1. Name Of The Medicinal Product
Calciparine, 25,000 IU Heparin activity per ml.
2. Qualitative And Quantitative Composition
Heparin Calcium 25,000 IU/ml
For excipients, see 6.1.
3. Pharmaceutical Form
Solution for injection.
Sterile clear solution of 25,000 International Units of Heparin activity per ml as the calcium salt in water for injections.
4. Clinical Particulars
4.1 Therapeutic Indications
It is indicated for use as an anticoagulant for the prophylaxis and treatment of thromboembolic phenomena, especially myocardial infarction, acute arterial embolism or thrombosis, deep vein thrombosis, thrombophlebitis or pulmonary embolism.
4.2 Posology And Method Of Administration
For subcutaneous administration only using a 26-gauge needle. The best site is the subcutaneous tissue of the lateral abdominal wall. The needle should be inserted perpendicularly into a pinched-up fold of skin and held gently but firmly within the skinfold until injection has been completed. Do not rub the site of injection.
Calciparine is not intended for intramuscular use.
Adults
Prophylaxis:
A standard prophylactic dose regimen is 5,000 IU by subcutaneous injection 2 hours before operation, followed by 5,000 IU by subcutaneous injection every 8 to 12 hours for seven days. In patients still confined to bed at the end of this period, the same dosage should be continued until they are ambulant.
The standard prophylactic dose following myocardial infarction is 5,000 IU by subcutaneous injection twice daily for 10 days or until the patient is mobile.
In other medical conditions in which there is an associated increased risk of thromboembolic phenomena, the same dosage is recommended.
These standard prophylactic regimens do not require routine control in the absence of contra-indications or conditions listed under special warnings and precautions.
If a myocardial infarction is shown to be anterior and therefore has a risk of mural thrombosis of the left ventricle, a higher dose of 12,500 IU twice daily for at least 10 days is recommended. For this dosage regimen, regular monitoring should be considered.
Treatment:
For the treatment of existing thrombosis the standard dose is 0.1ml Calciparine (2,500 IU) per 10kg body weight 12 hourly. To enable dosage to be individually adjusted to maintain a coagulation time in a range of 1.5 to 3 times that of control it is recommended that the thrombin clotting time, whole blood clotting time or the activated partial thromboplastin time be measured on blood withdrawn 5 to 7 hours after the first injection and then at intervals until the patient is stabilised. During long term therapy the test should be repeated at least once each week.
Children
Dosage should be individually adjusted according to changes in whole blood clotting time and/or thrombin clotting time and/or APTT. The initial dose should be 0.1ml Calciparine (2,500 IU) by subcutaneous injection for each 10kg of body weight. The usual interval between doses is 12 hours, but this also may require individual adjustment.
Other special groups
For both prophylaxis and treatment, higher doses are likely to be required in patients of abnormally high body weight and in those suffering from cancer, diabetes mellitus or other diseases associated with marked hypercoagulability. Lower doses are usually indicated in the elderly and in those with low serum albumin or impaired renal or hepatic function. In such patients coagulation times should be checked frequently and dosage adjusted accordingly.
Use in pregnancy
Heparin does not cross the placental wall; no malformation or foetotoxicity have been reported in humans. Nonetheless, particular caution should be exercised due to uteroplacental haemorrhagic risks, particularly at the time of delivery. Calciparine should be discontinued if peridural anaesthesia is likely. Individual control is essential and the aim should be to maintain plasma heparin levels between 0.1 and 0.4 units/ml, as assessed by anti-XA assay, and a whole blood clotting time of 15 to 20 minutes.
The standard prophylactic dosage of 5,000 IU by subcutaneous injection every 8 hours is a suitable starting dose in the first 3 or 4 months of pregnancy but higher doses are needed as pregnancy progresses, 10,000 IU two or three times daily being usual in the last trimester. Dosage must be reduced during labour and standard prophylactic dosage is suitable post-partum.
Heparin is not excreted into breast milk.
4.3 Contraindications
• hypersensitivity to heparin.
• history of thrombocytopenia occurring with any kind of heparin
• active bleeding or increased risk of haemorrhage in relation to haemostasis disorders, except for disseminated intravascular coagulation not induced by heparin.
• organic lesion likely to bleed (including gastric and duodenal ulcer).
• threatened abortion
• sub-acute infectious endocarditis.
• post-operative period following surgery of the brain, spinal cord and eye.
• haemorrhagic cerebral vascular accident.
• in patients receiving Calciparine for treatment rather than prophylaxis, locoregional anaesthesia in elective surgical procedures is contra-indicated.
• Calciparine should not be used in patients with advanced renal or hepatic dysfunction, in severe hypertension or patients in shock.
4.4 Special Warnings And Precautions For Use
4.4.1 Special warnings
Platelet count monitoring:
Platelet count must be performed before the treatment, and subsequently twice weekly; if a prolonged treatment is found to be necessary, this monitoring program must be respected, at least during the first month; after that time, monitoring can be carried out less frequently.
Some rare cases of thrombocytopenia, occasionally severe, have been reported; they may be associated (or not) with arterial or venous thrombosis, and the treatment should be discontinued; such diagnosis should be considered in the following cases:
• thrombocytopenia or,
• any significant decrease in platelet count (30 - 50% of the baseline value),
• worsening of the initial thrombosis while on therapy,
• thrombosis occuring on treatment,
• disseminated intravascular coagulation.
These effects are probably of immuno-allergic nature and in case of a first treatment they occur mainly between the 5th and the 21st day of therapy.
When a thrombocytopenia occurs with standard heparin, the substitution with a low molecular weight heparin may be considered if continuing the heparin treatment is necessary. In such cases, monitoring should be performed at least daily, and the treatment should be discontinued as soon as possible: initial thrombocytopenia continuing after substitution have been described.
In vitro platelet aggregation tests are only of limited value.
The concomitant use of salicylates, NSAIDs or antiplatelet agents represents a relative contra-indication for heparin administration (see 4.5, Interactions with Other Medicaments and Other Forms of Interactions).
4.4.2 Special precautions
Patients should be warned of an increased risk of bruising.
Administer with care in cases of:
• hepatic failure,
• renal failure,
• hypertension
• history of digestive ulcer or any other organic lesion likely to bleed,
• vascular diseases of the chorio-retina.
Special care should be taken in elderly patients and pregnant women.
Heparin can suppress adrenal secretion of aldosterone leading to hyperkalaemia, particularly in patients with a raised plasma potassium or at risk of increased plasma potassium levels such as patients with diabetes mellitus, chronic renal failure, pre-existing metabolic acidosis or taking drugs that may increase plasma potassium (e.g. ACE inhibitors, NSAIDs).
The risk of hyperkalaemia appears to increase with duration of therapy but is usually reversible. Plasma potassium should be monitored in patients at risk.
In patients undergoing peridural or spinal anaesthesia or spinal puncture, the prophylactic use of Calciparine may be very rarely associated with epidural or spinal haematoma resulting in prolonged or permanent paralysis. The risk is increased by the use of a peridural or spinal catheter for anaesthesia, by the concomitant use of drugs affecting haemostasis such as nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors or anticoagulants, and by traumatic or repeated puncture.
In decision-making on the interval between the last administration of Calciparine 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 anticoagulation 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 clinician if they experience any of these.
If signs or symptoms of epidural or spinal haematomas are suspected, urgent diagnosis and treatment including spinal cord decompression should be initiated.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Concomitant use of aspirin (or other salicylates), non-steroidal anti-inflammatory drugs, or the use of antiplatelet agents (see 4.4.1, Special warnings) is not recommended, as they may increase the risk of bleeding.
Where such combination cannot be avoided, careful clinical and biological monitoring should be undertaken.
Calciparine should be administered with care in patients receiving oral anticoagulant agents (additive anticoagulant effect), systemic corticosteroids (gluco-) and dextrans (parenteral administration).
During transfer from heparin to oral anticoagulant therapy, clinical monitoring should be particularly vigilant.
4.6 Pregnancy And Lactation
Pregnancy
Heparin does not cross the placental wall; no malformation or foetotoxicity have been reported in humans. Nonetheless, particular caution should be exercised due to uteroplacental haemorrhagic risks, particularly at the time of delivery. Calciparine should be discontinued if peridural anaesthesia is likely.
Lactation
Heparin is not excreted into breast milk.
4.7 Effects On Ability To Drive And Use Machines
None stated.
4.8 Undesirable Effects
Adverse reactions have been ranked under heading of system-organ class and frequency using the following convention: very commonly (>= 1/10); commonly (>= 1/100, <1/10); uncommonly (>= 1/1,000, <1/100); rarely (>= 1/10,000, <1/1,000); very rarely (<1/10,000).
Haematological and bleeding disorders:
• Very commonly: haemorrhagic manifestations at various sites, more frequent in patients with other risk factors (see Section 4.3 Contra-indications and Section 4.5 Interactions with Other Medicaments and Other Forms of Interaction).
• Commonly: thrombocytopenia, usually reversible, sometimes thrombogenic (see Section 4.4.1 Special warnings).
• Rarely: eosinophilia, reversible following treatment discontinuation.
• Very rarely: epidural or spinal haematoma in the context of peridural or spinal anaesthesia and of spinal puncture. These haematomas have caused various degrees of neurological impairment, including prolonged and permanent paralysis. (see Section 4.4.2 Special precautions).
Cutaneous and subcutaneous disorders:
• Very commonly: small hematomas at the injection site. In some cases, the emergence of firm nodules which do not indicate an encystment of the heparin may be noted. These nodules usually disappear after a few days and are not an indication to withdraw treatment. Pain and bruising may also occur.
• Uncommonly: localised or generalized hypersensitivity reactions, including angioedema, erythema, rash, urticaria, pruritus.
• Rarely: cutaneous necrosis usually occuring at the injection site. It is preceded by purpura or infiltrated or painful erythematous blotches, with or without systemic signs. In such cases, treatment should be immediately discontinued.
• Very rarely: Alopecia, calcinosis at injection site, especially in patients with severe renal failure
Hepato-biliary disorders:
• Commonly: raised transaminases, usually transient.
Metabolism and nutrition disorders:
• Rarely: osteoporosis after several months of treatment, at high doses.
• Very rarely: hypoaldosteronism with hyperkaliemia and / or metabolic acidosis particularly in patients at risk (diabetes, renal failure) (see Section 4.4 Special Warnings and Special Precautions for Use).
Reproductive disorders:
• Rarely: priapism
4.9 Overdose
Haemorrhage is the major clinical sign of overdosage. In case of bleeding, the platelet count and APTT should be determined. Minor bleeding rarely requires specific therapy, and reducing and/or delaying subsequent doses of Calciparine is usually sufficient.
The anticoagulant effect of heparin can be reversed immediately by intravenous administration of a 1% protamine sulphate solution. The dose of protamine sulphate required for neutralisation should be determined accurately by titrating the patient's plasma.
It is important to avoid overdosage of protamine sulphate because protamine itself has anticoagulant properties. A single dose of protamine sulphate should never exceed 50mg. Intravenous injection of protamine may cause a sudden fall in blood pressure, bradycardia, dyspnoea and transitory flushing, but these may be avoided or diminished by slow and careful administration.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Antithrombotic agent.
ATC Code: B01 AB01
Heparin calcium is a preparation containing the calcium salt of sulphated polysaccharide acid present in mammalian tissues. It is an anticoagulant which inhibits the clotting of blood in vitro and in vivo.
No further data are presented here as the pharmacodynamic properties of heparin calcium are well known and it is the subject of a European Pharmacopoeial monograph.
5.2 Pharmacokinetic Properties
The slow and regular absorption kinetics of calciparine (or similar calcium heparins) given subcutaneously make it especially suitable for low dose prophylactic therapy. Calciparine has been used effectively in the routine prophylaxis of postoperative thromboembolism.
No further data are presented here as the properties of heparin calcium are well known. Heparin calcium is the subject of a European Pharmacopoeial monograph.
5.3 Preclinical Safety Data
There is no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Water for injection, hydrochloric acid and calcium hydroxide solution.
6.2 Incompatibilities
Other preparations should not be mixed with Calciparine.
6.3 Shelf Life
48 months.
6.4 Special Precautions For Storage
Do not store above 25oC. Do not freeze.
6.5 Nature And Contents Of Container
Unit dose disposable syringe 5,000 IU in 0.2ml
6.6 Special Precautions For Disposal And Other Handling
Refer to Section 4.2 Posology and Method of Administration.
7. Marketing Authorisation Holder
Sanofi–Synthelabo Ltd
One Onslow Street
Guildford
Surrey GU1 4YS
8. Marketing Authorisation Number(S)
11723/0011
9. Date Of First Authorisation/Renewal Of The Authorisation
6th November 1998/23rd January 2003
10. Date Of Revision Of The Text
September 2004
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