epidural anaesthetic.
You should tell your doctor before you are given Orgaran if you have
now or ever have had:
kidney or liver disease
peptic ulcer
a history of asthma or allergy (sodium sulphite may rarely
cause severe reactions and bronchospasm. Symptoms include:
tightening of the chest, swelling, itching or rash) as extra
supervision may be necessary.
Special care is also needed if you are receiving Orgaran for
the prevention of blood clots and you have to have a spinal or
epidural anaesthetic.

Pregnancy and breast-feeding

If you are pregnant, or suspect that you are pregnant or if you are
breast-feeding then tell your doctor. Your doctor will decide whether
Orgaran can be given to you.

Driving and using machines:

Orgaran is not known to have any effects on the ability to drive and
use machines.

Using other medicines

Other medicines may effect how Orgaran works or Orgaran may
affect how they work. Tell your doctor if you are taking (or intend to
take) other medicines, such as:
oral anticoagulants
aspirin or anti-rheumatics
steroids.

3. How Orgaran is given

The medicine is given as an injection under the skin or as an infusion
by your doctor or nurse. The normal dose is 750 units, twice-a-day,
for 7 to 10 days. Higher doses may be necessary in some patients.

If too much Orgaran is given:

When too much Orgaran is given unusual blood loss may occur.
This may be shown by:
nosebleeds, bleeding gums;
blackened stools (may indicate blood loss from stomach or
intestines);
blood in the urine;
unusually severe menstruation.

4. Possible side effects

Like all medicines, Orgaran can have side-effects.
Sometimes:
increased bleeding or swelling composed of blood at the
operation site (haematoma)
bruises and / or pain around the injection site.
Rarely:
Allergic reaction
rash
a large drop in the number of blood platelets
(thrombocytopenia)
change in liver blood tests
If you have any of these or any other side effects, tell your doctor.

Very rarely:

When Orgaran is used at the same time as spinal anaesthesia
or puncture, bruising of the spine may occur.
If you notice any of the following symptoms you should tell
your doctor or nurse IMMEDIATELY as you may require
treatment:
back pain
tingling, numbness or weakness in the legs
bowel or bladder problems

5. Storing Orgaran
Do not store above 30°C.
Do not freeze.
Keep the ampoules in the outer carton to protect from light.
Keep out of the reach and sight of children.
Do not use after the expiry date printed on the carton and
ampoule label.
Return any unused medicines to your pharmacist for safe
disposal.

6. More information about Orgaran

Orgaran contains a natural substance, derived from pig-intestine,
which prevents the formation of blood clots in blood-vessels
(thrombosis). It belongs to the group of medicines called antithrombotics. Blood clots which form in veins may restrict the blood
flow causing tissue to die. Parts of the clot are liable to break off
and may block the blood circulation in the lungs. A blood clot in the
lungs may be very serious.
Patients who are bedridden have an increased risk of clot formation
in the veins of the legs, especially if they have undergone an
operation.
These patients receive Orgaran to prevent the formation of blood
clots.
Orgaran® is a registered trademark of N.V. Organon.
Leaflet revision & issue date (Ref): 24.10.08

Final draft

Assessed against UK PIL dated December 2001

INFORMATION FOR THE DOCTOR

1. Trade name of the medicinal product
Orgaran® Solution for injection/
Danaparoid Sodium 750 Anti-Xa Units/0.6ml solution for injection
This medicine is available using the names Orgaran® Solution for
injection/ Danaparoid Sodium 750 Anti-Xa Units/0.6ml solution for
injection, but will be referred to as Orgaran throughout the leaflet.

2. Qualitative and Quantitative Composition
Orgaran contains danaparoid sodium, which is a mixture of low
molecular weight sulphated glycosaminoglycuronans derived from
animal mucosa, comprising heparan sulphate, dermatan sulphate and
a minor amount of chondroitin sulphate. One ml contains 1250
amidolytic anti-factor Xa units danaparoid sodium and 0.15% (w/v)
sodium sulphite.
The anti-Xa unit is derived from the international heparin standard in
an antithrombin-III containing buffer system.

3. Pharmaceutical form
Orgaran is supplied in ampoules containing 750 anti-Xa units (0.6ml),
as a sterile, isotonic solution of pH7 in water for injections.
Orgaran is administered by subcutaneous injection.

4. Clinical Particulars
4.1 Therapeutic indications

Prevention of deep vein thrombosis and its possible
consequences in patients undergoing general or
orthopaedic surgery.
Treatment of thrombo-embolic disorders in patients who
require urgent parenteral anti-coagulation because of the
development or history of heparin-induced
thrombocytopenia (HIT)

4.2 Posology and method of administration
a) Non-HIT patients (DVT prophylaxis)

In general Orgaran should be administered by
subcutaneous injection at a dose of 750 anti-factor Xa
units, twice daily for 7 to 10 days or until the risk of
thromboembolism has diminished.
In surgical patients it is recommended to start this dosing
pre-operatively and to give the last pre-operative dose 1 –
4 hours before surgery.
Plasma anti-Xa activity is linearly related to the dose of
Orgaran given. If it is necessary to monitor anticoagulant
activity, and for individual dose setting, a functional antifactor Xa test using a chromogenic peptide substrate
should be used. In this test Orgaran should be used as
standard for constructing the reference curve.

b)

HIT patients

The diagnosis of HIT should as a minimum be based on:
1) Thrombocytopenia (platelet count < 100 x 109/L)
occurring during heparin administration and
2) Exclusion of all other causes of thrombocytopenia
In general monitoring of plasma anti-Xa activity is
not necessary. However, in patient suffering from
renal insufficiency and/or patients weighing over
90kg, monitoring (using an amidolytic assay) is
recommended.
Orgaran should be administered intravenously as a
bolus of 2500 anti-Xa units (for patient less than
55kg 1250 units, if over 90kg, 3750 units) followed
by an intravenous infusion of 400 units/h for 2 hours,
then 300 units/h for 2 hours, then a maintenance
infusion of 200 units/h for 5 days.
The expected plasma anti-Xa levels are
0.5 - 0.7 units/ml, 5 – 10 minutes after the bolus,
not higher than 1.0 units/ml during the adjustment
phase of maintenance infusion and 0.5 – 0.8 units/ml
during the maintenance infusion.

Dosage in the elderly:

Clearance of anti-factor Xa activity has not been shown to be
markedly reduced in the elderly and the usual dosage is
recommended.

Children:

There is insufficient experience with the use of Orgaran in children to
suggest a dosage regimen for this group of patients.

Dosage in patients with moderately impaired renal
and/or liver function:

Orgaran should be used with caution in patients with moderately
impaired renal and/or liver function with impaired haemostasis.
Conversion to anticoagulants is possible, however it is advisable only
to start such a therapy once there is adequate antithrombotic control
with Orgaran.

By whitneya at 7:38 am, Oct 27, 2008
Oral anticoagulants can be given with the infusion (maximum rate
300 units/h) which can then be stopped when the international
normalised ratio is ≥ 1.5.
If the bleeding risk is high then either:
a)
Stop the infusion and start Orgaran 750 anti-Xa units
subcutaneously twice a day, then 24 hours later start
anticoagulants 48 – 72 hours before Orgaran is withdrawn to
give time for the prothrombin time, Thrombotest and
international normalised ratio to reach therapeutic levels
(measurement of these parameters is not reliable within 5 hours
of Orgaran injection (See interactions with other medicaments
and other forms of interactions)) or
b) Stop the infusion, give no further Orgaran then start the
anticoagulants 12 hours later.

4.3 Contra-indications

As with heparins, in patients receiving Orgaran for treatment
rather than for prophylaxis, locoregional anaesthesia in elective
surgical procedures is contraindicated.
severe haemorrhagic diathesis, e.g. haemophilia and idiopathic
thrombocytopenia purpura, unless the patient also has HIT and
no alternative anti-thrombotic treatment is available.
haemorrhagic stroke in the acute phase
uncontrollable active bleeding state
severe renal – and/or hepatic insufficiency, unless the patient
also has HIT and no alternative anti-thrombotic treatment is
available
severe hypertension
active gastroduodenal ulcer, unless it is the reason for operation
diabetic retinopathy
acute bacterial endocarditis
hypersensitivity to Orgaran
a positive invitro aggregation test for the heparin-induced
antibody in the presence of Orgaran in patients with a history of
thrombocytopenia induced by heparin or heparin-like
anticoagulants
hypersensitivity to sulphite.

4.4 Special Warnings and Special precautions for use

Orgaran should be used with caution in patients with moderately
impaired renal, and/or liver function with impaired haemostasis,
ulcerative lesions of the gastro-intestinal tract or other diseases which
may lead to an increased danger of haemorrhage into a vital organ or
site.
Orgaran contains sodium sulphite. In asthma patients
hypersensitive to sulphite the latter can result in bronchospasm
and/or anaphylactic shock.
Since Orgaran has been shown to have a low incidence (< 10%)
of (platelet) cross-reactivity with plasma from patients sensitised
by heparin, Orgaran can be used for these patients but it is
advisable to rule out cross-reactivity by an in vitro test. Because
the risk of antibody-induced thrombocytopenia is very small, it is
advisable to check the number of platelets regularly. If antibodyinduced thrombocytopenia occurs, one should stop the use of
Orgaran and consider alternative treatment.
Orgaran should not be given by the intramuscular route.
The safety and efficacy of Orgaran in patients with nonhaemorrhagic stroke remains to be confirmed.
No incidence of osteoporosis have been reported in patients
treated with the recommended dose of Orgaran. However, as for
heparin, treatment with glycosaminoglycuronan may result in
osteoporosis if the dosage is inappropriate.
It should be noted that the anti-Xa of Orgaran have a different
relationship to clinical efficacy than those of heparin and low
molecular weight heparins.
As with heparins, in patients undergoing peridural or spinal
anaesthesia or spinal puncture, the prophylactic use of Orgaran
may theoretically be associated with epidural or spinal
haematoma resulting in prolonged or permanent paralysis. The
risk is increased by the prolonged use of a peridural or spinal
catheter for analgesia, by the concomitant use of drugs affecting
haemostasis such as nonsteroidal anti-inflammatory drugs
(NSAIDs), and by traumatic or repeated puncture.
In decision-making on the interval between the last
administration of Orgaran 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 Orgaran 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 (numbness and weakness in lower limbs) and bowel or
bladder dysfunction. Nurses should be trained to detect such
signs and symptoms. 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.

4.5 Interactions with other Medicaments and other
forms of Interaction
In clinical studies no clinically significant interactions with other
medications have been found.

Orgaran may be used together with oral anticoagulants, drugs which
interfere with platelet function (such as aspirin and non-steroidal antiinflammatory drugs) or potentially ulcerogenic drugs (such as
corticosteroids), but caution remains necessary. This is particularly
important in patients undergoing peridural or spinal anaesthesia or
spinal puncture see section 4.4.
Monitoring of anticoagulant activity of oral anticoagulants by
prothrombin time and thrombotest is unreliable within 5 hours after
Orgaran administration.
There is no data available on the effect of Orgaran on thyroid function
tests.

4.6

Pregnancy and Lactation

Animal studies have not demonstrated any teratogenic effect or
placental transfer. There is no data available about Orgaran secretion
into breast milk.
In the few cases in which human umbilical cord blood was tested for
the presence of anti-Xa activity, no activity was found.
Although Orgaran has been used with success in a small number of
pregnancies, the available information is still considered to be
insufficient to assess whether deleterious effects may occur in
pregnancy during the use of Orgaran. Therefore Orgaran cannot be
recommended during pregnancy and lactation.

4.7

Effects on Ability to Drive and Use Machines

4.8

Undesirable Effects

Orgaran is not known to have any effect on the ability to drive and
use machines.
Enhanced bleeding or haematoma may occur at the operation site.
Bruising and/or pain may occur at injection sites.
Skin rashes and other local or generalised hypersensitivity reactions
have occasionally been observed.
Antibody induced thrombocytopenia, as can be caused by (low
molecular weight) heparin, was observed in rare cases during the use
of Orgaran, but only in patients who were already sensitised to either
heparin or low molecular weight heparin (see section 4.4)
Liver abnormalities such as changes in transaminase and alkaline
phosphatase have been observed, but no clinical significance has
been demonstrated.
Very rarely, cases of epidural and spinal haematomas were reported
in association with prophylactic use of heparins in the context of
peridural or spinal anaesthesia and of spinal puncture. These
haematomas have caused various degrees of neurological
impairment, including prolonged or permanent paralysis (see Section
4.4 ‘Special warnings and precautions for use’).

4.9 Overdosage

In the event of serious bleeding other than caused by a surgical error,
Orgaran should be stopped and a blood transfusion should be
considered. Although protamine partially neutralises the
anticoagulant activity of Orgaran the relevance for the reversal of the
bleeding is not clear and therefore cannot be recommended.

5

Pharmacological Properties

5.1 Pharmacodynamic Properties

Danaparoid sodium has been shown both in animal models and in
human studies to be an effective antithrombotic substance. At
therapeutic doses danaparoid sodium has no or only a minor effect on
haemostatic plug formation, platelet function and platelet
aggregability with no significant effect on bleeding time at the
recommended doses. Occasionally, after high intravenous or
subcutaneous doses, a prolonged bleeding time has been observed.
The anticoagulant activity of danaparoid sodium in clotting assays
such as prothrombin time, activated partial thromboplastin time,
kaolin cephalin clotting time and prothrombin time is small, and
characterised by a very flat dose-response curve up to relatively high
doses.
The ultimate step in blood coagulation, the fibrinogen-fibrin
conversion, is critically dependent on prothrombin generation to
which Factor Xa and thrombin contribute substantially. The
anticoagulant profile of danaparoid sodium is characterised by a high
ratio of anti-factor Xa/antithrombin activities, resulting in an effective
inhibition of thrombin generation and thrombus formation. The antiXa activity is mediated by antithrombin-lll and is not inactivated by
endogenous heparin-neutralising factors. The small antithrombin
activity is mediated by heparin co-factor ll and antithrombin-lll. The
heparan sulphate fraction with low affinity for antithrombin-lll, lacking
significant effects on coagulation factors Xa and lla in vitro, has been
shown in animal studies to contribute substantially to the
antithrombotic activity by an as yet unexplained mechanism.
Orgaran shows low cross-reactivity (< 10%) with the heparin induced
antibody. This can be explained by the absence of heparin in Orgaran
and its low degree of sulphation (see section 4.4).

5.2 Pharmacokinetic Properties

Pharmacokinetic studies have primarily been based on the kinetics of
relevant anticoagulant activities of danaparoid sodium, because no
specific chemical assay methods are available. In animal models the
time courses of the long-lasting anti-Xa and antithrombotic activities
of danaparoid sodium were strongly related.
The absolute bioavailability of danaparoid sodium after subcutaneous
administration approaches 100%. In humans the time to reach peak
plasma anti-Xa activity levels is approximately 4-5 hours.
The half-lives of elimination of anti-Xa and thrombin generation
inhibiting activities of approximately 25 hours and 7 hours
respectively, after both subcutaneous and intravenous administration
are independent of the dose. Steady-state levels of plasma anti-Xa
activity are usually reached within 4-5 days of dosing. Measured by
thrombin generation inhibiting activity steady-state levels are reached
earlier, i.e. within 1-2 days.
Danaparoid sodium is mainly eliminated by renal excretion and
animal experiments indicate that the liver is not involved in its
metabolism. In patients with severely impaired renal function the
half-life of elimination of plasma anti-factor Xa activity may be
prolonged.

5.3 Preclinical Safety Data

The results of pre-clinical studies do not add to the information
included in the outer sections of the SmPC.

6.

Pharmaceutical Particulars.

6.1 List of Excipients
Sodium sulphite
Sodium chloride
Water for injection

6.2 Incompatabilities

When administered as an intravenous bolus or infusion, Orgaran
should be given separately and not mixed with other drugs.
However, Orgaran is compatible with, and therefore can be added to,
infusions of saline, dextrose or dextrose-saline.

6.3 Shelf Life

See expiry date on packaging.

6.4 Special Precautions for Storage

Do not store above 30°C. Do not freeze.
Keep the ampoules in the outer carton to protect from light.

6.5 Nature and Contents of Container

1-ml glass ampoules containing 750 anti-factor Xa units (0.6ml)
danaparoid sodium per ampoule (1250 anti-factor Xa units/ml) in
packs of 10 or 20 ampoules.

6.6 Instructions for Use/Handling
See section 4.2

This product is manufactured by: N.V. Organon, 5340 BH Oss,
The Netherlands.
Procured from within the EU and repackaged by: Doncaster
Pharmaceuticals Group Ltd, Kirk Sandall, Doncaster, DN3 1QR.
Product Licence holder: Doncaster Pharmaceuticals Group Ltd,
Kirk Sandall, Doncaster, DN3 1QR.
PL No: 04423/0597
Orgaran® is a registered trademark of N.V. Organon.
Leaflet revision & issue date (Ref): 24.10.08

Expand Transcript

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.

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