Source: Web Search Revision Year: 2020 Publisher: Sandoz SA (Pty) Ltd<sup>1</sup>, 72 Steel Road, Spartan, Kempton Park, 1619 1 Company Reg. No.: 1990/001979/07
There have been cases of intraspinal haematomas reported with the concurrent use of NOXFIBRA and spinal/epidural anaesthesia resulting in long-term or permanent paralysis. The risk is greater with higher NOXFIBRA dosage regimens, use of post-operative indwelling catheters or the concomitant use of additional medicines affecting haemostasis such as NSAIDs (see “INTERACTIONS”). The risk also appears to be increased by traumatic or repeated neuraxial puncture.
Placement and removal of the catheter is best performed when the anticoagulant effect of NOXFIBRA is low. Neuraxial techniques should be avoided in patients who have been administered a dose of NOXFIBRA 2 hours pre-operatively (general surgery).
Placement and removal of a catheter should be delayed for 10–12 hours after administration of DVT prophylactic doses of NOXFIBRA, whereas patients receiving higher doses of NOXFIBRA (1 mg/kg twice daily or 1,5 mg/kg once daily) will require longer delays (24 hours). The subsequent NOXFIBRA dose should be given no sooner than 2 hours after catheter removal.
Should the medical practitioner decide to administer anticoagulation in the context of epidural/spinal anaesthesia, extreme vigilance and frequent monitoring must be exercised to detect any signs and symptoms of neurological impairment such as midline back pain, sensory and motor deficits (numbness or weakness in lower limbs), bowel and/or bladder dysfunction. Patients should be instructed to inform their medical practitioner immediately if they experience any of the above signs or symptoms. If signs or symptoms of spinal haematoma are suspected, urgent diagnosis and treatment including spinal cord decompression should be initiated.
Low Molecular Weight Heparins such as NOXFIBRA should not be used interchangeably since they may differ in their manufacturing processes, molecular masses, specific anti-Xa activities, units and dosage. This results in differences in pharmacokinetics and associated biological activities {e.g. antithrombin (IIa) activity and platelet interactions}.
Special attention and compliance with the instructions for use specific to each proprietary medicinal product is therefore required.
Hyperkalaemia related to hypoaldosteronism has been reported in patients treated with low-molecularweight heparins, such as NOXFIBRA.
NOXFIBRA is to be used with extreme caution in patients with a history of heparin-induced thrombocytopenia, with or without thrombosis. The risk of heparin-induced thrombocytopenia may persist for several years. If a history of heparin-induced thrombocytopenia is suspected, the decision to use NOXFIBRA in such case must be made only in consultation with an expert in the field.
To minimise the risk of bleeding following the vascular instrumentation during the treatment of unstable angina, non-Q-wave myocardial infarction and acute ST-segment elevation myocardial infarction, adherence to the intervals recommended between NOXFIBRA doses is essential. It is important to achieve haemostasis at the puncture site after PCI. In case a closure device is used, the sheath can be removed immediately. If a manual compression method is used, the sheath should be removed 6 hours after the last IV/SC NOXFIBRA injection.
If the treatment of NOXFIBRA is to be continued, the next scheduled dose should be given no sooner than 6 to 8 hours after sheath removal. The site of the procedure should be observed for signs of bleeding or haematoma formation.
At doses used for prophylaxis of venous thromboembolism, NOXFIBRA does not influence bleeding time and global blood coagulation tests significantly, nor does it affect platelet aggregation or binding of fibrinogen to platelets. Inter-individual variations in bleeding and coagulation times may occur even when identical dosages are used.
At higher doses than used for prophylaxis, increases in APTT (activated partial thromboplastin time) and ACT (activated clotting time) may occur. Increases in APTT and ACT are not linearly correlated with increasing NOXFIBRA antithrombotic activity and therefore use unsuitable and unreliable for monitoring NOXFIBRA activity.
Bleeding may occur at any site (see “SIDE EFFECTS”).
If bleeding occurs, the origin of the haemorrhage should be investigated and appropriate treatment instituted.
These include major haemorrhages, reported at most in 4.2% of the patients (surgical patients). Some of these cases have been fatal.
In surgical patients, haemorrhage complications were considered major:
Standard clotting tests cannot be done to monitor treatment because unlike unfractionated heparin, NOXFIBRA in therapeutic doses does not modify coagulation time or platelet function and neither does it prolong APTT and TT.
Target anti-factorXa ranges for therapeutic doses have been well defined in previous studies. For twice daily and once daily dosing of subcutaneous enoxaparin, peak anti-factorXa levels of between 0.6 to 1.0 IU/ml and 1.0 to 2.0 IU/ml have been suggested respectively. Ranges between Low Molecular Weight Heparins (LMWH) may be sufficiently similar to aim for a standardized target range. However, there are significant differences in target levels between various LMWHs at therapeutic doses.
NOXFIBRA injection should be used with caution in conditions with increased potential for bleeding, such as:
History of peptic ulcer.Impaired haemostasis.Recent ischaemic stroke.Uncontrolled severe arterial hypertension.Diabetic retinopathy.Recent neuro-or ophthalmologic surgery.Concomitant use of medicines affecting haemostasis (see “INTERACTIONS”).The use of NOXFIBRA has not been adequately studied for thromboprophylaxis in patients with mechanical prosthetic heart valves.
Fatalities of prosthetic heart valve thromboses have been reported in patients with mechanical prosthetic heart valves who received enoxaparin sodium for thromboprophylaxis (see “CONTRAINDICATIONS”).
Elderly patients may be at an increased risk for bleeding complications with the therapeutic dosage ranges.
Careful clinical monitoring is advised (see “DOSAGE AND DIRECTIONS FOR USE – Elderly” and “PHARMACOLOGICAL ACTION – Elderly”).
In patients with renal impairment, there is an increase in exposure of NOXFIBRA which increases the risk of bleeding.
Since exposure of NOXFIBRA is significantly increased in patients with severe renal impairment (creatinine clearance <30 ml/min), a dosage adjustment is recommended for therapeutic and prophylactic dosage ranges. Although no dose adjustment is recommended in patients with moderate (creatinine clearance 30 to 50 ml/min) and mild (creatinine clearance 50 to 80 ml/min) renal impairment, careful clinical monitoring is advised (see “DOSAGE AND DIRECTIONS FOR USE – Renal impairment” and “PHARMACOLOGICAL ACTION – Renal impairment”).
An increase in exposure of NOXFIBRA with prophylactic dosages (non-weight adjusted) has been observed in low-weight women (below 45 kg) and low-weight men (below 57 kg) which may lead to a higher risk of bleeding. Therefore, careful clinical monitoring is advised in patients (see “PHARMALOGICAL ACTION – Weight”).
The risk of antibody-mediated heparin-induced thrombocytopenia also exists with NOXFIBRA. Should thrombocytopenia occur, it usually appears between the 5th and 21st day following the beginning of NOXFIBRA treatment.
Therefore it is recommended that the platelet counts be measured before the initiation of therapy with NOXFIBRA and then regularly thereafter during treatment. In practice, if confirmed significant decrease of the platelet count is observed (30 to 50 % of the initial value), NOXFIBRA treatment must be immediately discontinued and the patient switched to another therapy.
It is recommended that medicines which affect haemostasis should be discontinued prior to NOXFIBRA therapy unless strictly indicated, such as:
If the combination cannot be avoided, NOXFIBRA should be used with careful clinical and laboratory monitoring.
Safety of NOXFIBRA in pregnancy and lactation has not been established (see “WARNINGS AND SPECIAL PRECAUTIONS”).
Women receiving NOXFIBRA should not breastfeed their infants.
NOXFIBRA has no effect on the ability to drive and operate machines.
The following frequency rating has been used: Frequent: (>1/10); (>1/100, <1/10); Less frequent: (>1/1000, <1/100); (>1/10 000, <1/1000); (<1/10 000), including rare isolated cases.
Frequent: Haemorrhage, haemorrhagic anaemia*, thrombocytopenia, thrombocytosis.
Less frequent: Eosinophilia,
Cases of immuno-allergic thrombocytopenia with thrombosis; in some of them thrombosis was complicated by organ infarction or limb ischaemia
Frequent: Allergic reaction
Less frequent: Anaphylactic/Anaphylactoid reactions including shock
Frequent: Headache.
Less frequent: Spinal haematoma* (or neuraxial haematoma). These reactions have resulted in varying degrees of neurologic injuries including long-term or permanent paralysis
Frequent: Hepatic enzyme increases (mainly transaminases >3 times the upper limit of normality)
Less frequent: Hepatocellular liver injury, Cholestatic liver injury
Frequent: Urticaria, pruritus, erythema
Less frequent: Bullous dermatitis, Alopecia, Cutaneous vasculitis*, skin necrosis* usually occurring at the injection site (these phenomena have been usually preceded by purpura or erythematous plaques, infiltrated and painful). Injection site nodules (inflammatory nodules, which were not cystic enclosure of enoxaparin). They resolve after a few days and should not cause treatment discontinuation.
Less frequent: Osteoporosis
Frequent: Injection site haematoma, injection site pain, other injection site reaction (such as oedema, haemorrhage, hypersensitivity, inflammation, mass, pain, or reaction)
Less frequent: Local irritation, skin necrosis at injection site
Less frequent: Hyperkalaemia
During NOXFIBRA therapy, bleeding may occur in the presence of associated risk factors such as organic lesions liable to bleed, invasive procedures or the use of medications affecting haemostasis. The origin of the bleeding should be investigated and appropriate treatment initiated.
Transient, asymptomatic thrombocytopenia, has been reported during the first days of therapy. Asymptomatic and reversible increases in platelet counts have been reported. Gastrointestinal bleeding, haematuria and haemarthrosis have been reported. Major bleeding including retroperitoneal and intracranial bleeding has been reported. Some of these cases have been fatal. When nearaxial anaesthesia (epidural/spinal anaesthesia) or spinal puncture is employed, patients anticoagulated or scheduled to be anticoagulated with NOXFIBRA for prevention of thromboembolic complications are at risk of developing an epidural or spinal haematoma which can result in long-term or permanent paralysis. The risk of these events is increased by use of indwelling epidural catheters for administration of analgesia, or the concomitant use of medicines affecting haemostasis such as NSAIDs, platelet inhibitors, or other anticoagulants. The risk also appears to be increased by traumatic or repeated epidural or spinal puncture. Patients should be frequently monitored for signs and symptoms of neurological impairment. If neurologic compromise is noted, urgent treatment is necessary.
Cases of severe immuno-allergic thrombocytopenia with or without arterial thrombosis have been reported. In some cases, thrombosis was complicated by organ infarction or limb ischaemia (see “WARNINGS AND SPECIAL PRECAUTIONS – monitoring of platelets”).
Hard inflammatory nodules which are non-cystic enclosures of NOXFIBRA have been observed at the injection site. They resolve after a few days and should not cause treatment discontinuation. Cases of skin necrosis at the injection site have been reported with NOXFIBRA. This phenomena is usually preceded by purpura and erythematous plaques, infiltrated and painful. Treatment with NOXFIBRA must be discontinued.
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