Download Heparin Sodium-Fresenius 5,000 IU/1 ml (Injection)

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1. PROPRIETARY NAME (AND DOSAGE FORM)
Heparin Sodium-Fresenius
5,000 IU/1 ml (Injection)
2.
COMPOSITION
5 ml vial containing 5,000 IU /1 ml Heparin Mucosal
Preservative: Chlorocresol 0.1% m/v
Water for injection to 1 ml
Heparin is obtained from porcine intestinal mucosa.
3. PHARMACOLOGICAL CLASSIFICATION
A 8.2 Anticoagulants.
4. PHARMACOLOGICAL ACTION
Heparin inhibits the clotting of blood both in vitro and in vivo. Whole blood
clotting time, thrombin time and one-stage prothrombin time are prolonged,
and thromboplastin generation is abnormal. Clotting time is proportional to
the concentration of the medicine in the blood. However, with therapeutic
doses bleeding time is usually unaffected and a patient can carry on normal
activities, such as shaving, without danger of bleeding. The anticoagulant
action of heparin requires the presence of a plasma a-globulin, referred
to as “heparin cofactor”, a substance that appears to be identical with
normal plasma antithrombin (antithrombin III). Heparin does not block
prothrombin synthesis in the liver as do the oral anticoagulants but it does
inhibit factors involved in the conversion of prothrombin to thrombin. This
action is probably exerted by the facilitation of the formation of complexes
of the heparin cofactor (antithrombin) with each of the four activated
proteases of the coagulation cascade (activated factors IX, X, XI and XII).
A similar heparin-stimulated reaction also occurs between antithrombin
and thrombin. The detailed mechanism of this phenomenon may involve
a heparin-induced conformational change of the inhibitor. It requires 30
to 40 times more heparin to inhibit the action of formed thrombin than it
does to prevent thrombin formation.
Therefore the prevention of thrombin formation is probably its primary effect.
Heparin is not effective after oral or sublingual administration, but it is well
absorbed after subcutaneous injection. In the blood it is evenly distributed
between white cells and plasma. Heparin disappears exponentially from
the circulation at a rate dependent upon the dose. The half-lives of 100,
200 and 400 units/kg, injected intravenously, are 56, 96 and 152 minutes
respectively. Heparin is metabolized by the liver and a partially degraded,
weakly active form of heparin (uroheparin) is excreted in the urine; after very
large intravenous doses, up to 50% of nonmetabolized heparin may appear
in the urine. The exact mechanism of renal elimination is unknown.
5. INDICATIONS
Heparin is used as an anticoagulant in the treatment of arterial and
venous thrombosis and prevention of thromboembolic complications after
surgery.
6. CONTRAINDICATIONS
Heparin sodium should not be used in patients with severe thrombocytopenia,
in whom suitable blood coagulation tests e.g. the whole blood clotting time,
partial thromboplastin time, etc. could not 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). Heparin sodium should not be used in patients with an uncontrollable
active bleeding state, except when this is due to disseminated intravascular
coagulation.
Conditions where hemorrhage is a particular risk:
• Aneurysm, cerebral or aortic
• Risk of abortion
• Recent childbirth
• Pericarditis
• Severe vasculitis
• Active cavitating tuberculosis
• Visceral carcinoma if there is a possibility of intracranial metastasis
• Peptic ulceration
• During or after eye, brain or spinal cord surgery or trauma
• Prior to lumbar puncture or regional anesthetic block
• Surgical or traumatic wounds resulting in large open surfaces
• Severe renal function impairment
• Severe hepatic function impairment
• Esophageal varices
• Subacute bacterial endocarditis
7.
Hypersensitivity:
Avoid use in hypersensitive patients unless benefits outweigh risks.
WARNINGS
Heparin should not be used for intramuscular injection.
Due to the danger of physical/chemical incompatibilities, heparin may not
be administered drawn up with other medication in a hypodermic syringe
or an infusion.
Hemorrhage:
Hemorrhage can occur at any site in patients receiving heparin. In the event of
an unexplained fall in hematocrit or blood pressure or any other unexplained
symptom, consideration must be given to possible hemorrhage.
Heparin must be used cautiously in patients suffering from diseases with
a hemorrhage risk for example:
• Cardiovascular: severe/uncontrolled hypertension
• Surgical: during and immediately following spinal tap, spinal anesthesia
or major surgery involving the brain, spinal cord or eye
• Hematologic: conditions associated with increased bleeding tendencies
such as hemophilia, thrombocytopenia or vascular purpuras
• Gastrointestinal: ulcerative lesions and continuous tube drainage of
stomach or small intestine
• Other: menstruation, liver disease with impaired hemostasis
Coagulation testing:
Frequent blood coagulation tests must be performed on patients receiving
heparin and the product discontinued if necessary.
Thrombocytopenia:
Thrombocytopenia has been reported to occur in patients receiving
heparin with a reported incidence of 0 to 30%. Platelet counts should be
obtained at baseline and periodically during heparin administration. Mild
thrombocytopenia (count greater than 100,000/mm3) may remain stable or
reverse even if heparin is continued. If the count falls below 100,000/mm3 or
if recurrent thrombosis develops (see Heparin-induced Thrombocytopenia and
Heparin-induced Thrombocytopenia and Thrombosis), the heparin product
should be discontinued and, if necessary, an alternative anticoagulant
administered.
Heparin-induced Thrombocytopenia (HIT) and Heparin-induced
Thrombocytopenia and Thrombosis (HITT): HIT is a serious antibodymediated reaction resulting from irreversible aggregation of platelets. HIT
may progress to the development of venous and arterial thromboses, a
condition referred to as HITT. Thrombotic events may also be the initial
presentation for HITT. These serious thromboembolic events include deep
vein thrombosis, pulmonary embolism, cerebral vein thrombosis, limb
ischemia, stroke, myocardial infarction, mesenteric thrombosis, renal arterial
thrombosis, skin necrosis, gangrene of the extremities that may lead to
amputation and possibly death.
Delayed onset of HIT and HITT: HIT and HITT can occur up to several
weeks after discontinuation of heparin therapy. Patients presenting with
thrombocytopenia or thrombosis after discontinuation of heparin treatment
should be evaluated for HIT and HITT.
8. INTERACTIONS
Other platelet aggregation inhibitors:
Aspirin, sulfinpyrazone: inhibition of platelet function by these agents may
lead to hemorrhage because it impairs a homeostatic mechanism on which
heparin treated patients depend to prevent bleeding, hypoprothrombinemia
induced by large [antirheumatic] doses of aspirin, and the potential occurrence
of gastrointestinal ulceration or hemorrhage during therapy with NSAIDs,
aspirin, sulfinpyrazone, ticlopidine or clopidogrel may also cause increased
risk of bleeding in patients receiving heparin therapy.
Cefamandole or cefoperazone or cefotetan or plicamycin or valproic acid:
these medications may cause hypoprothrombinemia, in addition, plicamycin
or valproic acid may inhibit platelet aggregation; concurrent use with heparin
may increase the risk of hemorrhage and is not recommended.
Methimazole or propylthiouracil: these medications may cause
hypoprothrombinemia (which may enhance the anticoagulant effect of
heparin and increase the risk of bleeding).
Probenecid: probenecid may increase and prolong the anticoagulant effect
of heparin.
Thrombolytic agents:
Alteplase: (tissue-type plasminogen activator, recombinant), antistreptase
(anisoylated plasminogen-streptokinase activator complex; APSAC),
streptokinase, urokinase: concurrent or sequential use with heparin increases
the risk of bleeding complications; although heparin is sometimes given
before, and is usually given to decrease the risk of re-occlusion following
thrombolytic therapy, caution and especially careful monitoring of the
patient is recommended.
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Nitroglycerine: intravenous infusion of nitroglycerine might cause a
reduction of the effectiveness of heparin, therefore close controls of partial
thromboplastin time (PTT) together with heparin dosage adjustment are
required.
When alkaline medications such as tricyclic psychotropics, antihistamines
and quinine are concomitantly administered, salt formation with heparin
can cause loss of efficacy of both drugs.
Heparin shows numerous interactions with other preparations, whose
clinical significance is being evaluated differently.
9. PREGNANCY AND LACTATION
Heparin does not cross the placenta and therefore adverse effects to the
fetus would not be expected. Heparin is considered safer to the fetus than
warfarin when used during pregnancy.
Heparin has not been shown to cause birth defects or bleeding problems in
the baby. However, use during the last three months of pregnancy or during
the month following the baby’s delivery may cause bleeding problems in
the mother, and therefore monitoring is required.
The use of epidural anesthesia during labor, for women being medically
treated for anticoagulation, is absolutely contraindicated.
Heparin does not pass into breast milk.
10. DOSAGE AND DIRECTIONS FOR USE
Heparin Sodium-Fresenius is given intravenously, preferably by continuous
infusion, or by deep subcutaneous injection.
The usual practice is to give an initial intravenous injection of 12,500 units
of heparin, followed by doses of 10,000 units every 4 hours to maintain
the clotting time, tested not less than 3 hours after the last injection, at
about 3 times the pretreatment figure. The dose for this purpose usually
ranges from 6,000 to 12,000 units. For continuous infusion 10,000 to
20,000 units of heparin is added to 1 liter of Dextrose injection or Sodium
chloride injection and started at about 20 drops per minute.
A suggested initial dose for children is 50 units per kg body mass by intravenous
infusion in Dextrose injection 5% increased to 100 units per kg every 4
hours to keep the clotting time at 20 to 30 minutes.
It is advisable to only use high grade needles with a gauge of 22 to 25, when
extracting from the vial. DO NOT USE PREVIOUSLY USED NEEDLES. Pain at
the site of injection may be minimized by the addition of 2% solution of
procaine hydrochloride. If blood transfusions are required during anticoagulant
therapy, 3 units of heparin per ml may be added to the transfused blood
in addition to the dose already being administered. Bleeding from the site
of operation is unlikely if heparin is started after the fourth postoperative
day.
For treatment of venous thromboembolism: an intravenous loading dose
of 5,000 units (10,000 may be required in severe pulmonary embolism) is
followed by continuous intravenous infusion of 1,000 to 2,000 units/hour
or subcutaneous injection of 15,000 units every 12 hours. Alternatively,
intermittent intravenous dose of 5,000 to 10,000 units every 4 to 6 hours
undiluted or diluted in 50 to 100 ml of Dextrose 5% in water or Sodium
Chloride 0.9% is suggested.
Children and adolescents are given a lower intravenous dose followed by
maintenance with continuous infusion of 15-25 units/kg/hour or subcutaneous
injection of 250 units/kg every 12 hours.
For prophylaxis of postoperative venous thrombo-embolism:
subcutaneous doses used are 5,000 units 2 hours before surgery then 8-12
hours for 7 days or until the patient is ambulant. Similar doses are used to
prevent thromboembolism during pregnancy in women with a history of
deep-vein thrombosis or pulmonary embolism; the dose may need to be
increased to 10,000 units every 12 hours during the third trimester.
11. SIDE EFFECTS AND SPECIAL PRECAUTIONS
Side-effects:
Heparin can give rise to hemorrhage as a consequence of its action. It can
also cause thrombocytopenia, either through a direct effect or through an
immune effect producing a platelet-aggregating antibody. Consequent
platelet aggregation and thrombosis may therefore exacerbate the condition
being treated.
Heparin-induced Thrombocytopenia (HIT) and Heparin-induced
Thrombocytopenia and Thrombosis (HITT) and delayed onset of HIT and
HITT may occur. Discontinuation of heparin therapy with immediate corrective
treatment action is required if this happens. The patient must be informed
that he must not be treated with drugs containing heparin in the future.
Adrenal hemorrhage with subsequent acute adrenal insufficiency, can occur.
Discontinuation of heparin therapy with immediate corrective treatment
action is required if this happens.
Ovarian hemorrhage has occurred in women of reproductive age receiving short
to long-term therapy. This can be fatal if not recognized and treated.
Retroperitoneal hemorrhage can occur even if clotting time is not prolonged.
Hypersensitivity reactions may occur, as may local irritant effects, and
skin necrosis. General hypersensitivity reactions may manifest as chills,
fever, urticaria, asthma, rhinitis, lacrimation, headache, nausea, vomiting,
articular pains, pruritus, dyspnea, bronchospasm, decrease of blood pressure,
anaphylactoid reactions including shock. Itching and burning, especially on
plantar side of feet, may occur.
Alopecia and osteoporosis resulting in spontaneous fractures have occurred
after prolonged use of heparin.
Increased liver transaminases level may occur.
Special precautions:
Since heparin has caused thrombocytopenia with severe thromboembolic
complications, platelet counts should be monitored in patients receiving
heparin for more than a few days.
A test dose has been recommended for patients with a history of allergy.
Heparin inhibits the secretion of aldosterone which may cause hyperkalemia.
Plasma potassium levels should be monitored in those patients who are
susceptible to hyperkalemia (for example: patients who are concomitantly
treated with drugs that increase serum potassium level, diabetes mellitus,
etc.), especially when receiving heparin for more than 7 days. The problem
is normally resolved with the discontinuation of heparin.
Priapism has been associated with heparin administration.
Dosage of heparin may need to be reduced in old people; elderly
women appear to be especially susceptible to hemorrhage after heparin
administration.
Heparin resistance: Increased resistance to heparin is frequently encountered in
fever, thrombosis, thrombophlebitis, infections with thrombosing tendencies,
myocardial infarction, cancer and in post-surgical patients.
12. KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS
TREATMENT
The chief side-effect of heparin is hemorrhage. Careful laboratory control
is necessary. Bleeding may be encountered from an unsuspected lesion,
such as a peptic ulcer. The hemorrhagic complications recorded include
hematuria, hemarthrosis, wound hematoma and gastrointestinal bleeding.
The hemorrhage may produce a hematoma in the surgical wound, but
this is rarely serious if infection is prevented and larger accumulations of
blood are aspirated. Mild effects of heparin overdosage usually respond to
simple withdrawal of the medicine. When clinical circumstances (bleeding)
require reversal of neutralization of heparin effect the use of the specific
heparin antagonist, protamine sulphate, by slow infusion is imperative. No
more than 50 mg should be administered, very slowly, in any 10 minutes
period. 1 mg of protamine sulphate neutralizes approximately 100 IU of
heparin. The amount of protamine required decreases over time as heparin
is metabolized. Although the metabolism of heparin is complex, it may,
for the purpose of choosing a protamine dose, be assumed to have a half
life of about half an hour after intravenous injection. Nevertheless, the
required protamine sulphate dose varies according to the time of heparin
administration and dose administered. It is important to avoid overdosage
of protamine sulphate because protamine sulphate itself has anticoagulant
properties. For additional information see the labeling of protamine sulphate
injection products.
13. IDENTIFICATION
A clear colorless or straw-colored liquid in amber glass vials, free from
turbidity and from matter which deposits on standing.
14. PRESENTATION
1 ml and 5 ml amber glass vials packed in packs of 10.
15. STORAGE INSTRUCTIONS
Store below 25ºC. Do not freeze.
Keep out of reach of children.
16. REGISTRATION NUMBERS
Heparin Sodium-Fresenius 5,000 IU /1 ml 105.41.28959.00
17. NAME AND BUSINESS ADDRESS OF MANUFACTURER
BODENE (PTY) LIMITED trading as Intramed
6 Gibaud Road
Port Elizabeth 6001
South Africa
18. IMPORTER
Trima Israel Pharmaceutical Products Maabarot Ltd.,
Maabarot 4023000, Israel
For Medic-Trim Healthcare Ltd.
The format of this leaflet was determined by the Ministry of Health and its
content was checked and approved by it.
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9207910 PL 0113D