SUMMARY OF PRODUCT CHARACTERISTICS

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1. NAME OF THE MEDICINAL PRODUCT

, 750 anti-Xa units, solution for injection

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

contains danaparoid sodium, which is a non-heparin mixture of low molecular weight sulfated glycosaminoglycuronans derived from animal mucosa, comprising heparan sulfate, dermatan sulfate and a minor amount of chondroitin sulfates. One ampoule (0.6 ml) contains 750 anti-factor Xa units danaparoid sodium corresponding to 1250 anti-factor Xa units per ml. The anti-Xa unit is derived from the international heparin standard in an antithrombin containing buffer system.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Solution for injection.

Clear/colorless to pale yellow aqueous solution.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications a. Prevention of deep vein thrombosis (DVT) in situations where heparin should not be used, including patients with heparin-induced thrombocytopenia (HIT). b. Treatment of thrombo-embolic disorders in patients who require urgent parenteral anticoagulation because of the development or a history of HIT.

4.2 Posology and method of administration

Posology

Adults a. Posology for therapeutic indication "DVT Prophylaxis"  DVT prophylaxis in situations where Heparin should not be used In general should be administered by subcutaneous injection at a dose of 750 anti-Xa units, twice daily for a period of maximally 14 days unless it is required longer in patients for whom there is no reasonable antithrombotic alternative  DVT prophylaxis in HIT patients In patients with heparin-induced thrombocytopenia (HIT) without manifest thromboembolism dose recommendations for DVT propylaxis depend on the thrombotic risk. In patients with past HIT (>3 months before the present admission), dose recommendations are the same as for patients without HIT (See above "DVT prophylaxis in situations where heparin should not be used"). In patients with acute HIT ( 3 months), i.e. with circulating (LMW) heparin-induced antiplatelet antibody, higher daily dosages are necessary: 2250-3750 anti-Xa units subcutaneously, divided over three doses (8 hourly), administered for 7-10 days, unless it is required longer in patients for whom there is no reasonable antithrombotic alternative. The therapeutic dose for treatment of thrombo-embolic disorders in patients with HIT is provided below.

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In surgical patients it is recommended to start this dosing schedule pre-operatively and to give the last pre-operative dose 1-4 hours before surgery.

When choosing the dosing regimen, body weight and occurrence of bleeding should be considered. In general, a loading intravenous bolus injection given at the same time and equal to the first subcutaneous divided dose is recommended. For patients with a bleeding risk or if the patient is actively bleeding, or if the patient has recently been given a dose of heparin or low molecular weight heparin then the loading intravenous bolus should be omitted. For patients without an increased bleeding risk the intravenous infusion regimen (see under b. Treatment) is an alternative.

Plasma anti-Xa activity is linearly related to the dose of given. In general, monitoring of plasma anti-Xa activity is not necessary. For patients > 90 kg or with mild to moderate renal failure, monitoring the plasma anti-Xa activity response 3-5 days after treatment initiation is appropriate for the desired target range. If it is within range then no further check is necessary but if not, then the dose of should be adjusted and the plasma anti-Xa activity response re-checked 2-3 days later. If monitoring of anticoagulant activity is performed then a functional anti-factor Xa test using a specific chromogenic peptide substrate should be used. In this test should be used as the standard for constructing the reference curve.

The intended plasma anti-Xa activity levels should not go above 0.8 anti-Xa units/ ml at steady-state. In patients who are actively bleeding, unless it is the reason for surgical intervention, the intended plasma anti-Xa levels should not go above 0.4 anti-Xa units/ ml at steady-state.

Dosage in the elderly: clearance of anti-factor Xa activity has not been shown to be significantly reduced in the elderly in the absence of moderate to severe renal dysfunction and the usual dosage is recommended. With respect to the prophylactic use in HIT patients a number of dosing schedules has been applied in vascular operations or invasive vascular procedures; cardiopulmonary procedures and renal failure requiring treatment with an extracorporeal circuit (see section 5.1). b. Treatment of thrombo-embolic disorders in patients with HIT or history of HIT

Treatment The therapeutic dose is 2250 anti-Xa units (for patients <55 kg body weight 1500 anti-Xa units, if >90 kg body weight 3750 anti-Xa units) intravenously as a bolus, plus intravenous infusion of 400 anti-Xa units/h for 4 hours, then 300 anti-Xa units/h for 4 hours, then a maintenance infusion of 150-200 anti-Xa units/h for 5-7 days, unless it is required longer in patients for whom there is no reasonable antithrombotic alternative. Prophylaxis When it is considered that this intravenous regimen is no longer required, because therapy of HIT has been completed, then patients can be converted to a prophylactic dosage regime, i.e. oral anticoagulants, or 750 anti-Xa units subcutaneously, two or three times a day. The intended plasma anti-Xa levels are 1.0 anti-Xa units/ml 5-10 minutes after the bolus, and 0.5-0.8 anti-Xa units/ml during the maintenance infusion.

Conversion to oral anticoagulants (vitamin K antagonists) in patients with HIT: Conversion to oral anticoagulants (VKAs), is possible both during subcutaneous and intravenous dosing schedules. It is advisable only to start such a therapy when there is adequate antithrombotic control with . 1. 750 anti-Xa units subcutaneously two or three times a day: oral anticoagulants (VKAs) can be started 72-96 hours before is

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withdrawn to give time for the prothrombin time, Thrombotest or international normalized ratio (INR) to reach therapeutic levels. 2. 1250 anti-Xa units subcutaneously two or three times a day: when starting oral anticoagulants (VKAs) the dose should be reduced to 750 anti-Xa units subcutaneously two or three times a day and the procedure followed as in (1). 3. intravenous infusion: oral anticoagulants (VKAs) can be given with the infusion (maximum rate 300 anti-Xa units/h) which can then be stopped when the INR is in the required target range. If the bleeding risk is high then either (a) stop the infusion and start 750 anti-Xa units subcutaneously two or three times a day, then 24 hours later start oral anticoagulants (VKAs) according to (1)., or (b) stop the infusion, give no further , then start oral anticoagulants (VKAs) 12 hours later.

Paediatric population Dosage in children (age up to 17 years and weight <55 kg): Paediatric experience with is limited to 36 children, aged from two weeks to 17 years. The dosing schedules are generalized from the experience so far, however, even children of the same age and weight may respond differently to the dose given. Therefore, dosing should be guided by the plasma anti-Xa response and the balance between desired efficacy and risk of bleeding.

Clinical situation Age Dosing2 Plasma anti-Xa category1 activity Prophylaxis 2 years 8-144 U/kg/day 0.1-0.4 U/ml 9-17 years 20-25 U/kg/day Treatment 2 years No data 0.4-0.7 U/ml post- 9-17 years bolus i.v. 30 U/kg + i.v. bolus 29-130 U/kg/day 0.4-0.8 U/ml at steady state 1 no data for patients aged 3 to 8 years inclusive 2 U = anti-Xa unit

With respect to the prophylactic use in pediatric HIT patients a number of dosing schedules has been applied in specific clinical situations (see section 5.1).

Method of administration The method of administration depends on the indication for which is given. For the dosing regimen per indication, see the posology section above.

4.3 Contraindications

- severe haemorrhagic diathesis, e.g. haemophilia and idiopathic thrombocytopenia purpura, unless the patient also has HIT and no alternative antithrombotic treatment is available; - hemorrhagic cerebrovascular accident within the previous three months; - severe renal- and hepatic insufficiency, unless the patient also has HIT and no alternative antithrombotic treatment is available; - severe, uncontrolled hypertension; - active gastroduodenal ulcer, unless it is the reason for operation; - diabetic retinopathy; - acute bacterial endocarditis, unless the patient also has HIT and no alternative antithrombotic treatment is available; - hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1; - a positive in vitro test for heparin-induced antibody in the presence of in patients with a history of thrombocytopenia induced by heparin or heparin-like

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anticoagulant, unless the patient also has an ongoing thrombosis and no suitable alternative antithrombotic is available; - recent (<1 week) or active bleeding (e.g. intracranial, gastrointestinal, intraocular, pulmonary), unless the patient also has HIT and no alternative antithrombotic treatment is available; - damage to the central nervous system or brain, spinal or ophthalmological surgery, unless the patient also has HIT and no alternative antithrombotic treatment is available; - in patients receiving heparin for treatment rather than for prophylaxis, loco-regional anesthesia in elective surgical procedures is contra-indicated.

4.4 Special warnings and precautions for use

should not be given by the intramuscular route.

should be used with caution in patients with moderately impaired renal and/or liver function with impaired hemostasis, ulcerative lesions of the gastro-intestinal tract or other diseases which may lead to an increased danger of hemorrhage into a vital organ or site.

contains sodium sulfite. In asthma patients hypersensitive to sulfite the latter can result in bronchospasm and/or anaphylactic shock.

Since severe bleeding may occur post-operatively in HIT patients undergoing a cardiopulmonary bypass procedure, is not recommended during the procedure, unless no other antithrombotic treatment is available.

The incidence of serological cross-reactivity of with the heparin- induced antibody before the start of therapy is approximately 5%. The incidence of clinical cross- reactivity developing during therapy is approximately 3% and many of these patients had a negative pre-treatment serological cross-reactivity test. Although the risk of antibody-induced thrombocytopenia and thrombosis during therapy (i.e. clinical cross-reactivity) is very small, it is advisable to check the number of platelets daily during the first week of treatment, on alternate days during the second and third weeks, and weekly to monthly thereafter. If a pre-treatment cross-reactivity test with is positive but it is decided to use , then the number of platelets should be checked daily until treatment is stopped. If antibody-induced thrombocytopenia occurs, one should stop the use of and consider alternative treatment.

It should be noted that the anti-Xa units of have a different relationship to clinical effects than those of heparin and low molecular weight heparins.

should be used with caution in patients receiving oral anticoagulants or drugs which interfere with platelet functions (e.g. platelet inhibitors, non-steroidal anti-inflammatory drugs) (see Section 4.5). During use of low molecular weight heparins cases of intraspinal haematomas have been reported incidentally. Therefore, should be administered with caution and after careful individual risk-benefit assessment in patients undergoing lumbar puncture, spinal or epidural anaesthesia. In the event of the institution of central nervous blockage, patients should be frequently monitored for signs and symptoms of neurological impairment, paying particular attention to the persistence of sensory or motor deficit. If signs or symptoms of neuraxial haematoma are suspected, urgent diagnosis and treatment including spinal cord decompression are necessary.

This medicinal product contains sodium sulphite which may rarely cause severe hypersensitivity reactions and bronchospasm

This medicinal product contains less than 1 mmol sodium (23 mg) per 0.6mL, i.e. essentially ‘sodium- free’.

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Paediatric population The warnings and precautions as described above can also be applied to the paediatric population taken into account that there is little clinical experience in children (see section 5.1)

4.5 Interaction with other medicinal products and other forms of interaction

may be used together with oral anticoagulants, drugs which interfere with platelet function (such as aspirin and non-steroidal anti-inflammatory drugs), thrombolytics or potentially ulcerogenic drugs (such as corticosteroids), but caution remains necessary. Monitoring of anticoagulant activity of oral anticoagulants by prothrombin time and thrombotest is unreliable within 5 hours after . There is no data available on the effect of on thyroid function tests.

Paediatric population Interaction studies have only been performed in adults.

4.6 Fertility, pregnancy and lactation

Pregnancy For a very limited amount of data on pregnant patients are available. In all five cases in which human umbilical cord blood was tested for the presence of anti-Xa activity, no activity was found. Animal studies do not indicate direct or indirect harmful effects with respect to reproduction toxicity development (see section 5.3). As a precautionary measure, it is preferable to avoid use of in pregnancy in patients without heparin sensitivity, and in women with an abortus imminens. If alternative antithrombotic treatment is unacceptable for medical reasons (e.g. HIT patients) can be used. Epidural anaesthesia in pregnant women treated with anticoagulant agents is not advised during delivery.

Breast-feeding is excreted in breast milk in negligible amounts. As these amounts are hydrolyzed in the infant’s stomach and rendered harmless, no effects on the suckling child are anticipated. If alternative antithrombotic treatment is unacceptable for medical reasons (e.g. HIT patients) can be used during lactation.

Fertility There is no data available on the effect of on human fertility.

4.7 Effects on ability to drive and use machines

is not known to have any effect on the ability to drive and use machines.

4.8 Undesirable effects

has the potential to increase the risk of bleeding.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

System Organ Common Uncommon Rare Class (MedDRA) (≥1/100 to 1/10 of (≥1/1,000 to 1/100 of (≥1/10,000 to patients) patients) <1/1,000 of patients) Blood and the thrombocytopenia*, auto-immune

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lymphatic heparin-induced thrombocytopenia system disorders thrombocytopenia Immune system hypersensitivity, drug disorders hypersensitivity Skin and rash purpura, rash maculo- rash generalised, rash subcutaneous papular, rash maculovesicular, tissue disorders erythematous, pruritus, injection or infusion urticaria site rash, rash macular General Injection site reaction Injection (inj.) site: disorders and - hemorrhage administration - discomfort site conditions - hypersensitivity

- irritation - coldness - pruritus inj. or infusion site: - erythema - pain - swelling - warmth infusion site: - bruising - reaction Injury, post procedural post procedural incision site poisoning and hemorrhage hematoma, hemorrhage, procedural operative hemorrhage anastomotic complications hemorrhage

Note: terms are coded with MedDRA dictionary version 8.1

*Antibody-induced thrombocytopenia, as can be caused by (low molecular weight) heparin, was observed during the use of , but only in patients who were already sensitized to either heparin or low molecular weight heparin (see Section 4.4).

All above terms in this section and synonym terms (with same or less severity) coded with the MedDRA dictionary are considered as ‘listed’.

All hemorrhages are listed adverse events for . This also means that symptoms or signs which are clearly directly related to a hemorrhage (e.g. anaemia, decreased Hb, rbc, hematocrit, faintness, tiredness, tamponade) are listed adverse events.

Very rarely, cases of epidural and spinal hematomas were reported in association with prophylactic use of heparin in the context of epeidural or spinal anesthesia and of spinal puncture. These hematomas have caused various degrees of neurological impairment, including prolonged or permanent paralysis (see Section 4.4).

Paediatric population There is limited information on the use of in children. However, the safety profile of in the paediatric population did not seem to differ from that of adults.

4.9 Overdose

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In the event of serious bleeding other than caused by a surgical error, should be stopped and transfusion of fresh frozen plasma or, if uncontrollable, plasmapheresis should be considered. Although protamine partially neutralizes the anticoagulant activity of the relevance for the reversal of the bleeding is not clear and therefore it cannot be recommended. The effects of on anti-Xa activity cannot be antagonized with any known agent at this time.

Paediatric population The appropriate actions as described for adults should be taken into account in case of an overdose in the paediatric population. See section 5.1.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: antithrombotic agents, heparin group; ATC code B01A B09

Mechanism of action Danaparoid sodium has been shown both in animal models and in human studies to be an effective antithrombotic substance. At therapeutic doses danaparoid sodium has no or only a minor effect on hemostatic plug formation, platelet function and platelet aggregability with no significant effect on bleeding time at the recommended doses. Occasionally, after high intravenous or subcutaneous doses, a prolonged bleeding time has been observed. The anticoagulant activity of danaparoid sodium in clotting assays such as prothrombin time, activated partial thromboplastin time, kaolin cephalin clotting time and thrombin time is small, and characterized by a very flat dose-response curve up to relatively high doses. The ultimate step in blood coagulation, the fibrinogen-fibrin conversion, is critically dependent on thrombin generation to which factor Xa and thrombin contribute substantially. The anticoagulant profile of danaparoid sodium is characterized by a high ratio of anti-factor Xa/antithrombin activities, resulting in an effective inhibition of thrombin generation and thrombus formation. The anti-Xa activity is mediated by antithrombin and is not inactivated by endogenous heparin-neutralizing factors. The small thrombin inhibitory activity is mediated by heparin co-factor II and antithrombin. The heparan sulfate fraction with low affinity for antithrombin, lacking significant effects on coagulation factors Xa and IIa in vitro, has been shown in animal studies to contribute substantially to the antithrombotic activity which is only in part explained by an inhibitory effect on thrombin mediated activation of clotting factor IX. shows low serological cross-reactivity (approximately 5%) with the heparin-induced antibody. This can be explained by the absence of heparin in and its low degree of both sulfation and negative charge (see Section 4.4). has also been shown to interfere with the interaction of the heparin- induced anti-platelet antibody and its target, thus potentially reducing platelet activation.

Clinical efficacy and safety The following sections summarize the reported clinical experience of use in HIT (or other form of heparin intolerance) patients in specific clinical situations. The data are based on the clinical outcomes of patients treated with in clinical trials, a compassionate use program, literature search data, and data from spontaneous unsolicited SAE reports.  Vascular operations or invasive vascular procedures The clinical experience with use for perioperative thrombosis prophylaxis in peripheral (i.e. non-cardiac or great vessel) vascular surgery is based on 90 operations that consisted mainly of embolectomies, bypass insertion or repair and endarterectomies in patients with HIT. anticoagulation has also been used for 57 invasive vascular procedures in 54 patients with HIT, including PCTA (balloon angioplasty) with or without stenting, intra-aortic balloon pump insertion or removal, caval filter insertion or removal and cardiac catheterization. For operations which did not

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require a by-pass machine patients in general received an intravenous bolus of 2250 U pre- operatively/procedure (>90 kg bw 3750 U). Sixteen patients received continuing treatment for up to 7 days post (PCTA) procedure. For most of them (n=11) the intravenous bolus was followed by an intravenous infusion of 150-200 U/h.  Cardiopulmonary procedures: The clinical experience with in cardiopulmonary by-pass surgery is based on 130 operations in 129 patients. As there is a relatively high frequency of post- operative bleeding and cannot be neutralized is not recommended during cardiopulmonary procedures unless there is absolutely no alternative. It is mainly used for post-operative prophylaxis.

Thus, following the use of or another antithrombotic during cardiopulmonary by-pass surgery and to maintain thrombo-prophylaxis was (re)started once adequate hemostasis was achieved (12-24 hours post-operatively) at 1500-2250 U in divided doses subcutaneously (n=4), or an intravenous infusion at 150-200 U/h (n=8).When used intra-operatively, patients received intravenous 125 U/kg bw post- thoracotomy plus 3 U/ml into the priming fluid for the pump. After connection to by-pass 7 U/kg bw/h intravenous infusion was started until 45 minutes prior to bypass disconnection.

 Renal failure requiring treatment with an extracorporeal circuit

* Intermittent renal hemodialysis: The clinical experience with in intermittent hemodialysis is based on 232 cases. Patients in general received an intravenous bolus of 3750 U just before each of the two hemodialyses. To avoid accumulation of anticoagulant activity the dose was adjusted according to the pre-dialysis plasma anti-Xa levels. During the dialysis, the plasma anti-Xa level was kept between 0.5-0.8 anti-Xa units/ml After 3-5 dialyses the pre-dialysis doses usually remain constant.

* Continuous renal replacement therapy (hemofiltration, hemodialysis): The clinical experience with in CRRT is based on 106 case reports. A continuous dosing regimen as described for treatment of thrombosis was used (see section 4.2 ‘Treatment of thrombo-embolic disorders’). If the hemofilter life was seriously shortened by clotting during previous heparin therapy then during the initial hours of maintenance infusion the rate had to be higher (up to 600 U/h for four hours).  Flush doses: Based upon 14 cases in which was used to flush intravascular lines/access ports, 5-10 ml of a solution of one ampoule (= 750 U) of diluted into 50 ml saline has been used.

Paediatric population The experience with in children in specific clinical situations is based on limited cases. The dose regimens varied widely with the specific indications and age of the child.  Cardiac catheterization: one child ≤ 2 years received 48-120 U/kg/day.  Continuous ambulatory peritoneal dialysis: two children ≤ 2 years received 5-43 U/kg/day.  Hemodialysis: 5 children between 9-17 years received an intravenous bolus of 27-86 U/kg.  Cardiac surgery: one child ≤ 2 years received 350 U/kg/operation (assuming a four hour CPBS) and two children between 9-17 years received >150-311 U/kg/operation.

5.2 Pharmacokinetic properties

Pharmacokinetic studies have primarily been based on the kinetics of relevant anticoagulant activities of danaparoid sodium, because no specific chemical assay methods are available. In animal models the time courses of the thrombin generation inhibitory activity and antithrombotic activities of

9 danaparoid sodium were strongly related, but the simplest to measure is the effect on plasma anti-Xa activity. The absolute bioavailability of danaparoid sodium, as estimated from its effect on plasma anti-Xa activity, after subcutaneous administration approaches 100%. In humans the time to reach peak plasma anti-Xa activity levels is approximately 4-5 hours. The half-lives of elimination of anti-Xa and thrombin generation inhibiting activities of approximately 25 hours and 7 hours respectively, after both subcutaneous and intravenous administration are independent of dose, age and gender. Steady-state levels of plasma anti-Xa activity are usually reached within 4-5 days of dosing. Measured by thrombin generation inhibiting activity steady-state levels are reached earlier, i.e. within 1-2 days. Danaparoid sodium is mainly eliminated by renal excretion and animal experiments indicate that the liver is not involved in its metabolism. In patients with severely impaired renal function the half-life of elimination of plasma anti-factor Xa activity is prolonged.

5.3 Preclinical safety data

Animal studies have not demonstrated a teratogenic effect of . Placental transfer of the substance was negligibly low in the guinea pig.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

 sodium sulfite  sodium chloride  water for injections  hydrochloric acid (to adjust the pH)

6.2 Incompatibilities

When administered as an intravenous bolus or infusion, should be given separately and not be mixed with other drugs. However, is compatible with and can be added to the infusions mentioned in Section 6.6.

6.3 Shelf life

3 years

Chemical and physical in-use stability of diluted in common infusion fluids has been demonstrated for up to 48 hours at 15 to 25C.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.

6.4 Special precautions for storage

Do not store above 30C.

For storage conditions after dilution of the medicinal product, see section 6.3.

Store in the original package in order to protect from light.

6.5 Nature and contents of container

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Box with ten 1-ml glass ampoules, containing 750 anti-factor Xa units (0.6 ml) danaparoid sodium per ampoule (1250 anti-factor Xa units/ ml ).

6.6 Special precautions for disposal

is compatible with, and therefore can be added to, infusions of saline (0.9%), dextrose (5%), dextrose-saline, Ringer’s and lactated Ringer’s.

It is advisable to discard the product when the visual appearance has changed or when the container is damaged.

7. MARKETING AUTHORISATION HOLDER

Aspen Pharma Trading Limited 3016 Lake Drive Citywest Business Campus Dublin 24 Ireland

8. MARKETING AUTHORISATION NUMBER(S)

[To be completed nationally]

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

[To be completed nationally]

10. DATE OF REVISION OF THE TEXT

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