4.1. Therapeutic indications

Anticoagulation in adult patients with heparin-induced thrombocytopenia type II who require parenteral antithrombotic therapy. The diagnosis should be confirmed by the HIPAA (heparin induced platelet activation assay) or an equivalent test. However, such confirmation must not delay the start of treatment.

4.2. Posology and method of administration

Paediatric population

Currently available data are described in section 5.1 and 5.2 but no recommendation on a posology can be made.

Initial Dosage

Treatment with Exembol Multidose should be initiated under the guidance of a physician with experience in coagulation disorders.

The initial dosage in adult patients without hepatic impairment in HIT type II is 2 microgram/kg/min, administered as a continuous infusion (see Method of Administration). Before Exembol Multidose is administered, heparin therapy should be discontinued and a baseline aPTT value obtained.

Standard recommendations

Monitoring:

In general, therapy with Exembol Multidose is monitored using the activated partial thromboplastin time (aPTT).

Tests of anticoagulant effects (including the aPTT) attain steady-state levels typically within 1-3 hours following initiation of Exembol Multidose.

The target range for steady-state aPTT is 1.5-3.0 times the initial baseline value, but not exceeding 100 seconds.

Dose adjustment may be required to attain the target aPTT (see Dose Modifications). aPTT should be checked two hours after the start of the infusion to confirm that the aPTT is within the desired therapeutic range. Thereafter, the aPTT should be monitored at least once per day.

Dose modifications:

After the initial dose of Exembol Multidose, the dose can be adjusted based on the clinical course until the steady-state aPTT is within the desired therapeutic range (1.5 to 3.0 times the initial baseline value but not exceeding 100 seconds). In case of an elevated aPTT (greater than 3 times baseline or 100 seconds), the infusion should be discontinued until the aPTT is within the desired range of 1.5 to 3 times baseline (typically within 2 hours of discontinuation of infusion), and the infusion restarted at one half of the previous infusion rate. The aPTT should be checked again after 2 hours.

The maximum recommended dose is 10 microgram/kg/min. The maximum recommended duration of treatment is 14 days, although there is limited clinical experience of administration for longer periods (see section 5.1).

Standard dosing schedule

Initial Infusion Rate 2 mcg/kg/min.

Critically Ill/Hepatically impaired patients

Initial infusion rate 0.5 mcg/kg/min.

aPTT (s)

Infusion Rate change

Next aPTT

Infusion Rate change

Next aPTT

< 1.5 times baseline

Increase by 0.5 mcg/kg/min.

2 hours

Increase by 0.1 mcg/kg/min.

4 hours

1.5-3.0 times baseline (not exceeding 100 s)

No change

2 hours; after 2 consecutive aPTT's within target range, Check at least once per day

No change

4 hours; after 2 consecutive aPTT's within target range Check at least once per day

> 3.0 times baseline or > 100 s

Stop infusion until the aPTT is 1.5-3.0 times baseline; Resume at half of the previous infusion rate

2 hours

Stop infusion until the aPTT is 1.5-3.0 times baseline; Resume at half of the previous infusion rate

4 hours

Method of administration

Exembol Multidose is supplied as a concentrate (250 mg/2.5 ml) which must be diluted 100-fold prior to infusion to a final concentration of 1 mg/ml (see section 6.6).

Standard infusion rates for the 2 microgram/kg/min recommended initial dosage (1 mg/ml final concentration) are detailed in the table below. The standard infusion rates for patients with moderate hepatic impairment (Child-Pugh Class B), after cardiac surgery and critically ill patients with a starting infusion rate of 0.5 microgram/kg/min are also detailed in the table below:

Body Weight (kg)

Infusion Rate (ml/hr)

2 microgram/kg/min

0.5 microgram/kg/min

50

6

1.5

60

7

1.8

70

8

2.1

80

10

2.4

90

11

2.7

100

12

3.0

110

13

3.3

120

14

3.6

130

16

3.9

140

17

4.2

Additional Information on Special Populations:

Older people

The standard initial dosage recommendations for use in adults are applicable to elderly patients.

Paediatric population

Limited data from a prospective clinical study in 18 children (neonates to 16 years old) and published data is available. The safe and effective dose or the effective target range for aPTT or activated clotting time (ACT) of Exembol Multidose has not been clearly established in this patient population Currently available data are described in Section 5.1 and 5.2 but no recommendation on a posology can be made..

Renal impairment

The standard initial dosage recommendations for use in adults are applicable to patients with renal impairment (see section 5.2).

Limited data is available from the use of Exembol Multidose in haemodialysis. Based on the data, therapy could be initiated with an initial bolus (250 microgram/kg) followed by continuous infusion of 2 microgram/kg/min. The infusion is stopped 1 hour before the end of the procedure. The target ACT range is 170-230 seconds (measured using the Haemotec device).

In patients that are already being treated with Exembol Multidose no bolus dose is required.

Exembol Multidose clearance by high flux membranes used during haemodialysis and continuous venovenous haemofiltration was clinically insignificant.

Hepatic impairment

For patients with moderate hepatic impairment (Child-Pugh Class B), an initial dose of 0.5 microgram/kg/min is recommended (see section 4.4 and section 5.2). The aPTT should be monitored closely and the dosage should be adjusted as indicated clinically. Exembol Multidose is contra-indicated in patients with severely impaired liver function.

Patients with HIT Type II after cardiac surgery and critically ill patients

Limited data is available from the use of Exembol Multidose in patients with HIT Type II after cardiac surgery and critically ill patients / intensive care unit (ICU) patients with (multiple) organ system failure. Based on the data therapy could be initiated with a starting infusion rate of 0.5 microgram/kg/min (maximum 10 microgram/kg/min) and adjusted to the target aPTT range of 1.5-3.0 times baseline value (not exceeding 100 seconds).

In critically ill/ICU patients with severe (multiple) organ failure (as assessed by SOFA-II APACHE-II or comparable scores) a reduced maintenance dose is recommended.

The clinical status of the patient, especially acute changes in hepatic function, should be taken into account and the infusion rate should be carefully adjusted to maintain the aPTT in the desired range.

An increase in the frequency of monitoring is recommended to ensure the target aPTT values are achieved and maintained.

Patients with HIT Type II undergoing percutaneous coronary intervention (PCI)

Limited data is available from the use of Exembol Multidose in patients with HIT Type II undergoing percutaneous coronary intervention. Based on the data, when there is no alternative, therapy could be initiated with a bolus dose of 350 microgram/kg over 3 to 5 minutes followed by an infusion dose of 25 microgram/kg/min. ACT should be checked 5 to 10 minutes after the bolus dose is completed. The procedure may proceed if the ACT is greater than 300 sec. If the ACT is below 300 sec, an additional bolus dose of 150 microgram/kg should be administered, the infusion rate be increased to 30 microgram/kg/min, and the ACT should be checked 5 to 10 minutes later. If the ACT is higher than 450 sec, the infusion rate should be decreased to 15 microgram/kg/min and ACT values be checked 5 to 10 min later. Once a therapeutic ACT between 300 to 450 sec has been achieved, the infusion dose should be continued for the duration of the procedure. ACT measurements were recorded using both Haemotec and Haemochrom devices.

The efficacy and safety of Exembol Multidose use in combination with GPIIb/IIIa inhibitors has not been established.

Body Weight (kg)

For ACT 300-450 seconds Initial Dosage 25 mcg/kg/min

If ACT <300 seconds Dosage Adjustment† 30 mcg/kg/min

If ACT >450 seconds Dosage Adjustment 15 mcg/kg/min

Bolus Dose (mcg)

Infusion Dose (mcg/min)

Infusion Rate (ml/hr)

Bolus Dose (mcg)

Infusion Dose (mcg/

min)

Infusion Rate (ml/hr)

Infusion Dose (mcg/min)

Infusion Rate (ml/hr)

50

17500

1250

75

7500

1500

90

750

45

60

21000

1500

90

9000

1800

108

900

54

70

24500

1750

105

10500

2100

126

1050

63

80

28000

2000

120

12000

2400

144

1200

72

90

31500

2250

135

13500

2700

162

1350

81

100

35000

2500

150

15000

3000

180

1500

90

110

38500

2750

165

16500

3300

198

1650

99

120

42000

3000

180

18000

3600

216

1800

108

130

45500

3250

195

19500

3900

234

1950

117

140

49000

3500

210

21000

4200

252

2100

126

NOTE: Exembol Multidose concentrate is diluted before use to 1 mg/ml = 1000 microgram (mcg)/ml

† Additional IV bolus dose of 150 mcg/kg should be administered if ACT <300 seconds.

Specific dosing information on patients with hepatic impairment undergoing PCI is not available. Therefore, the use of Exembol Multidose for treatment of patients with hepatic impairment requiring PCI is not recommended.

Recommendations for use in patients scheduled for a conversion to oral anticoagulation

Use of oral anticoagulants (of the coumarin type) should be delayed until substantial resolution of thrombocytopaenia (e.g. platelets >100 x 109/l) to avoid coumarin associated microvascular thrombosis and venous limb gangrene. The intended maintenance dose should be started with no loading dose.

Quick type PT assay

Owren type PT assay

In a Quick type PT assay the recommendations below should be considered:

Co-administration of Exembol Multidose and oral anticoagulants of the coumarin type produces an additive effect on the INR when the Quick type PT assay is used.

The INR depends on both the dose of Exembol Multidose and the International Sensitivity Index (ISI) of the thromboplastin reagent used.

In general, with doses of e up to 2 microgram/kg/min, Exembol Multidose can be discontinued when the INR reaches a minimum of 4 on combined therapy.

When an Owren PT type assay is used the plasma samples is considerably diluted prior to analysis and the recommendations below should be considered:

In vitro tests indicate there is no clinically significant effect of Exembol Multidose on the INR value at a typical plasma concentration arising from a dose of around 2 microgram/kg/min. However, higher concentrations of Exembol Multidose may result in an increase of the INR values.

The target value for INR on co- therapy should be as recommended for the oral anticoagulant alone i.e. 2-3.

For both the Quick and Owren type PT assays;

Co-therapy of Exembol Multidose and oral anticoagulants (of the coumarin type) is recommended for a minimum of 5 days. INR should be measured daily while Exembol Multidose and oral anticoagulants are co-administered. The target value for INR should be within the therapeutic range for co-therapy according to the type of assay used (see above) for at least 2 days before Exembol Multidose is discontinued.

The INR measurement should be repeated 4-6 hours after discontinuation of Exembol Multidose. If the repeat INR is below the desired therapeutic range, the infusion of Exembol Multidose should be resumed and the procedure repeated daily until the desired therapeutic range on oral anticoagulants alone is reached.

For doses greater than 2 microgram/kg/min, the relationship between INR on oral anticoagulants alone or INR on oral anticoagulants plus Exembol Multidose is less predictable. With such higher doses, the dose of Exembol Multidose should be temporarily reduced to 2 microgram/kg/min in order to improve the prediction of INR on oral anticoagulants alone (see above). The INR on Exembol Multidose and oral anticoagulants should be measured 4 to 6 hours after reduction of the Exembol Multidose dose.

4.3. Contraindications

Exembol Multidose is contraindicated

• In patients with uncontrolled bleeding

• Hypersensitivity to argatroban or to any of the excipients

• Severe hepatic impairment.

4.4. Special warnings and precautions for use

Exembol Multidose causes a generally increased tendency to bleeding. An unexplained fall in haematocrit, fall in blood pressure, or any other unexplained symptom should lead to consideration of a haemorrhagic event.

Exembol Multidose should be used with extreme caution in disease states and other circumstances in which there is an increased danger of haemorrhage. These include treatment for severe hypertension; diabetic retinopathy; immediately following lumbar puncture; spinal anaesthesia; major surgery, especially involving the brain, spinal cord, or eye; haematological conditions associated with increased bleeding tendencies such as congenital or acquired bleeding disorders and gastrointestinal lesions such as ulcerations.

Parenteral anticoagulants: All parenteral anticoagulants should be discontinued before administration of Exembol Multidose. When Exembol Multidose is to be started after cessation of heparin therapy, sufficient time should be allowed for the effect of heparin on the aPTT to decrease prior to start of Exembol Multidose therapy (about 1-2 hours).

Hepatic Impairment: Caution should be exercised when administering Exembol Multidose to patients with hepatic disease, by starting with a lower dose and carefully titrating until the desired level of anticoagulation is achieved (see section 4.2). Also, upon cessation of Exembol Multidose infusion in the hepatically-impaired patient, full reversal of anticoagulant effects may require longer than 4 hours due to decreased clearance of argatroban.

Laboratory Tests: Measurements of aPTT are recommended for monitoring the infusion. Although other plasma coagulation tests including prothrombin time (PT, expressed for example as the International Normalized Ratio (INR)), the activated clotting time (ACT) and thrombin time (TT) are affected by Exembol Multidose; the therapeutic ranges for these tests have not been defined (with the exception of ACT) Plasma argatroban concentrations also correlate well with the anticoagulant effects.

The concomitant use of Exembol Multidose and oral anticoagulants of the coumarin type may result in prolongation of the PT (INR) beyond that produced by oral anticoagulants alone. Refer to section 4.2 for alternative approaches for monitoring concurrent Exembol Multidose and oral anticoagulants therapy.

This medicinal product contains ethanol. The maximum recommended daily dose (10 microgram/kg/min) of this medicine administered to an adult weighing 70 kg would result in exposure to 57.6 mg/kg of ethanol which may cause a rise in blood alcohol concentration (BAC) of about 9.6 mg/100 ml. Because this medicine is usually given slowly over several hours, the effects of alcohol may be reduced.

This medicinal product contains sorbitol. Patients with rare hereditary problems of fructose intolerance should not use this medicinal product.

There is no specific antidote to Exembol Multidose.

4.5. Interaction with other medicinal products and other forms of interaction

Concomitant use with antiplatelet agents, thrombolytics, and other anticoagulants may increase the risk of bleeding.

Oral anticoagulant agents: Pharmacokinetic drug interactions between Exembol Multidose and warfarin (7.5 mg single oral dose) have not been demonstrated. However, the concomitant use of Exembol Multidose and warfarin (5-7.5 mg initial oral dose followed by 2.5-6 mg/day orally for 6-10 days) results in an increase of the International Normalized Ratio (INR). Refer to section 4.2 for recommendations for managing the switch from Exembol Multidose to oral anticoagulation.

Thrombolytics, anti-platelet and other agents: The safety and effectiveness of Exembol Multidose with thrombolytic agents have not been established.

The risks for interaction with argatroban have not been evaluated. Caution is needed when concomitant medicinal products are commenced for the first time .

As Exembol Multidose contains ethanol, an interaction with metronidazol or disulfiram cannot be excluded.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no adequate data from the use of Exembol Multidose in pregnant women. The effect of argatroban on reproduction has been incompletely studied in animal experiments, as technical issues have limited systemic exposure (see section 5.3 for results of animal studies). The increased bleeding risk with Exembol Multidose may constitute a risk in treatment during pregnancy. Exembol Multidose contains ethanol. A 70 kg patient administered the maximum recommended daily dose (10 µg/kg/min) would receive a dose of approximately 4 g ethanol per day. Exembol Multidose should be used during pregnancy only if treatment is clearly necessary.

Lactation

It is unknown whether argatroban/metabolites are excreted in human milk. Animal studies using radiolabelled argatroban have shown that radioactivity reaches greater levels in breast milk than in maternal blood. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Exembol therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

Fertility

There are no data on potential effects of Exembol Multidose on fertility.

4.7. Effects on ability to drive and use machines

In theory, the presence of ethanol in the formulation (1 g per vial) may impair the patient's ability to drive or operate machinery. However, this is unlikely to be of clinical relevance in patients receiving Exembol Multidose.

4.8. Undesirable effects

Bleeding complications, as is to be expected given the pharmacological properties, constitute the main adverse events. In the clinical trials involving patients with HIT type II anticoagulated with Exembol Multidose, the incidence of major bleeds was 31/568 (5.5%) and minor bleeds 221/568 (38.9%). The incidence of major bleeds was almost three times higher in those patients in whom the aPTT level exceeded more than three times the baseline value than in those whose aPTT was within the therapeutic range. Dosage of Exembol Multidose should be adjusted to achieve a target aPTT level of 1.5-3.0 x baseline not exceeding 100 seconds (see section 4.2).

The incidence of adverse reactions in clinical trials (568 patients with HIT Type II) which are considered to be possibly related to Exembol Multidose is stated below.

Organ system

Common

(≥1/100, ≤1/10)

Uncommon

(≥1/1000, ≤1/100)

Not Known

(frequency cannot be estimated from the available data)

Infections and infestations

Infection, urinary tract infection

Blood and lymphatic system disorders

Anaemia

Coagulopathy, thrombocytopenia, leukopenia

Cerebral haemorrhage

Metabolism and nutrition disorders

Anorexia, hypoglycaemia, hyponatraemia

Psychiatric disorders

Confusional state

Nervous system disorders

Dizziness, headache, syncope, cerebrovascular accident, hypotonia, speech disorder

Eye disorders

Visual disturbance

Ear and labyrinth disorders

Deafness

Cardiac disorders

Atrial fibrillation, tachycardia, cardiac arrest, myocardial infarction, arrhythmia supraventricular, pericardial effusion, ventricular tachycardia, hypertension, hypotension,

Vascular disorders

Deep vein thrombosis, haemorrhage

thrombosis, phlebitis, thrombophlebitis, thrombophlebitis leg superficial, shock, peripheral ischaemia, peripheral embolism

Respiratory,thoracic and mediastinal disorders

Hypoxia, pulmonary embolism, dyspnoea, pulmonary haemorrhage, pleural effusion, hiccups

Gastrointestinal disorders

Nausea

Vomiting, constipation, diarrhoea, gastritis, gastrointestinal haemorrhage, melaena, dysphagia, tongue disorder

Hepatobiliary disorders

Hepatic function abnormal, hyperbilirubinaemia, hepatic failure, hepatomegaly, jaundice

Skin and subcutaneous tissue disorders

Purpura

Rash, sweating increased, dermatitis bullous, alopecia, skin disorder, urticaria

Musculoskeletal and connective tissue disorders

Muscular weakness, myalgia

Renal and urinary disorders

Haematuria, renal insufficiency

General disorders and administration site conditions

Pyrexia, pain, fatigue, application site reaction, injection site reaction, oedema peripheral

Investigations

Prothrombin complex level decreased, coagulation factor decreased, coagulation time prolonged, aspartate aminotransferase increased, alanine aminotransferase increased, blood alkaline phosphatase increased, blood lactate dehydrogenase increased

Injury and poisoning and procedural complications

Wound secretion

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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Excessive anticoagulation, with or without bleeding, may be controlled by discontinuing Exembol Multidose or by decreasing the infusion rate. In clinical studies, anticoagulation parameters return to baseline generally within 2 to 4 hours after discontinuation of Exembol Multidose. Reversal of anticoagulant effect may take longer in patients with hepatic impairment.

No specific antidote to Exembol Multidose is available. If life-threatening bleeding occurs and excessive plasma levels of argatroban are suspected, Exembol Multidose should be discontinued immediately and aPTT and other coagulation tests should be performed. Symptomatic and supportive therapy should be provided to the patient.

Lethal single intravenous doses of argatroban for mice, rats, rabbits, and dogs were 200, 124, 150, and 200 mg/kg respectively. The symptoms of acute toxicity were loss of righting reflex, tremors, clonic convulsions, paralysis of hind limbs, and coma.

Each vial contains 1 g ethanol.