Nadroparin Calcium
Nadroparin calcium is prepared by nitrous acid depolymerisation of heparin obtained from the intestinal mucosa of pigs. The majority of the components have a 2-O-sulpho-a-L-idopyranosuronic acid structure at the non-reducing end and a 6-0-sulpho-2.5-anhydro-D-mannitol structure at the reducing end of their chain. The mass-average molecular mass ranges between 3600 and 5000. with a characteristic value of 4300. The mass percentage of chains lower than 2000 is not more than 15%. The degree of sulphation is about 2.1 per disaccharide unit.
The Ph. Eur. specifies that potency is not less than 95 units and not more than 130 units of anti-factor Xa activity per mg with reference to the dried substance and that the ratio of anti-factor Xa activity to anti-factor lla (antithrombin) activity is between 2.5 and 4.0.
Nadroparin calcium is a low-molecular-weight heparin with anticoagulant properties. It is used in the treatment and prophylaxis of venous thrombo-embolism (p.802) and to prevent clotting during extracorporeal circulation. Doses are expressed in terms of anti-factor Xa activity (anti-Xa units) although different values may be encountered in the literature depending upon the reference preparation used. For
prophylaxis of venous thrombo-embolism during surgery, patients at moderate risk of thrombosis are given 2850 anti-Xa units (Ph. Eur.) or 3075 anti-Xa units (WHO standard) of nadroparin calcium by subcutaneous injection daily for at least 7 days or until the patient is ambulant: the first dose is given 2 to 4 hours before the procedure. For patients at high risk of thrombosis the dose is adjusted according to body-
weight. Usual doses are 38 anti-Xa units (Ph. Eur.) or 41 anti-Xa units (WHO standard) per kg 12 hours before surgery, 12 hours postoperatively and then daily until 3 days after the procedure; the dose is then increased by 50% to 57 anti-Xa units (Ph. Eur.) or 61 anti-Xa units (WHO standard) per kg daily. The total duration of treatment should be at least 10 days.
For the treatment of thrombo-embolism, nadroparin calcium is given in a dose of 85 anti-Xa units (Ph. Eur.) or 92 anti-Xa units (WHO standard) per kg by subcutaneous injection every 12 hours for 10 days.
For prevention of clotting in the extracorporcal circulation during haemodialysis sessions lasting less than 4 hours, nadroparin calcium is administered into the arterial line of the circuit at the beginning of the dialysis session. The usual dose is 70 anti-Xa units (WHO standard) per kg; doses expressed in anti-Xa units (Ph. Eur.) are 2850 units for patients weighing less than 50 kg, 3800 units for patients weighing 50 to 69 kg, and 5700 units for patients weighing 70 kg or more.
Doses should be reduced in patients at high risk of haemorrhage.
treatment of thrombo-embolic disrders :
dose - 0.1 mg / 10 kg body wt , s/c twice daily for 10 days
orthopaedic surgery _ dose as per body wt. initial dose - 12 hrs before surgery & 12 hrs afdter surgery. then once daily dose for atleast 10 days. prophylaxis pursued through pout the risk period & at least till the patient is ambulatory.
References.
1. Bairadell LB. Buckley MM. Nadroparin calcium: a review of
its pharmacology and clinical applications in (he prevention
and treatment of thrombocmbolic disorders. Drubs 1992; 44:
S58-88.
Nadroparin Calcium Injection
FRAXODI'
nadroparin
Qualitative and Quantitative Composition:
Formulation for I ml of Solution for injection :
β’ Prefilled syringes:
Nadroparin calcium (INN) 19,000 IU antiXa
Calcium hydroxide solution
or dilute hydrochloric acid q.s. pH=4.5to7.5
Water for injecrions q.s. I ml
Pharmaceutical Form
Solution for injection
Clinical Particulars
Therapeutic indications
This product is a low molecular weight heparin (LMWH).
It is indicated tor the following:
curative treatment of established deep vein thrombosis.
Poslogy and Method of Administration
Subcutaneous Route
This presentation is suitable for use in adults.
Do not inject by the I.M. Route
I ml ofFRAXODI corresponds to about 19,000 1.U. anti-Xa nadroparin.
Technique for subcutaneous injection
Do not expel the air bubble.
The subcutaneous injection of nadroparin should preferentially be administered in the supine patient, into the subcutaneous tissue of the anterior and posterior lateral abdominal wall, alternating the right and left sides. The needle must be introduced perpendicularly, not tangentially, throughout its entire length into the thickness of skin fold held by the operator between the thumb and forefinger. This skin-fold should be maintained carefully throughout the duration of the injection.
β’ General recommendation:
It is imperative to monitor platelet count regularly throughout the entire treatment period because of the risk of heparin-induced thrombocytopenia (HIT).
(see Special warnings and special precautions for use).
β’ Curative treatment of deep vein thrombosis (DVT)
Any suspected deep vein thrombosis must be rapid confirmed by appropriate examinations.
*Administration frequency:
I injection daily.
*Dose administered:
The dose per injectionis 1711.U.Anti-Xa/kg.
LMWH dosages have not been evaluated on a weight basis in patients weighing more than 100 kg or less than 40 kg. LMWH may appear to be less effective in patients weighting more than 100 kg, or the risk of bleeding may be augmented in patients weighing less than 40 kg. Special clinical monitoring is therefore required.
As a rough guide, the doses to be administered on the basis of 0.1 ml/10 kg once daily for different patient weights are given in the
table below:
BODY WT.IN KG VOL. OF FRAXODI / INJ
40 - 49 0.4 ML
50 - 59 0.5 ML
60 - 69 0.6 ML
70 - 79 0.7 ML
80 - 89 0.8 ML
90 - 99 0.9 ML
> 100 1.0 ML
When adjusting the dose to patient weight, it may be necessary to modify the volume administered by holding the syringe vertically
and pushing the plunger to the required graduation.
DVT treatment duration:
Treatment with LMWH should rapidly be replaced by oral anticoagulants unless these are contra-indicated. LMWH should not be administered for more than 10 days, including the time required for equilibration with vitamin K antagonists, unless equilibration difficulties arc encountered (see Precautions for use: platelet monitoring). Oral anticoagulants must therefore be started as soon as possible.
β’ Contra-Indications
This medication MUST NOT BE USED in the following situations:
β’ hypersensitivity to nadroparin.
β’ history of severe, type-ll heparin-induced
thrombocytopenia (HIT) caused by unfractionated heparin or low molecular weight heparin (see Precautions for use).
β’ current bleeding or patient prone to bleeding because of haemostatis disorders (disseminated intravascular coagulation may be an exception to this rule when not related to treatment with heparin (-see Precautions for use).
β’ organic lesion likely to bleed:
β’ cerebral haemorrhage;
β’ in the absence of pertinent data, severe kidney failure (defined as creatininine clearance of about 30 ml/min calculated using the Cockroft formula), apart from the special case of dialysis. Use unfractionated heparin in patients with severe kidney failure.
A recent measurement of patient weight is required for the Cockroft formula (see Precautions for use)
β’ In addition, epidural or spinal anaesthesia should never be used during curative treatment with LMWH.
This medication is GENERALLY INADVISABLE in the
following cases:
β’ in the acute phase of ischaemic stroke, with or without consciousness disorders. When stroke is due to embolism, allow 72 hours before starting the treatment. No proof has yet been established that curative doses of LMWH are effective in cerebral infarction, and this irrespective of origin, magnitude and clinical severity;
β’ acute infectious endocarditis (apart from certain cases of emboligenic heart disease);
β’ mild to moderate kidney failure (creatinine clearance >30
nd<60ml/min.)
In addition, this medicinal product is GENERALLY INADVISABLE in combination with (see Interactions with other medicinal products and other forms of interactions).
1. + acetylsalicylic acid at analgesic, antipyretic and antiinflammatory doses;
2. +NSAIDs (systemic route),
3. +dextran 40 (parenteral route).
β’ Special warnings and special precautions for use:
Although the concentrations of the different proprietary medicinal products containing low molecular weight heparin are all expressed
in anti-Xa international units, their efficacy is not restricted to this anti-Xa effect. It would therefore be hazardous to replace the
regimen of a particular LMWH by that of another, since each regimen has been validated by specific clinical studies. Special care
must therefore be taken and the specific method for use for each medicinal product must be observed.
β’Warnings
FRAXODI is reserved for the curative treatment of deep vein thrombosis and is administered assingle daily injection.
β’ Risk of bleeding:
It is imperative to follow exactly the recommended treatment regimen (dosage and duration). Otherwise, haemorrhagic accidents may occur, particularly in high-risk subjects (the elderly, kidney failure, etc). Serious haemorrhagic accidents have notably been observed:
In the elderly, notably because of an age-related deterioration in kidney function.
β’ in patients with kidney failure,
β’ in patients weighing less than 40 kg.
β’ when treatment was extended beyond the recommended 10 days,
β’ when the recommended regimen was not observed (notably treatment duration and dose adjustment for weight in curative treatments)
β’ in combination with other medicinal products that increase the likelihood of bleeding (see Interactions with other medicinal products and other forms of interaction). Accordingly, particularly close monitoring is indispensable in the elderly and/or in kidney failure, and in cases where the treatment is extended beyond 10 days.
The measurement of anti-Xa activity may be useful to detect accumulation in certain cases (see Precaution for use/Laboratory
monitoring).
Risk of heparin-induced thrombopenia (HIT)
When a patient receiving LMWH treatment (at curative or preventive doses) suffers a thrombotic event, such as:
β’ a deterioration in the thrombosis for which they are receiving treatment,
β’ phlebitis,
β’ pulmonary embolism,
β’ acute ischemia of the lower limbs,
β’ even myocardial infarction or ischemic stroke, heparin-induced thrombocytopenia (HIT) should systematically be suspected and a platelet count should be established urgently (see Precautions for use).
Use in children
In the absence of pertinent data, LMWHs are not recommended for use in children.
Precautions for Use
β’ Kidney function
Before starting LMWH treatment, it is indispensable to evaluate kidney function, particularly in the subjects aged 75 years or more, by calculating creatinine clearance (Cicr) using Cockroft formula, on the basis of a recent patient weight measurement:
In men, Cicr = (140-age) x weight / (0.814 x creatinine) with age expressed in years, weight in kg and creatinine in lLJ.mol/L.
This formula must be corrected for women by multiplying the result by 0.85.
When creatinine is expressed in mg/ml, multiply by 8.8.
If the calculation shows severe kidney impairment (Cicr about 30 ml/min), this prohibits the prescription of LMWH in curative indications (see Contraindications).
β’ Laboratory monitoring
Platelet monitoring
Heparin-induced thrombopenia (HIT)
Heparin (unfractionated heparin and less often low molecular weight heparin) may induce severe, so called type II thrombocytopenia by an immunological mechanism which may induced a thrombus (see also Undesirable effects). Because of the risk of HIT, platelet count must be monitored closely, and this irrespective of the indication and the dose administered.
A platelet count should be established prior to and at most 24 hours after treatment initiation, then twice weekly throughout the regular
treatment duration.
HIT should be suspected if platelet count is <100,000/mm and/or if platelets fall by 30 to 50% between 2 successive counts. This effect generally appears between 5th and 21st day after starting the heparin (with incidence reaching a peak around the 10th day). However, the effect can also occur far earlier if the patient has a history of heparin-induced thrombocytopenia, and occasional cases have been reported beyond 21 days. Before the treatment is started, the patient should therefore be asked systematically, during an in-depth interview, about any previous incidents. In addition, the possibility of a recurrence when heparin is re-started may persist for several years, or even indefinitely (see Contra-indications).
The onset of HIT constitutes an emergency and requires a specialist opinion.
Any significant reduction in platelet count (30 to 50% of the initial value) should sound the alert, even before the value falls to a critical
threshold. In all cases, a reduction in platelet count requires:
1. immediate verification of the count;
2. suspension of heparin treatment if the verification confirms the reduction or shows worsening, in the absence of any other obvious aetiology.
A blood sample should be drawn onto citrate for in vitro platelet aggregation and immunological tests. But in this situation, the immediate therapeutic approach does not depend on the results of these in vitro platelet aggregation or immunological tests since only specialist laboratories practice such tests routinely and the results, in the best of cases, are obtained only after several hours. These test must nevertheless be performed to contribute to the diagnosis of this complication since the risk of thrombosis is high if the heparin treatment is continued.
3. prevention or treatment of thrombotic complications of HIT. If anticoagulation is considered indispensable, the heparin must be replaced by another type of antithrombotic: e.g. danaparoid sodium or hirudin, prescribed at preventive or curative doses depending on the patient.
Replacement by vitamin K antagonists is only possible once the platelet count has returned to normal since vitamin K antagonists may worsen the thrombotic phenomena.
β’ Replacing heparin by oral anticoagulants.
In such cases clinical and laboratory tests should be reinforced (Quick time expressed in INR) to monitor the effects of the vitamin K antagonist.
Because of the lag time before the vitamin K antagonist exerts its full effect, the heparin should be continued at the same dose until the INR reaches the target therapeutic zone for the indication in two successive tests.
β’ Control of anti-factor Xa activity
Given that most of the clinical trials showing LMWH to be effective were conducted using doses adjusted for patient weight but without special laboratory monitoring, it has not been established whether laboratory monitoring is useful in evaluating the efficacy of LMWH treatment. Still, laboratory monitoring through the determination of anti-Xa activity may be useful in managing the haemorrhagic risk that arises in certain clinical situations, often associated with a risk of overdosing. These situations mainly concern the curative indications of
LMWH, because of the higher doses involved, and when the patient shows:
β’ mild to moderate renal impairment (clearance calculated using the Cockroft formula about 30 to 60 ml/min): unlike standard unfractionated heparin, LMWHs are primarily nadroparin excreted in the urine and any renal impairment can lead to a relative overdose.
As far as severe kidney failure is concerned, this contraindicates the use of LMWH at curative doses (see Contra-indications);
β’ extreme weight (thinness or cachexia, obesity);
β’ unexplained bleeding.
If necessary, in an effort to detect any accumulation after several administrations, it is recommended to draw blood from the patient at the activity peak (determined on the basis of the data available), i.e. about 4 hours after the 2nd administration when the medicinal product is administered as I subcutaneous injection daily. Repeating the determination of anti-Xa activity to measure heparinernia, e.g. every 2-3 days, should be discussed on a case-by-case basis depending on the results of the previous assay and a possible modification in the LMWH dose may be envisaged. The anti-Xa activity generated is different for each LMWH and each therapeutic regimen. As a rough guide, on the basis of the data available, the mean observed (+ standard deviation) 4 hours after the administration ofnadroparin.
β’ at a dose of 83 IU/kg by injection, as 2 injections per 24 h, was 1.01+0.18 IU.
β’ at a dose of 166 IU/kg as a single injection per 24 h, was 1.34+0.15 IU.
This mean value was observed in the course of clinical trials conducted to assays anti-Xa activity by a chromogenic (amidolytic) method.
β’ Activated partial thromboplastin time (APTT)
Some LMWHs cause moderate lengthening of APTT. In the absence of any pertinent clinical data, monitoring based on this test is irrelevant.
High-risk situations:
Treatment monitoring should be reinforced in the following cases:
β’ liver impairment,
β’ history of gastroiniestinal ulcers or any other organic lesions likely to bleed.
β’ vascular diseases of the chorioretina,
β’ post-operative period following surgery on the brain or spinal cord,
β’ lumbar puncture should be discussed and the risk of intra-spinal bleeding taken into account. This should be deferred when possible.
INTERACTIONS WITH MEDICINAL PRODUCTS AND
OTHER FORMS OF INTERACTION
Some drugs or drug categories may increase the risk of hyperkaliemia: potassium salts, potassium-sparing diuretics, angiotensin converting enzyme inhibitors, angiotensin II inhibitors, non-steroidal anti-inflammatory drugs, heparins (low molecular weight or unfractionated heparins), cyclosporine and tacrolimus, trimethoprim. The onset of hyperkaliemia may depend on the presence of
concomitant risk factors. This risk is augmented if the above-mentioned drugs are given concomitantly.
β’ Inadvisable combinations
+ Acetylsalicylic acid at analgesic, antipyretic and anti-inflammatory doses (and by extrapolation, other salicylates) Increased risk of bleeding (salicylates inhibit platelet function and attack the gastro-duodenal mucosa)
Use a non-salicylate analgesic/antipyretic (e.g. Paracctamol).
nadroparin + NSAIDs (systemic route) Increased risk of bleeding (non-steroidal anci-inflammatory drugs inhibit platelet function and attack the gastro-duodenal mucosa). If such combination is unavoidable, start close clinical monitoring.
+ Dextran 40 (parenteral route)lncreased risk of bleeding (Destran-40 inhibits platelet function).
β’ Combinations requiring precautions for use
+ Oral anticoagulants
These potentiate the anticoagulant effect. When replacing heparin by an oral anticoagulant, reinforce clinical monitoring.
β’ Combinations to be taken into account
+ Antiplatelet drugs (other than acetylsajicylic acid at analgesic, antipyretic and anti-inflammatory doses; NSAIDs): abciximab, acetylsalicylic acid at antiplatelet doses in cardiological and neurological indications: beraprost, clopidogrel, eptifibatide, iloprost, ticlopidine, tirofiban - Increased risk of bleeding.
β’ PREGNANCY AND LACTATION
β’ Pregnancy
Studies in animals have not shown nadroparin to exert any teratogenic effects. In the absence of any teratogenic effect in animals, no malformative effect is expected in humans. In fact, to date, substances responsible for malformations in humans have been shown to produce teratogenic effects in animals during well-conducted studies in two different animal species.
Preventive treatment during I st. trimester and curative treatment :
In a clinical context, there are not yet enough relevant data in order to evaluate a possible teratogenic or foerotoxic effect ofnadroparin
when aciministered at a preventive dose during the first trimester of pregnancy or at a curative dose throughout the pregnancy.
Consequently, as a precautionary measure, it is preferable to avoid use ofnadroparin at a preventive dose during the first trimester of
pregnancy or at a curative dose throughout pregnancy.
Preventive treatment in the 2nd and 3rd trimester :
In a clinical contest, the use of nadroparin during 2nd and 3rd trimesters ot a limited number of pregnancies does not appear to have evidenced any teratogenic or foetotoxic effects to date. However, further studies are necessary in order to evaluate the consequences of exposure under these conditions. Consequently, the use ofnadroparin at a preventive dose during the 2nd and 3rd trimesters of pregnancy must only be envisaged during pregnancy must only be envisaged if necessary.
β’ Lactation:
Since gastrointestinal absorption is improbable in new-borns, treatment with nadroparin is not contraindicated in breast-feeding
β’ EFFECT ON ABILITY TO DRIVE AND USE MACHINES
Not applicable
β’ UNDESIRABLE EFFECTS
β’ Haemorrhagic effects: these manifest primarily:
β’ Concomitant risk factors: organic lesions liable to bleed, certain drug combinations (see Contraindications and Interactions with other medicinal products and other forms of interactions), age, renal impairment, low weight.
β’ When trcaternent methods are not observed, notably treatment duration and dose adjustment of dose for weight (See Warnings/risk of bleeding). Rare cases of intraspinal haematomas have been reported with low molecular weight heparin administered during spinal anaesthesia and epiduralanalgesia or anaesthesia. These events caused neurological lesions of variable severity, including prolonged or permanent paralysis (sec Precautions for use).
β’ The subcutaneous administration may induce injection site haematomas. These are accentuated when the injection recommendations are not observed or inadequate injection materials are used. Hard nodules that disappear in a few days are indicative of an inflammatory process and to not require treatment discontinuation.
β’ Cases of thrombocytopenia have been reported. These are divided into two types :
The most frequent type I cases are generally moderate (>100,000/mm), occur early (before the 5th day and do not require treatment discontinuation, Rare cases of severe, immuno allergic, type II thromboytopenia (HIT). Their prevalence has not been fully evaluated (see Special warning and special precautions for use)
β’ Rare cases of skin necrosis at the injection site have been reported with heparins. These reactions may be preceded by purpura or painful, infiltrated erythematous plaques. The treatment should be suspended immediately.
β’ Rare cases of skin necrosis at the injection site have been reported with heparins. These preceded by purpura or painful, infiltrated erythematous plaques. The treatment should be suspended immediately.
β’ Rare cases of allergic skin reactions or general allergy, which, in certain cases, require treatment discontinuation.
β’ In the same manner as with unfractionated heparins, the possibility of osteoporosis cannot be excluded when long term treatment is given.
β’ Transient elevation in transaminases.
β’ A tew cases oi hyperkalaemia.
Overdose
Accidental overdosing by the subcutaneous administration of massive doses of low molecular weight heparin could lead to haemorrhagic complications. In the event of bleeding protamine sulphate may be indicated in certain cases, after taking into account of the
following:
β’ Its efficacy is far less than that reported after over dosing with unfractionated heparin;
* Because of its adverse effects (particularly, anaphylactic shock), the benefit / risk ratio protamine sulpfate should be carefully evaluated prior to its prescription.
Neutralisation is achieved by the slow intravenous injection of protamine (sulphate or hydrochloride).
The appropriate protamine dose depends on:
β’ The heparin dose injected (100 AHLJ of protamine may be used to neutralise 100 1.U. anti-Xa of low molecular weight heparin),
β’ The time elapsed since the heparin injection, possible with an antidote dose reduction.
However it is impossible to neutralise the anti-Xa activity entirely.
Furthermore, the absorption kinetics of low molecular weight heparin may render this neutralisation short-lived and require fragmentation of the calculated total protamine dose into several injections (2 to 4) over 24 hours.
β’ In the event oi massive ingestion of low molecular weight heparin (no cases ever reported), no serious consequences are to be feared since the product undergoes very little gastric or intestinal absorption.
β’ Pharmacological Properties
Pharmacodynamic Properties
BOI AB 06: Anti-Thrombotics
Nadroparin is a low-molecular weight heparin in which the antithrombotic and anticoagulant activities of standard heparin have been dissociated. It is characterised by its greater anti-Xa activity than anti-lla or antithrornbin activity.
For nadroparin, the ratio between these two activities is between 2.5 and 4.
Ac curative doses, AP'FT may be prolonged at the activity peak by 1.4 fold the control rime. This prolongation is a reflection of the
residual antithrombin activity exerted by nadroparin.
β’ Pharmacokinetic Properties
Pharmacokmetic parameters have been studied on the basis of changes in plasma anti-Xa activity.
β’ Bioavailability
The product is rapidly and almost completely absorbed after subcutaneous injection; maximum plasma activity is observed 3 to 4 hours post-injection if nadroparin is injected twice daily. This peak is deferred to between 4 and 6 hours if nadroparin is administered as a single daily injection.
β’ Metabolism
This is primarily hepatic (desulphatation, depolymerisation).
β’ Distribution
Aher subcutaneous injection, the anti-Xa activity half-life is longer for low molecular weight herparins than for unfractionated heparins.
"this half-life is about 8 to 10 hours. Aher dosing with low molecular weight heparins, anti-lla activity disappears more rapidly from the plasma than anti-Xa activity.
β’ Excretion:
The product is primarily excreted in the urine after undergoing little or no metabolism.
β’ High-risk populations:
*elderly subjects:
Since kidney function is physiologically diminished in the elderly, the product is excreted more slowly. This does not have any consequences for dose or injection frequency in preventive treatment, on condition that the kidney function of these patients remains within acceptable limits, i.e. only slightly altered.
Before starting treatment with LMWH in subjects aged more than 75 years it is indispensable systematically to evaluate their kidney function using Cockroft formula (see Precaution for use).
* Mild to moderate kidney failure ( creatinine clearance > 30 ml/ min )
In certain patients the determination of circulating anti-Xa activity may be useful to avoid overdosing in curative indications ( see precautions for use )
Store below 30"C
Store in original packaging until used
β’ Instructions for Use and Handling
Use of needle protection system: after injection, slide the
FRAXODJ syringe safety system into position. Hold the syringe
in one hand by gripping the safety shield, then use the other hand.