Desirudin

In patients with mild or moderate renal impairment (creatinine clearance between 31 and 90 ml/min) activated partial thromboplastin time (aPTT) should be monitored.

In patients with mild to moderate liver impairment aPTT monitoring is recommended.

During prophylaxis, concomitant use of medicinal products containing heparins (unfractionated and low-molecular weight heparins) and dextrans is not recommended. The effects of desirudin and unfractionated heparins on prolongation of aPTT have been shown to be additive.

Reproductive toxicology studies in animals showed desirudin to be teratogenic with changes comprising spina bifida in rabbits and omphaloceles in rats. Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.

As with other anticoagulants desirudin should be used with caution in conjunction with medicinal products which affect platelet function these medicinal products include: acetylsalicylic acid and NSAIDs, ticlopidine and clopidogrel, glycoprotein IIb/IIIa antagonists (abciximab, eptifibatide, tirofiban) and iloprost.

Desirudin may cause allergic reactions including anaphylaxis and shock. Fatal anaphylactic reactions have been reported in patients re-exposed to hirudin product therapy in a second or subsequent treatment course. Although fatal reactions have not been reported with desirudin, alternative treatment options must be considered before the decision to re-expose a patient to desirudin. As these reactions are immune-mediated, patients with previous exposure to hirudin or hirudin analogue may be at an increased risk. Treatment initiation with desirudin should be undertaken only in a setting where medical assistance is readily available and where there is access to treatment for anaphylactic reactions. Patients should be informed that they have received desirudin.

Desirudin should be used with caution in conditions with increased risks of haemorrhage such as major surgery, biopsy or puncture of a non-compressible vessel within the last month; a history of haemorrhagic stroke, intracranial or intraocular bleeding including diabetic (haemorrhagic) retinopathy; a cerebral ischaemic attack within the last 6 months, a known haemostatic disorder (congenital or acquired, e.g. haemophilia, liver disease) or a history of gastrointestinal or pulmonary bleeding within the past 3 months.

When desirudin is administered in patients with increased risk of bleeding complications, mild to moderate hepatic dysfunction and/or mild to moderate renal impairment, aPTT should be monitored and peak aPTT should not exceed twice the control value. If necessary, therapy with desirudin should be interrupted until aPTT returns to less than twice the control value at which time treatment with desirudin can be resumed at a reduced dose.

There are no adequate data from the use of desirudin in pregnant women. Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown. Desirudin is contraindicated in pregnancy.

It is not known whether desirudin is excreted in human milk. However, lactating mothers should be advised to avoid breast feeding or alternative medicinal products used.

Desirudin has no or negligible influence on the ability to drive and use machines.

In controlled clinical trials investigating desirudin 15 mg twice daily and a standard dose of unfractionated heparin, the nature of the hip surgery operation and the mode of action of the two drugs studied account for most of the adverse experiences reported. As with other anticoagulants, bleeding is the most common adverse reaction.

The following related adverse reactions were listed below by system organ class and within each frequency grouping, adverse reactions are presented in order of decreasing seriousness: common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000).

Investigations

Uncommon: Increase in serum transaminases

Blood and the lymphatic system disorders

Common: Anaemia

Nervous system disorders

Uncommon: Dizziness, insomnia, confusion

Respiratory, thoracic and mediastinal disorders

Uncommon: Dyspnoea

Gastrointestinal disorders

Common: Nausea

Uncommon: Haematemesis, vomiting, constipation

Renal and urinary disorders

Uncommon: Haematuria, urinary retention

Skin and subcutaneous tissue disorders

Uncommon: Rash, urticaria

Metabolism and nutrition disorders

Uncommon: Hypokalaemia

Infections and infestations

Uncommon: Urinary tract infection, cystitis

Injury, poisoning and procedural complications

Common: Wound secretion

Uncommon: Impaired wound healing

Vascular disorders

Common: Hypotension, deep thrombophlebitis

Uncommon: Epistaxis, hypertension

General disorders and administration site conditions

Common: Fever, injection site mass, haematomas, oedema in legs

Uncommon: Pain in legs, pain, abdominal and chest pain

Immune system disorders

Common: Allergic reactions have been reported in the same proportion (1.6%) of patients treated with desirudin (N=2,367) or with unfractionated heparin (N=1,134) in clinical trials, regardless of causality.

Rare: Anti-hirudin antibodies have been detected upon re-exposure to desirudin in clinical trials.

Adverse reactions irrespective of trial drug relationship reported during clinical trials were bleeding episodes, oliguria, hyperpyrexia and joint dislocation.

In post-marketing surveillance, rare reports of major haemorrhages, some of which were fatal; and rare reports of non-fatal anaphylactic or anaphylactoid reactions leading to shock have been received.