CALCIPARINE 7500 IU/0,3 ml subcutaneous injection solution in prefilled syringe 2Syringe/0,3ml

Solution for injection in pre-filled syringe.

Each prefilled syringe contains 7 500 IU of calcium heparin* in 0,3 mL of injectable solution, corresponding to 25 000 IU/mL.

*produced from porcine intestinal mucosa.

Excipients:

This heparin is a classic heparin, called unfractionated. Its indications are as follows:

• Treatment:

• Established deep vein thromboses and pulmonary embolism, in the acute phase.
• Myocardial infarction with or without Q wave and unstable angina, in the acute phase.
• Extracerebral arterial embolisms.

• Prevention of venous thromboembolic events:

• In surgical settings.
• In bedridden patients presenting with an acute medical condition (notably post-infarction, in cases of heart failure, after an ischemic stroke with paralysis of the lower limbs). Use is in this case reserved for severe renal insufficiency (creatinine clearance of the order of less than 30 mL/min according to the estimate from the Cockcroft formula) as a possible alternative to the prescription of a low molecular weight heparin.

Dosage

The concentration of this heparin is 25 000 IU/mL. As not all heparins are at the same concentration, prescriptions must be written in IU.

a) Curative treatment

Dosing regimen

This heparin must be administered subcutaneously.

A bolus of 50 to 100 IU/kg IV of sodium heparin may be administered at the same time as the first subcutaneous injection, by direct intravenous route, to achieve an effective heparinemia from the start of treatment.

The initial dose is 500 IU/kg every 24 hours by subcutaneous route, divided into two (every 12 h) or three (every 8 h) injections per day, depending on the volume to be injected. Indeed, subcutaneous injection of a volume greater than 0,6 mL could reduce heparin absorption.

The heparin dose will then be adjusted according to the results of biological monitoring.

Biological monitoring

It must be performed at least daily, the first sampling must take place exactly between the first two injections (i.e. 6 or 4 hours after the first, depending on whether 2 or 3 injections are planned during the day). A sample must be taken after each dose modification.

Depending on the case, the following may be used:

• The activated partial thromboplastin time (aPTT) should be between 1 and a half to three times the control, depending on the sensitivity of the reagent used (to be defined by the laboratory).

• Anti-Xa activity (heparinemia), which is a specific test. It should be between 0,2 and 0,6 IU/mL. This test will be preferred in cases of pre-existing aPTT abnormalities, in intensive care patients and in cases of marked inflammatory syndrome.

Bridging from heparin to oral anticoagulants (VKA)

Whenever possible, VKAs (Vitamin K Antagonists) will be introduced between the first and third day of treatment, so that the total duration of heparin therapy does not exceed 7 to 10 days.

Due to the latency period preceding the full effect of the VKA used, heparin will only be discontinued when the INR (International Normalized Ratio) has been within the desirable therapeutic range for 2 consecutive days. This range varies depending on the condition being treated.

During this period, aPTT monitoring will be particularly careful to avoid a risk of haemorrhage.

b) Prevention of venous thromboembolic events

In surgical settings

A standard therapeutic regimen may be proposed for patients undergoing general, digestive, urological, or gynecological surgery: 5000 IU of subcutaneous heparin 2 hours before the procedure, then 5000 IU every 12 hours for at least 10 days after the procedure. Biological monitoring is not essential.

In certain medical situations

The usual dosage is 5000 IU every 12 hours.

In case of high thromboembolic risk In a surgical or medical setting, the dosage may possibly be increased to 5 000 IU 3 times per day and adjusted so as to produce a moderate prolongation of the aPTT (1,2 to 1,3 times the control time), when the sample is taken midway between two injections. In practice, it is recommended to prefer the use of a LMWH over this complex regimen.

Heparin resistance

Some patients exhibit heparin resistance, i.e. an alteration of the response to heparin, requiring abnormally high doses of heparin to achieve the desired anticoagulant effect (see section Warnings and precautions).

Method of administration

STRICTLY SUBCUTANEOUS ROUTE.

Do not inject intramuscularly.

Injection technique

The injection must be performed into the subcutaneous cellular tissue of the antero-lateral and postero-lateral abdominal belt, alternating between the right and left sides.

The needle must be inserted perpendicularly and not tangentially, into a skin fold formed between the operator's thumb and index finger. The fold must be maintained throughout the duration of the injection.

• Whatever the doses (therapeutic or prophylactic), this medicine MUST NOT BE PRESCRIBED in the following situations:

• Hypersensitivity to heparin or to any of the excipients listed in section Composition.
• History of severe type II thrombocytopenia (heparin-induced thrombocytopenia or HIT), under unfractionated heparin or low molecular weight heparin (see section Warnings and precautions - HIT).
• Constitutional haemorrhagic diseases.
• In case of treatment with direct-acting oral anticoagulants DOACs (apixaban, edoxaban, rivaroxaban, etc.) (see section at a curative dose, in the following situations: Interactions).

• At a therapeutic dose, in the following situations:

• Organic lesion likely to bleed.
• Haemorrhagic manifestations or tendencies related to haemostasis disorders.
• Intracerebral haemorrhage.
• In addition, epidural or spinal anaesthesia must never be performed during treatment with heparin at a curative dose.

• At a therapeutic dose, this medicine is GENERALLY NOT RECOMMENDED in the case of:

• Extensive acute-phase ischaemic stroke, with or without impaired consciousness. When the stroke is of embolic origin, the delay is 72 hours. Evidence of the efficacy of heparin at a curative dose has not been established to date, regardless of the cause, extent and clinical severity of the cerebral infarction.
• Acute infectious endocarditis (other than that occurring on a mechanical prosthesis).
• Uncontrolled arterial hypertension.

• Prophylactic use of this medicine is GENERALLY NOT RECOMMENDED within 24 hours following an intracerebral haemorrhage.

• Regardless of dose, the following medicines are GENERALLY NOT RECOMMENDED in combination with heparin (see section Interactions) :

• defibrotide,
• acetylsalicylic acid (as an analgesic and antipyretic),
• NSAIDs,
• dextran.

Warnings

When a patient on heparin (at a curative or preventive dose) presents with a thrombotic event, such as:

• An ischaemic stroke.

• A myocardial infarction.

• Acute ischaemia of the lower limbs.

• A pulmonary embolism.

• Phlebitis.

• A worsening of the thrombosis for which he/she is being treated.

Heparin-induced thrombocytopenia (HIT) should always be considered, and a platelet count should be performed urgently (see section "Warnings and precautions").

In the case of spinal anaesthesia, the injection of the prophylactic dose of heparin must be given 6 hours after the intraspinal catheters have been removed.

The benefit-risk ratio of administering a low dose of heparin before an intrathecal or epidural loco-regional anaesthesia must be assessed for each patient. The risk of developing an epidural haematoma depends on the technique used and the experience of the operator. It increases in the following order:

• Spinal anaesthesia without catheter.

• Spinal anaesthesia with catheter placement.

• Epidural anaesthesia.

• Epidural anaesthesia with catheter placement.

A higher incidence of bleeding has been reported in patients, particularly in elderly women.

Precautions for use

Risk situations

Treatment monitoring will be reinforced in cases of a history of peptic ulcers, vascular chorioretinal diseases, or in the postoperative period following brain and spinal cord surgery.

Lumbar puncture should be considered taking into account the risk of intraspinal bleeding. It should be deferred whenever possible.

Heparin may inhibit aldosterone secretion and lead to rare cases of hypoaldosteronism with hyperkalemia and/or metabolic acidosis. This has been observed particularly in patients with elevated potassium levels and in patients at risk (diabetics, patients with chronic renal insufficiency, pre-existing metabolic acidosis, treatment with medicinal products likely to increase potassium levels such as ACE inhibitors and NSAIDs).

The risk of hyperkalemia increases with the duration of treatment and is usually reversible. In cases of prolonged treatment, monitoring of potassium levels may be performed in patients at risk.

Platelet monitoring

Due to the risk of HIT, monitoring of the platelet count is necessary regardless of the indication for treatment and the dose administered.

Perform a platelet count before treatment, then twice weekly during the first month. Beyond this period, if prolonged treatment proves necessary in certain specific cases, the monitoring frequency may be reduced to once weekly, until treatment is discontinued.

Heparin-induced thrombocytopenia or HIT

There is a risk of severe thrombocytopenia, which may be fatal, sometimes thrombotic, induced by heparin (unfractionated heparin and less frequently low molecular weight heparins), of immunological origin known as type II (see section Adverse effects). HIT is defined by a platelet count < 100 000 and/or a relative platelet drop of 30 to 50 % over 2 successive counts. These effects are caused by platelet-activating antibodies and occur essentially between the 5th and the 21th day following initiation of heparin treatment (with a peak frequency around day 10th ) but may occur much earlier when there is a history of heparin-induced thrombocytopenia. For this reason, these must be systematically sought during a thorough interview before starting treatment. Furthermore, the risk of recurrence upon reintroduction of heparin may persist for several years, or even indefinitely (see section Contraindications).

In rare cases, delayed heparin-induced thrombocytopenia (HIT), possibly associated with thrombosis, may occur after discontinuation of heparin treatment and persist despite alternative anticoagulation.

In all cases, the onset of HIT constitutes an emergency situation and requires specialist advice.

Any significant decrease (30 to 50 % of the initial value) in the platelet count should prompt an alert, even before this value reaches a critical threshold. The observation of a decrease in the number of platelets requires in all cases:

1) Immediate check of the platelet count by performing HIT probability tests (for example, the 4 T score).

2) Discontinuation of heparin treatment, if the drop is confirmed or even worsens on this check.

Under the conditions described above, the immediate course of action does not rely on the result of platelet aggregation tests in vitro or immunological tests; indeed, the result is obtained at best only after several hours. These tests must nevertheless be performed to help diagnose this complication. If heparin treatment is continued, the risk of thrombosis is major.

3) Perform HIT-specific laboratory tests in order to rule out or confirm HIT

4) Prevention or treatment of thrombotic complications of HIT.

If continuation of anticoagulation appears essential, heparin must be replaced by another class of antithrombotic: danaparoid sodium or hirudin, prescribed depending on the case at a prophylactic or curative dose.

Transition to VKAs will only be undertaken after normalisation of the platelet count, because of the risk of worsening the thrombotic phenomenon with VKAs.

Therapy must be adapted according to the results.

Heparin resistance

Interindividual variability in the anticoagulant response to heparin has been demonstrated. The phenomenon termed "heparin resistance" or "relative heparin inefficacy" defines an inadequate response to heparin administered at standard dose to achieve the desired therapeutic anticoagulation target.

This resistance is mainly related to antithrombin (AT) activity below 60 % of normal, and/or to a decrease in the availability of heparin due to increased protein binding, making it unavailable to bind to AT and consequently reducing its anticoagulant activity.

Factors predisposing to AT levels below 60 % are:

• congenital deficiency

• acquired deficiency, notably in the case of 

• hepatic insufficiency
• consumption of antithrombin due to previous heparin injections
• induction by treatment with nitroglycerin

Factors predisposing to an increase in protein binding of heparin are:

• any inflammatory syndrome (infection, surgical trauma, surgery, extracorporeal circulation, uncontrolled chronic disease, cancer) / increase in inflammatory proteins binding heparin)

• any situation leading to an increase in platelets and fibrinogen (thromboembolic disorders)

• higher volume of distribution than standards in cases of obesity

• hypersplenism

• hepatic insufficiency

Heparin resistance may also be encountered during pregnancy or the postpartum period, in elderly subjects (over 65 years), in cases of hypoalbuminemia or in cases of thrombocytosis.

To help the practitioner manage this resistance, the measurement of the Activated Partial Thromboplastin Time (APTT) and the anti-Xa assay must be performed on the same sample. In addition, the anti-Xa assay must be performed with plasma not enriched in AT. In order to avoid a potentially dangerous escalation of heparin doses, particularly in the case of non-elevation of the APTT, heparin dose adjustment will be based on anti-Xa levels.

Finally, close monitoring of the patient is essential in order to anticipate a risk of sudden hypocoagulation, as this resistance is temporary and may abruptly subside, in particular through desaturation of all heparin binding sites or a decrease in them, i.e. regression of the inflammatory syndrome.

Taking this medicinal product is not recommended in combination with defibrotide, acetylsalicylic acid at analgesic, antipyretic and anti-inflammatory doses, NSAIDs, dextran (see section Interactions).

Contraindicated combination

Whatever the dose of heparin:

+ Oral anticoagulants of the DOAC type (apixaban, edoxaban, rivaroxaban, etc.)

Increased risk of bleeding.

Direct-acting oral anticoagulants must not be administered concomitantly with heparin. When switching from one to the other, respect the interval between doses.

Combinations not recommended

Whatever the dose of heparin:

+ Defibrotide

Increased bleeding risk.

With curative doses of heparin and/or in elderly subjects :

+ Acetylsalicylic acid as an anti-inflammatory (doses ≥ 1 g per dose and/or ≥ 3 g per day) or as an analgesic or antipyretic (doses ≥ 500 mg per dose and/or < 3 g per day).

Increased bleeding risk (inhibition of platelet functions and damage to the gastroduodenal mucosa by acetylsalicylic acid).

Use another anti-inflammatory or another analgesic or antipyretic.

+ Non-steroidal anti-inflammatory drugs (NSAIDs)

Increased bleeding risk (damage to the gastroduodenal mucosa by non-steroidal anti-inflammatory drugs).

If the combination cannot be avoided, close clinical monitoring.

+ Dextran

Increased bleeding risk (inhibition of platelet functions by dextran 40).

Associations requiring precautions for use

Whatever the dose of heparin:

+ Oral anticoagulants of the vitamin K antagonist type

Increased risk of bleeding.

During the heparin/vitamin K antagonist bridging (requiring several days), reinforce clinical and biological monitoring.

+ Cobimetinib

Increased risk of bleeding. Clinical monitoring.

Associations to be taken into account

With preventive doses of heparin :

+ Acetylsalicylic acid

The concomitant use of medicinal products acting at various levels of haemostasis increases the risk of bleeding. Thus, in subjects under 65 years of age, the combination of heparins at preventive doses with acetylsalicylic acid, whatever the dose, must be taken into account, maintaining clinical and possibly biological monitoring.

+ N.S.A.I.D.s

Increased risk of bleeding.

With curative doses of heparin :

+ Acetylsalicylic acid at antiplatelet doses (from 50 mg to 375 mg per day)

Increased risk of bleeding (inhibition of platelet function and irritation of the gastroduodenal mucosa by acetylsalicylic acid).

+ Thrombolytics

Increased risk of bleeding.

Whatever the dose of heparin :

+ Platelet antiaggregants

Increased risk of bleeding.

+ Other hyperkalaemic agents

Risk of increased hyperkalaemia, potentially lethal.

+ Corticosteroids (gluco-) (except hydrocortisone)

Increased risk of bleeding.

Pregnancy

Heparin does not cross the placenta.

No malformation or foetotoxicity of heparin has been described in animals, nor to date in humans.

When used in pregnant women, particular caution is required due to the risk of uteroplacental haemorrhage, particularly at the time of delivery.

If epidural anaesthesia is considered, it is necessary to suspend heparin (see sections Contraindications and Warnings and precautions).

Breast-feeding

Heparin is not excreted into breast milk and does not cross the digestive barrier, so breastfeeding is possible.

Like all medicines, CALCIPARINE can cause side effects, but they do not occur systematically in everyone. The frequencies of side effects have been defined according to the following convention:

Very common	≥ 1/10
Common	≥ 1/100 to < 1/10
Uncommon	≥ 1/1 000 to < 1/100
Rare	≥ 1/10 000 to < 1/1 000
Very rare	< 1/10 000
Frequency not determined	cannot be estimated from the available data

 

 

System organ class	Frequency	Undesirable effect(s)
Blood and lymphatic system disorders	very common	Hemorrhagic manifestations at various sites, including some cases with a fatal outcome. Risk factors such as organic lesions liable to bleed, renal insufficiency, certain drug associations (see sections Contraindications and Interactions) may increase these manifestations.
	frequent	Thrombocytopenias
	rare	Eosinophilia
Immune system disorders	uncommon	Hypersensitivity (localised or generalised)
	frequency not known	Anaphylactic/anaphylactoid shock
Metabolism and nutrition disorders	very rare	Hypoaldosteronism with hyperkalaemia and/or metabolic acidosis, particularly in patients at risk (diabetes, renal insufficiency) (see section Warnings and precautions).
Vascular disorders	very common	Subcutaneous administration may very frequently result in haematomas at injection sites. They are increased by failure to follow the injection technique or by use of inadequate injection equipment.
	very rare	Spinal haematomas in the context of epidural or spinal anaesthesia and lumbar punctures (see sections Contraindications and Warnings and precautions)
Skin and subcutaneous tissue disorders	uncommon	• Hypersensitivity (localized or generalized), notably angioedema, erythema, rash, urticaria, pruritus, conjunctivitis, rhinitis, asthma, cyanosis, tachypnea, sensations of oppression, fever, chills. In certain cases their occurrence should lead to discontinuation of treatment.
	Rare	Skin necrosis (which may occur at the injection site or at a distance from the injection site). These reactions may be preceded by purpura or erythematous, infiltrated and painful plaques, with or without systemic effects. Treatment must be stopped immediately.
	very rare	Alopecia
	frequency not known	Bullous haemorrhagic dermatosis
Musculoskeletal and connective tissue disorders	frequency not known	Osteoporosis during long-term treatment.
Disorders of the reproductive system and breast	very rare	Priapism
General disorders and administration site conditions	very common	Firm nodules disappearing within a few days reflect an inflammatory process and are not a reason to discontinue treatment.
	very rare	Calcinosis at the injection site, mainly in patients with severe renal insufficiency.
Investigations	frequent	Increase in transaminases, generally transient Increase in Gamma-GT

 

Description of selected adverse reactions

Thrombocytopenia

Two types of thrombocytopenia have been described:

• The more common type I is generally moderate (> 100 000), of early onset (before day 5) and does not require discontinuation of heparin.

Rarely, a severe type II thrombocytopenia (HIT), with a possible fatal outcome. Their prevalence has not yet been properly assessed (see sections Contraindications and Warnings and precautions).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system: National Agency for the Safety of Medicines and Health Products (ANSM) and the network of Regional Pharmacovigilance Centres - Website: https://signalement.social-sante.gouv.fr/.

• Accidental overdose following administration of massive doses of heparin may lead to bleeding complications. The bleeding risk is proportional to the level of hypocoagulability and to the vascular integrity of each patient.

An antidote exists: protamine sulfate, which neutralises heparin by forming an inactive complex with heparin.

100 anti-Xa IU of protamine neutralizes the activity of 100 IU of heparin.

The useful dose of protamine depends on:

• Of the dose of heparin injected.
• Of the time elapsed since heparin injection, with possible reduction of the antidote doses.

However, the use of this antidote must take into account its potential adverse effects.

• In case of massive oral ingestion of heparin, no serious consequence is, a priori, to be feared, given the very low absorption of the product at the gastric and intestinal levels.

Pharmacotherapeutic class: Antithrombotics, ATC code: B01AB01.

This medicine is an unfractionated heparin, an immediate-acting anticoagulant.

The binding of heparin to antithrombin (formerly antithrombin III) considerably increases (x 1000) the natural activation of the inhibitor against thrombin, factor Xa and all activated coagulation factors. This results in a potent anticoagulant activity that depends on the heparin concentration, the antithrombin concentration and those of the coagulation factors. The term heparinemia is used for the measurement of heparin activity resulting from these complex interactions.

When injected subcutaneously, the concentrated calcium heparin solution diffuses slowly into the bloodstream.

After passing into the circulation, a portion of the administered heparin molecules is neutralised by numerous factors (platelet factor 4, blood proteins including fibrinogen, reticuloendothelial system) and eliminated by cellular uptake. The excess is eliminated by the kidneys. At normal doses of use, the kidneys do not play a role in the elimination of heparin. The remaining portion undergoes dilution, the value of which varies according to plasma volume and in particular the haematocrit, and associates with the cofactor of heparin (antithrombin).

After subcutaneous injection of an effective dose, heparin activity appears after a delay of the order of 30 to 60 min, reaches a maximum level between 120 and 150 min and disappears after a duration of 8 to 14 hours depending on the subject. The apparent half-life is approximately 4 hours.

These different parameters of neutralisation, elimination and association with cofactors vary from one subject to another and in the same subject from one moment to another.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

3 years.

To be stored at a temperature below 30°C

No special requirements.

List I

Marketing authorisation (AMM)

CIP 3400955243281 (10 Ser/0,3 ml).

Social security reimbursement at 65% (2 Ser/0,3 ml).
Hospital model(s) (10 Ser/0,3 ml).
Collect (10 Ser/0,3 ml).