Microsoft word - 101119_revasc product information - marketed _eh s

MARKETED PRODUCT INFORMATION
REVASC® (Desirudin)
NAME OF THE MEDICINE
DESCRIPTION
The active substance of Revasc is desirudin (recombinant hirudin sequence variant I orrecombinant desulphatohirudin), a highly potent and selective inhibitor of human thrombin.
Desirudin is a single chain polypeptide consisting of 65 amino acid residues and 3 disulphidebridges.
The protein structure of desirudin is nearly identical in structure and amino acid sequence to the natural anticoagulant hirudin variant I, found in saliva of the leech Hirudomedicinalis, differing only by the absence of a sulfate group on Tyr-63 found in the naturalpeptide. Revasc (desirudin) is produced in yeast cells by recombinant DNA technology and isprovided as a lyophilised dry powder which must be reconstituted prior to subcutaneousadministration.
Each mg desirudin corresponds to approximately 18,000 antithrombin units (ATU) withreference to the WHO Second International Standard for -thrombin.
Desirudin is available as a 15mg vial of lyophilised powder to be reconstituted with 0.5 mLmannitol solution (3%) prior to subcutaneous injection. The diluent is supplied with the product.
Excipients: One vial contains, in addition to desirudin, magnesium chloride and sodium
hydroxide for injection. One solvent ampoule contains mannitol dissolved in water for injection.
PHARMACOLOGY
Pharmacodynamics
Pharmacotherapeutic group: anticoagulant.
Desirudin is a highly potent and selective inhibitor of free circulating and clot-bound thrombin.
At therapeutic serum concentrations it has no effect on other enzymes of the haemostaticsystem such as factors IXa, Xa, kallikrein, plasmin, tPA, or activated protein C. In addition, itdoes not display any effect on other serine proteases, such as the digestive enzymes trypsinor chymotrypsin, or on complement activation by the classical or alternative pathways.
The anticoagulant properties of desirudin are demonstrated by its ability to prolong the clottingtime of human or rat plasma whether induced directly (thrombin time TT) or via the intrinsic(activated partial thromboplastin time aPTT) or extrinsic (prothrombin time PT) pathways.
Desirudin has no profibrinolytic activity.
In two controlled double blind clinical trials, the overall rate of thromboembolic events inpatients treated with Revasc 15 mg twice daily was half that in patients treated with a standarddose of unfractionated heparin (5,000 IU s.c. t.i.d.) while the rate of proximal deep veinthrombosis was only one fifth that observed with heparin.
PHARMACOKINETICS
Absorption:
Mean absorption time of subcutaneous (s.c.) desirudin is 4.1, 4.5 and 5.4 h for dose levels of
0.1, 0.3 and 0.5 mg/kg, respectively (overall mean = 4.6 h). Absorption is complete based on
mean area under the curve (AUC) values.
Following administration of single s.c. doses of 0.1-0.75 mg/kg, plasma concentrations ofdesirudin increased rapidly to maximum levels (Cmax) between 1 and 3 h. Both Cmax andAUC values are dose proportional.
Distribution:
Desirudin is distributed in the extracellular space with a distribution volume at steady state of
0.25 L/kg which is independent of the dose.
Metabolism:
In vitro and in vivo animal data indicate that desirudin is for the most part metabolised and
eliminated by the kidney. Desirudin was only minimally degraded in human liver homogenates
within 8 h with only traces of unidentified metabolites observed by HPLC. There is no data on
the elimination of the thrombin-desirudin complex. Hepatic elimination of desirudin does not
appear to be significant.
Elimination:
The disappearance of desirudin from plasma is rapid with approximately 90 % of an i.v. bolus
dose eliminated within the first 2 hours following injection. A slower terminal elimination phase
follows with a dose-independent mean terminal elimination half-life of 2 to 3 h. The mean
residence times are 1.7-2 h and 6-7 h after i.v. and s.c. administration, respectively.
The total urinary excretion of unchanged desirudin amounts to 40-50 % of the administereddose. Metabolites lacking 1 or 2 C-terminal amino acids constitutes a minor proportion of thematerial recovered from urine (< 7%). Animal studies have shown that lysosomal degradationoccurs and this may account for the clearance of the remaining drug in humans.
The mechanisms of renal clearance of desirudin are mainly filtration and reabsorption with thedifference observed between the apparent renal clearance and the creatinine clearance (122mL/min) possibly accounted for by reabsorption.
administration (0.02 to 0.5 mg/kg) around 50% of the dose was excreted in urine, resulting in amean renal clearance of approximately 80 mL/min (1.1 mL/min/kg).
healthy volunteers, saturation of the clearance mechanism was not reached even at doses ashigh as desirudin 1.8 mg/kg i.v. infusion.
The clearance of desirudin is reduced in renal impairment, the mean terminal elimination half-life being 12h in severe renal impairment (creatinine clearance < 31 mL/min). Bioavailabilitywas not significantly increased in mild renal impairment (creatinine clearance 61-90 mL/min);however, it increased three times in moderate renal impairment (creatinine clearance 31-60mL/min) and seven times in severe renal impairment compared with normal renal function.
AUC with respect to prolongation of aPTT reflected AUC with respect to desirudin plasmaconcentration, being twice normal in moderate renal impairment and six times normal in severerenal impairment.
Effect of age on pharmacokinetics:
Although the renal clearance of desirudin is slightly reduced in elderly subjects the total
clearance of desirudin is unaffected.
CLINICAL TRIALS
Evidence supporting the efficacy and safety of desirudin was obtained in three double-blind,randomised, multi-centre trials. The first two trials compared the efficacy of desirudin (15 mg,s.c., b.i.d.) with that of unfractionated heparin (5,000 IU, s.c., t.i.d.) in patients undergoingelective hip replacement surgery.
The prophylaxis period for both trials was 9-12 days.
Pooled results from the two trials are provided in the table below.
Desirudin
Unfractionated Heparin
15 mg s.c. b.i.d.
5000 IU s.c. t.i.d
< 65 years: 37.4%; >65 years: 62.6% absolute risk reduction 15.8% (95% CI: 10.1% - 21.5%) a A thromboembolic event was defined as fatal/non-fatal pulmonary embolism, deep venousthrombosis (proximal and/or distal) or unexplained death. The superior efficacy of desirudinwas mainly due to the reduction of proximal deep venous thrombosis since distal (calf vein)thrombosis rates were similar in both treatment groups.
The third trial compared the efficacy of desirudin (15 m,g s.c., b.i.d.) with that of a LowMolecular Weight Heparin (LMWH) enoxaparin (40 mg, s.c., o.d.) in patients undergoingelective hip replacement surgery.
The percentage of patients who had a thromboembolic event was 25.7% in the enoxaparin group (evaluable patients n = 768) versus 18.8% in thedesirudin group (evaluable patients n = 773) (P<0.01). Desirudin was significantly superior toenoxaparin with a relative risk reduction of 26.9%.
thromboembolic event was 6.9% (95% confidence interval 2.8% - 11.0%).
INDICATIONS
Prevention of venous thromboembolism after elective hip replacement.
CONTRAINDICATIONS
Revasc is contraindicated in patients with known hypersensitivity to natural or recombinanthirudins or to any of the excipients (see "ADVERSE REACTIONS"), in patients with activebleeding and/or irreversible coagulation disorders, in patients with severe renal or hepaticimpairment (see "PRECAUTIONS") and during pregnancy (see "Use in Pregnancy").
Revasc is also contraindicated in patients with severe uncontrolled hypertension and subacutebacterial endocarditis.
PRECAUTIONS
Revasc should not be administered by intramuscular injection owing to the risk of localhaematoma, and intramuscular injections with any drug should be avoided during therapy withRevasc.
Allergy to Yeasts
Since desirudin is produced in a genetically-modified yeast, reactions may occur in patientswho are allergic to yeasts.
Antibodies/Re-exposure:
Antibodies have been reported in patients treated with hirudins. Potential for cross-sensitivityto hirudin products cannot be excluded. Fatal anaphylactic/anaphylactoid reactions have beenreported with hirudin product therapy. Hirudin-specific IgE evaluations may not be indicative ofsensitivity to desirudin as this test was not always positive in the presence of symptoms.
Use With Caution In The Following Circumstances:
Revasc, like other anticoagulants, should be used with caution in conditions with increased riskof haemorrhage such as major surgery, biopsy or puncture of a non-compressible vesselwithin the last month; a history of haemorrhagic stroke, intracranial or intraocular bleedingincluding diabetic (haemorrhagic) retinopathy; a cerebral ischaemic attack within the last 6months, a known haemostatic disorder (congenital or acquired eg. haemophilia, liver disease)or a history of gastrointestinal or pulmonary bleeding within the past 3 months.
Until further information is available, patients with known or suspected impaired liver functionand coagulation disorders should be carefully monitored for signs of overt and occult bleeding.
Revasc should be used with care in patients receiving anticoagulants, and/or platelet inhibitors,and/or thrombolytic agents, and/or non steroidal anti-inflammatory medicinal products.
Monitoring for evidence of bleeding is advised (see "Interactions With Other Drugs").
Use In Special Patient Groups
Children:
There is no clinical experience with Revasc in children.
Patients with renal impairment:
Revasc is contraindicated in severe renal impairment (see “CONTRAINDICATIONS”). As thereis limited clinical experience with desirudin in patients with renal impairment, it is advisable tomonitor aPTT and reduce the dose appropriately in patients with mild to moderate impairment(see "DOSAGE AND ADMINISTRATION - Monitoring").
Patients with liver impairment:
Revasc is contraindicated in severe hepatic impairment (see "CONTRAINDICATIONS"). Inpatients with mild to moderate liver impairment aPTT monitoring is recommended (see"DOSAGE AND ADMINISTRATION" - Monitoring").
Effects on ability to drive and use machines:
Preclinical Safety Data
General toxicology studies with a variety of laboratory animal species have not displayed anyevidence of target organ or systemic toxicity. Doses were limited by the pharmacologicalactivity of desirudin, which was characterised by bleeding at the sites of injection and in someorgans resulting from the inhibition of blood clotting activity. A low grade vasculitis and fibrinoidnecrosis were observed in the dog only. These effects correlated with the appearance ofantibodies to desirudin which were not found in the rabbit or baboon. They have beenattributed to a species-specific immunological reaction, and do not appear to have any clinicalsignificance. The allergic potential of Revasc in immunocompetent healthy volunteers is rare,even upon re-exposure.
No mutagenic potential was demonstrated.
Use In Pregnancy (Category B3)
Reproductive toxicology studies showed desirudin to be teratogenic. In animal experiments,low incidences of spina bifida (rabbit) and omphalocele (rat) have been observed at 0.6mg/kg/d IV and above, and at 15 mg/kg/d SC, respectively.
Revasc is contraindicated during pregnancy since there is inadequate clinical experience tosupport its use in pregnant women.
Use In Lactation
It is not known whether Revasc is excreted in human or animal milk. However, lactatingmothers should be advised to avoid breast feeding or alternative drugs used.
Carcinogenesis, Mutagenesis and Impairment of Fertility
Long term studies to investigate the carcinogenic potential of desirudin have not beenperformed.
Desirudin showed no evidence of genotoxicity in a series of assays for gene Desirudin had no effect on the fertility of male and female rats at doses up to 10 mg/kg/daySC.
Interactions With Other Drugs
Any agents which may enhance the risk of haemorrhage should be discontinued prior
to commencing therapy with Revasc.
If co-administration cannot be avoided, close
clinical and laboratory monitoring should be conducted.
Anticoagulant, antiplatelet and thrombolytic agents:
During prophylaxis, concomitant medication with heparins (unfractionated and low-molecularweight heparins) and dextrans is not recommended. The effects of Revasc and unfractionatedheparins on prolongation of aPTT are additive.
Revasc prolongs PT. When an oral anticoagulant is given with Revasc, the PT (INR) may bemisleadingly high until 24 hours past the last dose of Revasc.
No significant pharmacokinetic and pharmacodynamic (aPTT, PT, thrombin- or ADP-inducedplatelet aggregation) interactions with acetylsalicylic acid (ASA) have been found.
Other drug interactions:
Non-steroidal anti-inflammatory drugs (NSAIDs) e.g. diclofenac, piroxicam administered withRevasc had no clinically significant effects on the pharmacokinetics of desirudin, on aPTT,bleeding time, platelet adhesion and factors released by platelets. However caution should beexercised when desirudin is administered with medicinal products which affect plateletfunction: these include systemic salicylates, NSAIDs including ketorolac, acetylsalicyclic acid,ticlopidine, dipyridamole, sulfinpyrazone, abciximab, clopidogrel and glycoprotein IIb/IIIaantagonists.
Use in patients switching from oral anticoagulants to Revasc or from Revasc to oral
anticoagulants: If a patient is switched from oral anticoagulants to Revasc therapy or vice
versa, the anticoagulant activity should be taken into account in the evaluation of the overall
coagulation status of the patient during the switch.
ADVERSE REACTIONS
In post marketing surveillance, isolated cases of fatal haemorrhage have been reported.
The nature of the hip surgery operation and the mode of action of the two drugs testedaccount for most of the adverse experiences reported in controlled clinical trials using Revasc15 mg twice daily and a standard dose of unfractionated heparin. All adverse experiencespossibly related to trial drug and reported with an incidence of more than 1.0 % are shown indecreasing order of frequency in the table below.
(5,000 IU s.c. t.i.d.)
Other adverse experiences reported to be drug-related with a frequency below 1% included:allergic reactions, application site reactions, oedema in legs, dizziness, insomnia, chest pain,cramps or pain in legs, vomiting, haematemesis, increases in serum transaminases, rash andhaematuria.
More generally and irrespective of the indication and of the cause, allergic reactions werereported in 1.6 % of patients treated with Revasc (N=2367) and in 1.6 % of patients treatedwith unfractionated heparin (N=1134).
The table below provides the incidence of common adverse events at least possibly-related totreatment and reported with an incidence of more than 1% in a trial of desirudin versusenoxaparin in the prevention of thromboembolic disease after elective hip replacement.
DOSAGE AND ADMINISTRATION
Adults (including those over 65 years of age):
The recommended dose is 15 mg twice daily. The first injection should be initiated within 30minutes before surgery but after induction of regional block anaesthesia, if used. Treatmentwith Revasc is then continued twice daily post-operatively for 9 to 12 days or until the patient isfully ambulant. Currently, there is no data to support the use of Revasc beyond 12 days.
Administration is by subcutaneous injection, preferably at an abdominal site. Injections shouldbe rotated between at least four different sites.
Patients with renal impairment:
No dosage adjustment is necessary in patients with an estimated creatinine clearance of morethan 90mL/min. In patients with renal impairment aPTT should be monitored (see"Monitoring").
An initial dosage of 7.5 mg by subcutaneous injection twice daily in mild to moderate renalimpairment (creatinine clearance 31-90 mL/min) is recommended. The adjustment of dosageby titration against aPTT, is also recommended.
Monitoring
aPTT should be monitored in patients with increased risk of bleeding complications, renal orhepatic impairment and in patients receiving anticoagulants and/or thrombolytics.
patients peak aPTT should not exceed twice the control value.
Revasc should be interrupted until aPTT falls to less than twice the control value at which timetreatment with Revasc can be resumed at a reduced dose.
Instructions for use
To prepare the reconstituted aqueous solution, 0.5 mL of the accompanying mannitol solution(3%) is added under aseptic conditions to the vial containing the dry substance. The drug israpidly redispersed by shaking gently.
The reconstituted solution should be used as soon as possible, within 24 hours ofreconstitution.
If the reconstituted product cannot be used immediately or as soon as practicable after preparation, store at 2-8C for not more than 24 hours.
Desirudin should not be mixed/injected with other agents/solvents.
OVERDOSAGE
Accidental overdosage of Revasc can lead to bleeding complications. There is no antidote toRevasc, and excessive bleeding during therapy must be managed empirically until the drug iscleared, by maintaining intravascular volume and transfusing with blood or blood componentsas appropriate.
PRESENTATION
Vial: containing desirudin 15mg as a lyophilised powder for reconstitution.
Ampoule: containing mannitol solution (3%) as diluent.
Carton contains 10 vials and ampoules.
Storage:
Store below 25C; Protect from light.
NAME AND ADDRESS OF THE SPONSOR
Emerge Health Pty LtdLevel 1, 287 Auburn RoadHawthorn Victoria 3122Australia POISONS SCHEDULE OF THE MEDICINE
Schedule 4
Date of TGA Approval: 30 October 1997Date of Most Recent Amendment: 21 December 2010  = Revasc is a Registered Trademark licensed to Canyon Pharmaceuticals AG, Switzerland.

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