Source: European Medicines Agency (EU) Publisher: Aspen Pharma Trading Limited, 3016 Lake Drive, Citywest Business Campus, Dublin 24, Ireland
Nadroparin 19,000 I.U. should not be used in patients with:
Because of the possibility of heparin-induced thrombocytopenia, the platelet count should be monitored throughout the course of treatment with nadroparin.
Rare cases of heparin-induced thrombocytopenia that occasionally became severe have been reported, which may be associated with arterial or venous thrombosis. Such diagnosis should be considered in the following situations:
In this event, nadroparin treatment must be discontinued.
These effects are probably of an immuno-allergic nature and, in the case of a first treatment, are reported mainly between the 5th and the 21st day of treatment. They may also occur much earlier if there is a history of heparin-induced thrombocytopenia.
If there is a history of thrombocytopenia with heparin (either standard or low-molecular weight heparin), treatment with nadroparin may be considered, if necessary. In such cases, careful clinical monitoring and platelet count measurement should be performed at least daily. If thrombocytopenia occurs, treatment must be discontinued immediately.
When thrombocytopenia occurs with heparin (either standard or low-molecular weight heparin), substitution with a different class of antithrombotic drugs should be considered. If not available, substitution with another low-molecular weight heparin may be considered if administration of heparin is inevitable. In such cases, platelet count measurement should be performed at least daily and treatment should be discontinued as soon as possible, as cases of initial thrombocytopenia that have continued after substitution have been described (see section 4.3).
In-vitro platelet aggregation tests are only of limited value in the diagnosis of heparin-induced thrombocytopenia.
Caution should be exercised when nadroparin is administered in the following situations, as they may be associated with an increased risk of bleeding:
Nadroparin 19,000 I.U. should be used with caution in patients with impaired liver or pancreatic function, in patients with kidney and/or ureteral stones, in patients who are taking medicines that increase the plasma potassium concentration, as well as in patients who recently underwent surgery and are receiving a high-dosage treatment with Nadroparin 19,000 I.U.
The use of Nadroparin 19,000 I.U. is not recommended in patients who underwent surgery within the last 5 days.
Heparin may suppress adrenal secretion of aldosterone, which can lead to hyperkalaemia particularly in patients with elevated plasma potassium concentrations or in patients at risk for elevated plasma potassium concentrations, such as patients with diabetes mellitus, persistent renal function impairment, pre-existing metabolic acidosis, or in patients taking drugs that increase potassium plasma concentrations (for instance ACE inhibitors [angiotensin-converting enzyme], non-steroidal anti-inflammatory drugs [NSAIDs]). The risk of hyperkalaemia appears to increase with duration of treatment, but is generally reversible. Plasma potassium concentrations should therefore be monitored in patients at risk.
Because of an increased risk of hematoma formation, which may lead to persistent neurological deficits and paraplegia, lumbar puncture, spinal or epidural anaesthesia is contraindicated in patients who receive a curative treatment with Nadroparin 19,000 I.U. (see section 4.3). Nadroparin 19,000 I.U. should be used with caution and after careful individual risk/benefit assessment in patients who receive preventive treatment and who receive a lumbar puncture, or spinal or epidural anaesthesia. The risk of a spinal/epidural hematoma is increased by in-dwelling epidural catheters or by the concomitant use of other drugs, which also affect haemostasis, such as NSAIDs, platelet inhibitors, or other anticoagulants. The risk also appears to be increased by traumatic or repeated epidural or spinal puncture. So far, no results from randomized, controlled clinical studies are available that substantiate the safe use of higher doses of Nadroparin 19,000 I.U. (for instance for the prophylaxis of deep venous thrombosis in patients with high thromboembolic risk) with concomitant administration of regional spinal anaesthesia.
Therefore, the concomitant prescription of a neuraxial blockade and treatment with anticoagulants should be decided on after careful individual benefit-risk assessment in the following situations:
In the case of patients with spinal lumbar puncture, spinal anaesthesia or epidural anaesthesia, a minimum of 12 hours should elapse between the nadroparin injection at prophylactic doses or 24 hours at treatment doses and the insertion or the removal of the spinal/epidural catheter or needle, whereby the product characteristics and the patient profile must be taken into account. For patients with renal impairment, longer intervals may be considered. Subsequent doses should only be given if at least four hours have passed. New administration of nadroparin should be postponed until the surgery is completed.
Patients should be frequently monitored for signs and symptoms of neurological impairment, such as backaches, sensory and motor deficits (numbness and weakness in the lower limbs), intestinal and/or bladder dysfunction. If neurological impairment is determined, urgent treatment should begin immediately. Nursing personnel should be trained to detect such signs and symptoms. Patients should be instructed to call their doctor immediately if they perceive any of these symptoms.
If signs and symptoms of spinal hematoma are suspected, an immediate diagnosis and treatment, including spinal cord decompression, should be initiated.
If, during placement of the catheter, significant or obvious bleeding occurs, a careful benefit-risk assessment should take place before starting or continuing heparin treatment.
The concomitant use of acetylsalicylic acid, other salicylates, non-steroidal anti-inflammatory and antiplatelet drugs is not recommended, as they may increase the risk of bleeding. Where such combinations cannot be avoided, careful clinical and biological monitoring should be performed.
No adequate clinical data for use of Nadroparin 19,000 I.U. in children is presently available. The use of Nadroparin 19,000 I.U. in children is therefore not recommended until more data are available.
It is recommended to monitor the renal function prior to starting treatment (see section 4.3).
Nadroparin is primarily excreted via the kidneys, which leads to elevated nadroparin exposure in patients with renal impairment (see section 5.2). Patients with impaired renal function should be treated with caution, as they are at increased risk of bleeding.
For patients with mild to moderate renal insufficiency (creatinine clearance 30 ml/min and <60 ml/min), who are receiving a curative treatment, a reduced dose may be taken into consideration (see section 4.2).
In very rare cases, cutaneous necrosis has been observed, typically at the injection site under treatment with standard or low-molecular weight heparin, that was preceded by purpura or infiltrated or painful erythematous skin, with or without general symptoms. In such cases, treatment should be discontinued immediately.
Nadroparin 19,000 I.U. must not be injected intramuscularly or intravenously.
Due to risk of bruising during Nadroparin 19,000 I.U. treatment, intramuscular injection of other medications should be avoided.
Nadroparin should be administered with caution in patients who receive oral anticoagulants, systemic (gluco-) corticosteroids and dextrans.
Administration of Nadroparin 19,000 I.U. in patients who are switched to oral anticoagulants, should be continued until a stable INR (International Normalized Ratio) in the desired range has been reached.
The concomitant use of acetylsalicylic acid (or other salicylates), non-steroidal anti-inflammatory and anti-platelet drugs is not recommended, as they may increase the risk of bleeding (see section 4.4).
The interaction of heparin with intravenous nitroglycerin that can lead to a reduced efficacy of heparin also cannot be ruled out for Nadroparin 19,000 I.U. Medicines that increase blood potassium concentrations may only be used concomitantly with Nadroparin 19,000 I.U. under very close medical supervision.
Animal studies have not shown any teratogenic or fetotoxic effects. However, there is only limited clinical data concerning transplacental passage of nadroparin. Experiences based on a limited number of applications of nadroparin calcium during pregnancy have shown no adverse effects on the pregnancy or the health of the foetus/new-born. Further epidemiological data are not available. Therefore, the use of nadroparin during pregnancy is not advised, unless the therapeutic benefits outweigh the possible risks.
There is insufficient information on the excretion of nadroparin calcium in breast milk. Therefore, the use of Nadroparin 19,000 I.U. during breast-feeding is not recommended.
There are no clinical studies on the effect of nadroparin on fertility.
There are no data on the effects on the ability to drive and use machines.
The most common adverse effects include haemorrhagic manifestations, minor hematomas at the injection site, open or hidden bleeding complications (particularly affecting the skin, mucous membranes, lesions, as well as the gastrointestinal tract region), elevated transaminase concentration, irritations at the injection site, elevated serum calcium concentrations and elevated aminotransferase, gamma-GT and lipase concentrations.
Adverse reactions are listed below by system organ class and frequency:
The following conventions have been used for the classification of adverse reactions in terms of frequency: 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), Not known (cannot be estimated from the available data).
Clinical investigations comparing Nadroparin 19,000 I.U. with the conventional twice-daily administration of nadroparin calcium confirmed the established safety profile of the drug. In this study, 3.8% of the patients treated once daily with nadroparin calcium and 4.5% of the patients treated twice daily with nadroparin calcium experienced adverse effects.
Application experience with nadroparin calcium shows that about 3% of the prophylactically treated patients had adverse reactions.
Very common: Haemorrhagic manifestations on various sites (including cases of spinal hematomas), more frequent in patients with other risk factors (see sections 4.3 and 4.4)
Common: Open or hidden bleeding complications (particularly affecting the skin, mucous membranes, lesions, as well as the gastrointestinal tract and urogenital tract regions) that can lead to haemorrhagic anaemia
Uncommon: Mild transient thrombocytope nia (Type I)
Rare: Thrombocytopenia (including antibodymediated heparin-induced thrombocytope nia (Type II) see section 4.4), thrombocytosis, Eosinophilia, which is reversible after discontinuation
Very rare: Thrombocytope nia above 1,000,000/mm³, primarily observed postoperatively
Rare: Anaphylactic shock, anaphylactoid reactions, angioedema
Very rare: Hypersensitivity reactions (including cutaneous reactions)
Not known: Headache, Migraine
Rare: Reversible hyperkalaemia
Very rare: Reversible hyperkalaemia in conjunction with heparininduced aldosterone suppression, particularly in patients at risk (see section 4.4)
Common: Elevated transaminases, usually transient
Very rare: Priapism
Rare: Rash, urticaria, erythema, pruritus alopecia, Skin necrosis, usually at the injection site (see section 4.4)
Very common: Minor hematomas at the injection site
In some cases, the occurrence of firm nodules, which do not indicate an encapsulation of heparin, may be observed. These nodules usually disappear after a few days.
Common: Reactions at the injection site.
Rare: Calcinosis at the injection site. Calcinosis occurs more frequently in patients with abnormal calcium phosphate product, such as in some cases of chronic renal insufficiency. Allergic reactions with symptoms such as nausea, vomiting, elevated body temperature, headache, urticaria, pruritis, dyspnoea, bronchospasm, hypotension
Common: Increases in serum potassium concentration. Elevated aminotransferas e, gamma-GT, LDH and lipase levels
Cases of serious adverse effects, such as intracranial bleeding and ocular bleeding have also been reported. Epidural bleeding in the lumbar region following catheterized spinal anaesthesia that can lead to paraplegia has been observed.
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.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
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