EXEMBOL Solution for infusion Ref.[6214] Active ingredients: Argatroban

Exembol 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 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. When Exembol 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 therapy (about 1-2 hours).

Hepatic Impairment: Caution should be exercised when administering Exembol 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 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; the therapeutic ranges for these tests have not been defined. Plasma argatroban concentrations also correlate well with the anticoagulant effects.

The concomitant use of Exembol and oral anticoagulants 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 and oral anticoagulants therapy.

Ethanol: Exembol contains ethanol. A 70kg patient administered the maximum recommended daily dose (10 microgram/kg/min) would receive a dose of approximately 4g ethanol per day.

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.

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

Oral anticoagulant agents: Pharmacokinetic drug interactions between Exembol and warfarin (7.5 mg single oral dose) have not been demonstrated. However, the concomitant use of Exembol 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 to oral anticoagulation.

Thrombolytics, anti-platelet and other agents: The safety and effectiveness of Exembol 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.

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

Pregnancy

There are no adequate data from the use of Exembol in pregnant women. Animal studies are insufficient with respect to reproductive toxicity, as technical issues have limited systemic exposure (see section 5.3 for results of animal studies). The increased bleeding risk with Exembol may constitute a risk in treatment during pregnancy. Exembol contains ethanol. A 70kg patient administered the maximum recommended daily dose (10 microgram/kg/min) would receive a dose of approximately 4g ethanol per day.

Exembol 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 on fertility.

In theory, the presence of ethanol in the formulation (200 mg 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.

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, 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 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 is stated below.

Common (≥1/100, ≤1/10)
Uncommon (≥1/1000, ≤1/100)
Not Known (frequency cannot be estimated from the available data)

Infections and infestations

Uncommon: Infection, urinary tract infection

Blood and lymphatic system disorders

Common: Anaemia

Uncommon: Coagulopathy, thrombocytopenia, leukopenia

Not Known: Cerebral haemorrhage

Metabolism and nutrition disorders

Uncommon: Anorexia, hypoglycaemia, hyponatraemia

Psychiatric disorders

Uncommon: Confusional state

Nervous system disorders

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

Eye disorders

Uncommon: Visual disturbance

Ear and labyrinth disorders

Uncommon: Deafness

Cardiac disorders

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

Vascular disorders

Common: Deep vein thrombosis, haemorrhage

Uncommon: Thrombosis, phlebitis, thrombophlebitis, thrombophlebitis leg superficial, shock, peripheral ischaemia, peripheral embolism

Respiratory, thoracic and mediastinal disorders

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

Gastrointestinal disorders

Common: Nausea

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

Hepatobiliary disorders

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

Skin and subcutaneous tissue disorders

Common: Purpura

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

Musculoskeletal and connective tissue disorders

Uncommon: Muscular weakness, myalgia

Renal and urinary disorders

Uncommon: Haematuria, renal insufficiency

General disorders and administration site conditions

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

Investigations

Uncommon: 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

Uncommon: 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.

This medicinal product must not be mixed with other medicinal products.