EXEMBOL MULTIDOSE

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.

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. 0 times the initial baseline value but not exceeding 100 seconds). 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. 1). Standard dosing schedule Initial Infusion Rate 2 mcg/kg/min. 5 mcg/kg/min. 5 mcg/kg/min. 1 mcg/kg/min. 6). Standard infusion rates for the 2 microgram/kg/min recommended initial dosage (1 mg/ml final concentration) are detailed in the table below.

2 Additional Information on Special Populations: Elderly patients The standard initial dosage recommendations for use in adults are applicable to elderly patients. Children and adolescents (<18 years) Limited data from a prospective clinical study in 18 children (neonates to 16 years old) and published data is available.

2). 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.

Bleeding complications, as is to be expected given the pharmacological properties, constitute the main adverse events. 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.

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) Infections and infestations Infection, urinary tract infection Blood and lymphatic system disorders Anaemia Coagulopathy, thrombocytopenia, leukopenia 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, Organ system Common (≥1/100, ≤1/10) Uncommon (≥1/1000, ≤1/100) 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.

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).

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. 2 for alternative approaches for monitoring concurrent Exembol Multidose and oral anticoagulants therapy.

Exembol Multidose is contraindicated in patients with uncontrolled bleeding. Hypersensitivity to argatroban or to any of the excipients. Severe hepatic impairment.