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Drug Details

Refludan 50 mg powder for solution for injection or infusion

• Drug Class Description
  Antithrombotic agent – direct thrombin inhibitor - ATC Code: B01AE02
• Generic Name
  Lepirudin
• Presentation
  Powder for solution for injection or infusion. White to almost white lyophilised powder. .
• Description
  Each vial contains 50 mg lepirudin. (Lepirudin is a recombinant DNA product derived from yeast cells)
• Indications
  

  Anticoagulation in adult patients with heparin-induced thrombocytopenia (HIT) type II and thromboembolic disease mandating parenteral antithrombotic therapy.

  The diagnosis should be confirmed by the HIPAA (heparin induced platelet activation assay) or an equivalent test.

• Adult Dosage
  

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

  Initial dosage

  Anticoagulation in adult patients with HIT type II and thromboembolic disease:

  – 0.4 mg / kg body weight intravenously as a bolus dose

  – followed by 0.15 mg / kg body weight / hour as a continuous intravenous infusion for 2 - 10 days or longer if clinically needed.

  Normally, the dosage depends on the patient's body weight. This is valid up to a body weight of 110 kg. In patients with a body weight exceeding 110 kg the dosage should not be increased beyond the 110 kg body weight dose (see also tables 2 and 3, below).

  Monitoring and modification of the Refludan dosage regimen

  Standard recommendations

  Monitoring:

  – In general, the dosage (infusion rate) should be adjusted to the activated partial thromboplastin time, aPTT.

  – The first aPTT determination should be done 4 hours after start of Refludan therapy.

  – The aPTT should be monitored at least once daily. More frequent determinations may be necessary, for example, in patients with renal impairment or with an increased risk of bleeding.

  – Target range (therapeutic window) for the aPTT:

            - Using "Actin FS" or "Neothromtin" on automated coagulometers the target range for the aPTT is 1.5 fold to 3 fold prolongation of the normal control value.

            - With other reagents, the upper limit of the therapeutic aPTT window should be reduced to 2.5 fold prolongation of the normal control value.

            - To obtain specific and exact aPTT limits, the laboratory equipment / test reagent used may be calibrated by spiking standardised human plasma with 0.15 μg/ml lepirudin (lower limit) and 1.5 μg/ml lepirudin (upper limit).

  Dose modifications:

  – Any aPTT value out of the target range is to be confirmed at once before drawing conclusions with respect to dose modifications, unless there is a clinical need to react immediately.

  – If the confirmed aPTT value is above the target range, the infusion should be stopped for two hours. At restart, the infusion speed should be decreased by 50 % (no additional intravenous bolus should be administered). The aPTT should be determined again 4 hours later.

  – If the confirmed aPTT value is below the target range, the infusion speed should be increased by 20 %. The aPTT should be determined again 4 hours later.

  – In general, an infusion rate of 0.21 mg/kg/hour should not be exceeded without checking for coagulation abnormalities which might be preventing an appropriate aPTT response.

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

  If a patient is scheduled to receive coumarin derivatives (vitamin K antagonists) for oral anticoagulation after Refludan therapy, the following should apply: Coumarin derivatives should be initiated only when platelet counts are normalising. The intended maintenance dose should be started with no loading dose. To avoid prothrombotic effects when initiating coumarin, continue parenteral anticoagulation for 4 to 5 days (see oral anticoagulant package insert for information). The parenteral agent can be discontinued when the International Normalised Ratio (INR) stabilises within the desired target range.

  Recommendations for use in patients with renal impairment

  As lepirudin is almost exclusively excreted and metabolised renally, the patient's renal function should be considered prior to administration. In case of renal impairment relative overdose might occur even under standard dosage regimen. Therefore, the bolus dose and infusion rate must be reduced in case of known or suspected renal insufficiency (creatinine clearance below 60 ml/min or creatinine value above 15 mg/l [133 μmol/l]).

  In clinical trials, Refludan was not therapeutically administered to HIT type II patients with significant renal impairment. The following dosage recommendations are based on single-dose studies in a small number of patients with renal impairment. Therefore, these recommendations are only tentative.

  Whenever available, dose adjustments should be based on creatinine clearance values as obtained from a reliable method (24 h urine sampling). In all other cases the dose adjustment is based on the creatinine value.

  In any case, the bolus dose must be reduced to 0.2 mg / kg body weight.

  The infusion rate must be reduced according to table 1. Additional aPTT monitoring is mandatory.

  Table 1: Reduction of infusion rate in patients with renal impairment

  Creatinine clearance [ml/min]	Creatinine value [mg/l (μmol/l)]	Adjusted infusion rate [% of original dose]
  45 – 60	16 – 20 (141 - 177)	50 %
  30 – 44	21 – 30 (178 - 265)	30 %
  15 – 29	31 - 60 (266 - 530)	15 %
  below 15*	above 60 (530)*	avoid or STOP infusion !*

  * In haemodialysis patients or in case of acute renal failure (creatinine clearance below 15 ml/min or creatinine value above 60 mg/l [530 μmol/l]), infusion of Refludan is to be avoided or stopped.

  Only if aPTT values have fallen below the lower therapeutic limit (see Monitoring: target range), further intravenous bolus doses of 0.1 mg / kg body weight may be considered every other day.

  Method of administration

  Initial intravenous bolus:

  For intravenous bolus injection, a solution with a concentration of 5 mg/ml is needed.

  Intravenous injection is to be carried out slowly.

  Table 2: Examples for standard injection volume according to body weight

  Body weight	Injection volume [ml]
  [kg]	Dosage 0.4 mg / kg body weight	Dosage 0.2 mg / kg body weight
  50	4.0	2.0
  60	4.8	2.4
  70	5.6	2.8
  80	6.4	3.2
  90	7.2	3.6
  100	8.0	4.0
  110	8.8	4.4

  Intravenous infusion:

  For continuous intravenous infusion, a solution with a concentration of 2 mg/ml is needed.

  The speed of the perfusor automate [ml per hour] is to be set in a body weight dependent fashion.

  Table 3: Examples for standard infusion speed according to body weight

  Body weight	Infusion speed [ml/h]
  [kg]	Dosage 0.15 mg / kg body weight / h	Dosage 0.1 mg / kg body weight / h
  50	3.8	2.5
  60	4.5	3.0
  70	5.3	3.5
  80	6.0	4.0
  90	6.8	4.5
  100	7.5	5.0
  110	8.3	5.5

   

   

   

• Child Dosage
  Not recommended.
• Contra Indications
  

  – Known hypersensitivity to lepirudin, to hirudins or to any of the excipients

  – Pregnancy and lactation

  Where there is active bleeding or bleeding tendency it is generally not advisable to administer Refludan. The physician should carefully weigh the risk of Refludan administration versus its anticipated benefit, taking into account possible measures to control bleeding.

  This particularly includes the following situations with increased bleeding risk:

  – Recent puncture of large vessels or organ biopsy

  – Anomaly of vessels or organs

  – Recent cerebrovascular accident, stroke, or intracerebral surgery

  – Severe uncontrolled hypertension

  – Bacterial endocarditis

  – Advanced renal impairment

  – Haemorrhagic diathesis

  – Recent major surgery

  – Recent bleeding (e.g. intracranial, gastrointestinal, intraocular, pulmonary)

  – Overt signs of bleeding

  – Recent active peptic ulcer

  – Age > 65 years.

• Special Precautions
  

  – Anaphylaxis: Refludan may cause allergic reactions including anaphylaxis and shock. Fatal anaphylactic reactions have been reported in patients re-exposed to Refludan in a second or subsequent treatment course. Therefore, alternative treatment options must be considered before the decision to re-expose a patient to Refludan. As these reactions are immune-mediated, patients with recent exposure to hirudin or hirudin analog may be at an increased risk. Treatment initiation with Refludan 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 Refludan.

  – In case of renal impairment relative overdose may occur even under a standard dosage regimen. Therefore, the treating physician should carefully weigh the risk of administration versus its anticipated benefit. It may be necessary to exclude patients with renal impairment from treatment with lepirudin regimen. The rate of infusion must be reduced in case of known or suspected renal insufficiency.

  –There is no experience with lepirudin in patients with significant liver impairment. Liver cirrhosis may also affect the renal excretion of lepirudin. Serious liver injury (e.g. liver cirrhosis) may enhance the anticoagulant effect of lepirudin due to coagulation defects secondary to reduced generation of vitamin K-dependent coagulation factors.

  – Formation of anti-hirudin antibodies was observed in about 40 % of HIT type II patients and have been reported especially with a treatment period exceeding five days. This may result in an enhanced anticoagulant effect of lepirudin, possibly due to delayed renal elimination of active lepirudin-antihirudin complexes. Therefore, strict monitoring of aPTT is necessary also during prolonged therapy. No evidence of a neutralisation of lepirudin or of an allergic reaction associated with the positive antibody test results was found.

  – Experience of combined therapy with thrombolytic agents in patients with HIT type II is very limited. Since the risk of serious bleeding is considerable in this situation, the dosage of Refludan should be substantially reduced. The optimal dose regimen of Refludan in these circumstances is not known.

  – Paediatric Use: Safety and effectiveness in paediatric patients have not been established.

  – Elderly: Patients of advanced age have an increased risk of bleeding complications with anticoagulation. With respect to lepirudin dosage the potential of renal impairment in elderly patients is to be taken into account. No specific dosage adjustment is made for elderly patients. Dosing adjustments are based on renal function, weight, and aPTT.

• Interactions
  

  No interaction studies have been performed.

  Concomitant treatment with thrombolytics (e.g. rt-PA or streptokinase) may

  – increase the risk of bleeding complications

  – considerably enhance the effect of Refludan on aPTT prolongation.

  Concomitant treatment with coumarin derivatives (vitamin K antagonists) and drugs that affect platelet function may also increase the risk of bleeding.

  Concomitant use with

  – antiplatelet agents other than acetylsalicylic acid, such as ticlopidine or clopidogrel,

  – GpIIb/IIIa receptor antagonists such as eptifibatide, tirofiban, or abciximab,

  – other thrombin inhibitors such as low molecular weight heparins

  has not been assessed.

• Adverse Drug Reactions
  

  The majority of undesirable effects experienced by patients treated with Refludan were generally related to bleeding (>1/10). Life-threatening bleeding events (including intracranial bleeding) were uncommonly reported (1/1,000 to <1/100) in patients with acute coronary syndrome included in clinical studies. In intensified post-marketing surveillance in HIT type II, fatal bleeding was reported in 1 % and intracranial bleeding in 0.2 % of patients

  Adverse events reported on Refludan are shown in the table below:

  Very common (>1/10); Common (>1/100, <1/10); Uncommon (>1/1,000 <1/100); Rare (>1/10,000 <1/1,000); Very Rare (<1/10,000)
  System Organ Class	Very common	Rare
  Immune System Disorders		Anaphylactic/oid reactions
  Vascular Disorders	Anemia or drop in the haemoglobin value without obvious source of bleeding Haematoma Bleeding from puncture sites Epistaxis Haematuria Gastrointestinal bleeding Vaginal bleeding Rectal bleeding Pulmonary haemorrhage Postoperative haemothorax Haemopericardium Intracranial bleeding	Hot flushes Shock including fatal shock
  Respiratory, thoracic and mediastinal disorders		Cough Stridor Dyspnea
  Skin and Subcutaneous Tissue Disorders		Allergic Skin Reactions (including rash) Pruritus Urticaria Angio-oedema (including: face oedema, tongue oedema, larynx oedema)
  General Disorders and Administration Site Conditions		Fever Chills Injection site reactions including pain.