Microsoft word - novastan 100 mgml conc for sol for inf eng

SUMMARY OF THE PRODUCT CHARACTERISTICS
NAME OF THE MEDICINAL PRODUCT
Novastan 100 mg/ml concentrate for solution for infusion. QUALITATIVE AND QUANTITATIVE COMPOSITION
1 ml concentrate for solution for infusion contains 100 mg argatroban. 1 Vial with 2.5 ml concentrate for solution for infusion contains 250 mg argatroban. Final concentration after dilution as recommended is 1 mg/ml (see section 6.6). PHARMACEUTICAL FORM
Concentrate for Solution for Infusion. Clear colourless to pale yellow solution. CLINICAL PARTICULARS
Therapeutic indications
Anticoagulation in adult patients with heparin-induced thrombocytopenia type II who require parenteral antithrombotic therapy. The diagnosis should be confirmed by the HIPAA (heparin induced platelet activation assay) or an equivalent test. However, such confirmation must not delay the start of treatment. Posology and method of administration
Treatment with Novastan 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 Novastan is administered, heparin therapy should be discontinued and a baseline aPTT value obtained. Standard recommendations Monitoring: In general, therapy with Novastan 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 Novastan. The target range for steady-state aPTT is 1.5-3.0 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.
Dose modifications:
After the initial dose of Novastan, the dose can be adjusted based on the clinical course until
the steady-state aPTT is within the desired therapeutic range (1.5 to 3.0 times the initial
baseline value but not exceeding 100 seconds). In case of an elevated aPTT (greater than 3
times baseline or 100 seconds), the infusion should be discontinued until the aPTT is within
the desired range of 1.5 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. The maximum recommended
duration of treatment is 14 days, although there is limited clinical experience of
administration for longer periods (see section 5.1).
Recommendations for use in patients scheduled for a conversion to oral anticoagulation
Use of oral anticoagulants (of the coumarin type) should be delayed until substantial
resolution of thrombocytopaenia (e.g. platelets >100 x 109/l) to avoid coumarin associated
microvascular thrombosis and venous limb gangrene. The intended maintenance dose should
be started with no loading dose.
Quick type PT assay
Owren type PT assay
In a Quick type PT assay the recommendations below used the plasma samples is considerably diluted prior to Co-administration of Novastan and oral anticoagulants of analysis and the recommendations the coumarin type produces an additive effect on the INR below should be considered: The INR depends on both the dose of Novastan and the International Sensitivity Index (ISI) of the thromboplastin Novastan on the INR value at a In general, with doses of Novastan up to 2 microgram/kg/min, Novastan can be discontinued when microgram/kg/min. However, the INR reaches up to 4 on combined therapy. higher concentrations of Novastan may result in an increase of the INR values. The target value for INR on co- therapy should be as recommended for the oral anticoagulant alone i.e. 2-3. For both the Quick and Owren type PT assays; Co-therapy of Novastan and oral anticoagulants (of the coumarin type) is recommended for a minimum of 5 days. INR should be measured daily while Novastan and oral anticoagulants are co-administered. On co-therapy the target value for INR should be within the therapeutic range according to the type of assay used (see above) for at least 2 days before Novastan is discontinued. The INR measurement should be repeated 4-6 hours after discontinuation of Novastan. If the repeat INR is below the desired therapeutic range, the infusion of Novastan should be resumed and the procedure repeated daily until the desired therapeutic range on oral anticoagulants alone is reached. For doses greater than 2 microgram/kg/min, the relationship between INR on oral anticoagulants alone or INR on oral anticoagulants plus Novastan is less predictable. With such higher doses, the dose of Novastan should be temporarily reduced to 2 microgram/kg/min in order to improve the prediction of INR on oral anticoagulants alone (see above). The INR on Novastan and oral anticoagulants should be measured 4 to 6 hours after reduction of the Novastan dose. Elderly patients The standard initial dosage recommendations for use in adults are applicable to elderly patients. Renal impairment The standard initial dosage recommendations for use in adults are applicable to patients with renal impairment (see section 5.2). Hepatic impairment For patients with moderate hepatic impairment (Child-Pugh Class B), an initial dose of 0.5 microgram/kg/min is recommended (see section 4.4 and section 5.2). The aPTT should be monitored closely and the dosage should be adjusted as indicated clinically. Novastan is contra-indicated in patients with severely impaired liver function. Children and adolescents (<18 years) Not recommended. The safety and effectiveness of Novastan in patients below the age of 18 years have not been established. Novastan is supplied as a concentrate (250 mg/2.5 ml) which must be diluted 100-fold prior to infusion to a final concentration of 1 mg/ml (see section 6.6). Standard infusion rates for the 2 microgram/kg/min. recommended initial dosage (1 mg/ml final concentration) are as follows: Body Weight (kg)
Infusion Rate (ml/hr)
Contraindications
Novastan is contraindicated in patients with uncontrolled bleeding. Hypersensitivity to argatroban or to any of the excipients. Severe hepatic impairment. Special warnings and special precautions for use
Novastan 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. Novastan 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 Novastan. When Novastan 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 Novastan therapy (about 1-2 hours). Hepatic Impairment: Caution should be exercised when administering Novastan 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 Novastan 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 Novastan; the therapeutic ranges for these tests have not been defined. Plasma argatroban concentrations also correlate well with the anticoagulant effects. The concomitant use of Novastan 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 Novastan and oral anticoagulants therapy. Ethanol: Novastan contains ethanol. A 70kg patient administered the maximum recommended daily dose (10µg/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 Novastan. Interaction with other medicinal products and other forms of interaction
Concomitant use with antiplatelet agents, thrombolytics, and other anticoagulants may
increase the risk of bleeding.

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

Thrombolytics, anti-platelet and other agents: The safety and effectiveness of Novastan 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 Novastan contains ethanol, an interaction with metronidazol or disulfiram cannot be
excluded.
Pregnancy and lactation
There are no adequate data from the use of Novastan in pregnant women. The effect of argatroban on reproduction has been incompletely studied in animal experiments, as technical issues have limited systemic exposure (see section 5.3 for results of animal studies). The increased bleeding risk with Novastan may constitute a risk in treatment during pregnancy. Novastan contains ethanol. A 70kg patient administered the maximum recommended daily dose (10µg/kg/min) would receive a dose of approximately 4g ethanol per day. Novastan should be used during pregnancy only if treatment is clearly necessary. Information concerning the passage of argatroban into human milk is not available. Animal studies using radiolabelled argatroban have shown that radioactivity reaches greater levels in breast milk than in maternal blood. Breast feeding is not recommended during treatment. Effects on ability to drive and use machines
In theory, the presence of ethanol in the formulation (1g 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 Novastan. Undesirable effects
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 Novastan, 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 Novastan 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 Novastan is stated below. Organ system
Uncommon
(≥1/100,
(≥1/1000, ≤1/100)
≤1/10)
Dizziness, headache, syncope, cerebrovascular accident, hypotonia, speech disorder Atrial fibrillation, tachycardia, cardiac arrest, myocardial infarction, arrhythmia supraventricular, pericardial effusion, ventricular tachycardia, hypertension, hypotension, thrombosis, phlebitis, thrombophlebitis, thrombophlebitis leg superficial, shock, peripheral ischaemia, peripheral dyspnoea, pulmonary haemorrhage, pleural effusion, hiccups Vomiting, constipation, diarrhoea, gastritis, gastrointestinal haemorrhage, melaena, dysphagia, tongue disorder Hepatic function abnormal, hyperbilirubinaemia, hepatic failure, hepatomegaly, jaundice bullous, alopecia, skin disorder, urticaria Pyrexia, pain, fatigue, application site reaction, injection site reaction, oedema peripheral Prothrombin complex level decreased, coagulation factor decreased, coagulation time prolonged, aspartate aminotransferase increased, alanine aminotransferase increased, blood alkaline phosphatase increased, blood lactate dehydrogenase increased Overdose
Excessive anticoagulation, with or without bleeding, may be controlled by discontinuing Novastan or by decreasing the infusion rate. In clinical studies, anticoagulation parameters return to baseline generally within 2 to 4 hours after discontinuation of Novastan. Reversal of anticoagulant effect may take longer in patients with hepatic impairment. No specific antidote to Novastan is available. If life-threatening bleeding occurs and excessive
plasma levels of argatroban are suspected, Novastan should be discontinued immediately and
aPTT and other coagulation tests should be performed. Symptomatic and supportive therapy
should be provided to the patient.
Lethal single intravenous doses of argatroban for mice, rats, rabbits, and dogs were 200, 124, 150, and 200 mg/kg respectively. The symptoms of acute toxicity were loss of righting reflex, tremors, clonic convulsions, paralysis of hind limbs, and coma. PHARMACOLOGICAL PROPERTIES
Pharmacodynamic properties
Pharmacotherapeutic group: Antithrombotic agents, direct thrombin inhibitors. Argatroban, a synthetic L-arginine derivative, is a direct thrombin inhibitor (molecular weight 526.65) that binds reversibly to thrombin. Argatroban exerts its anticoagulant effect independently of antithrombin III and inhibits fibrin formation; activation of coagulation factors V, VIII and XIII; activation of protein C; and platelet aggregation. Argatroban is highly selective for thrombin; inhibitory constant (Ki) values in studies in vitro with synthetic tripeptides ranged from 5 to 39 nM. Argatroban is capable of inhibiting the action of both free and clot-associated thrombin. It does not interact with heparin-induced antibodies. There was no evidence of formation of antibodies against argatroban in patients who received multiple doses of argatroban. Evidence of the efficacy of Novastan in HIT type II derives from data from two studies where a total of 568 adult patients were treated with Novastan. The average treatment duration employed in these clinical studies was 6 days with a maximum of 14 days. In the first prospective trial, a significant improvement in the composite outcome at 37 days (death, amputation, new thrombosis) was observed in the Novastan group versus the historical controls. The reduction of the incidence of the primary endpoint was consistent in the subgroups of patients having HIT type II without thromboembolic complications (25.6% vs 38.8%) and HIT type II with thromboembolic complications (43.8% vs 56.5%). The reduction of the incidence of individual endpoints for patients having HIT type II without and with thromboembolic complications respectively was as follows: mortality (16.9 vs 21.8%) and (18.1 vs 28.3%), amputation (1.9 vs 2.0) and (11.1 vs 8.7%), new thromboses (6.9 vs 15%) and (14.6 vs 19.6). In the second follow-on study, a similar improvement in outcome was observed in the Novastan group versus historical controls. Pharmacokinetic properties
Steady-state levels of both argatroban and anticoagulant effect are typically attained within 1-3 hours and are maintained until the infusion is discontinued or the dosage adjusted. Steady-state plasma argatroban concentrations increase proportionally with dose (for infusion doses up to 40 microgram/kg/min in healthy subjects) and are well correlated with steady-state anticoagulant effects. For infusion doses up to 40 microgram/kg/min, argatroban increases, in a dose-dependent fashion, the activated partial thromboplastin time (aPTT), the activated clotting time (ACT), the International Normalized Ratio (INR) and the thrombin time (TT) in healthy volunteers and cardiac patients. Distribution
Argatroban distributes mainly in the extra-cellular fluid. The volume of distribution (Vdβ) was 391 ± 155 ml/kg (mean ± SD). Argatroban is 54% bound in human serum proteins, with binding to albumin and α1-acid glycoprotein being 20% and 34% respectively. Metabolism
The metabolism of argatroban has not yet been fully characterized. The metabolites identified (M-1, M-2, and M-3) are formed by hydroxylation and aromatization of the 3-methyltetrahydroquinoline ring in the liver. The formation of the metabolites is catalysed in vitro by cytochrome P450 enzymes CYP3A4/5, but this is not a major path of elimination in vivo. The primary metabolite (M1) exerts 40-fold weaker antithrombin effect than argatroban. Metabolites M-1, M-2 and M-3 were detected in the urine, and M-1 was detected in plasma and faeces. There is no interconversion of the 21-(R) and 21-(S) diastereoisomers. The ratio of
diastereoisomers is unchanged by metabolism or hepatic impairment, remaining constant at
65:35 (±2%).
Excretion
On termination of the infusion, the concentration of argatroban decreased rapidly. The
apparent terminal elimination half life (mean ± SD) is 52 ± 16 min. Clearance (mean ± SD)
was 5.2 ± 1.3 ml/kg/min.
Argatroban is excreted mainly in the faeces, presumably through biliary secretion. Following intravenous infusion of 14C-radiolabelled argatroban 21.8 ± 5.8% of the dose was excreted in urine and 65.4 ± 7.1% in the faeces. Special populations
Elderly patients: clearance is approximately 15% lower then in younger persons. No age related dose adjustment is necessary. Renal impairment: compared with patients with normal renal function (creatinine clearance ≥ 80ml/min) who had a terminal half-life of 47±22 min, patients with severely impaired renal function (creatinine clearance ≤ 29ml/min) had only slight prolongation of this value (65±35 min). No initial dose regimen adjustment with respect to renal function is necessary. Hepatic impairment: in patients with hepatic impairment (Child Pugh score 7 to 11) clearance was 26% of that of healthy volunteers. Initial dose reduction is required in patients with moderate hepatic impairment. Novastan is contraindicated in patients with severe hepatic impairment. Preclinical safety data
Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology and genotoxicity. Toxicity studies with continuous intravenous infusions and reproduction toxicity studies using daily intravenous bolus injections achieved only limited systemic exposure to argatroban (2 times the exposure seen in humans). Although these studies do not suggest any particular risk to humans, their value is limited by the low systemic exposure realised. PHARMACEUTICAL PARTICULARS
List of excipients
Sorbitol (E 420i) anhydrous ethanol water for injections Incompatibilities
Novastan must not be mixed with other medicinal products except those mentioned in section 6.6. Shelf-life
3 years. Diluted solution: chemical and physical in-use stability has been demonstrated for up to 14 days at 25ºC and 2 to 8ºC in sodium chloride 9 mg/ml (0.9%) solution for infusion, glucose 50 mg/ml (5%) solution for infusion, or Sodium Lactate Intravenous Infusion Compound (see Section 6.6). From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would not normally be longer than 24 hours at 2 to 8 ºC unless dilution has taken place in controlled and validated aseptic conditions. Special precautions for storage
Keep vial in the outer carton in order to protect from light. Diluted solutions should not be exposed to direct sunlight. Do not freeze. Nature and content of container
Clear type I glass vial sealed with a teflon-coated chlorobutylrubber stopper and an aluminium crimp-seal with a polypropylene flip-off cap. Each vial contains 2.5 ml of concentrate for solution for infusion. Vials are supplied in cardboard cartons of 1 or 6 vials. Not all pack-sizes may be marketed. Instructions for use and handling, and disposal (if appropriate)
Novastan should be diluted in sodium chloride 9 mg/ml (0.9%) solution for infusion, glucose 50 mg/ml (5%) solution for infusion, or Sodium Lactate Intravenous Infusion Compound to a final concentration of 1 mg/ml. If the solution is cloudy, or if an insoluble precipitate is noted, the vial should be discarded. Each 2.5 ml vial should be diluted 100-fold by mixing with 250 ml of diluent. The vial is for single use only. Use 250 mg (2.5 ml) per 250 ml of diluent or 500 mg (5 ml) per 500 ml of diluent. The constituted solution must be mixed by repeated inversion of the diluent bag or bottle for one minute. The diluted solution should be clear and practically free from visible particles. Upon preparation, the solution may show slight but brief haziness due to the formation of microprecipitates that rapidly dissolve upon mixing. The pH of the intravenous solution prepared as recommended is 3.2-7.5. Light resisting measures such as foil protection for intravenous lines are not necessary. No significant potency losses have been noted following simulated delivery of the solution through intravenous tubing. Any unused product or waste material should be disposed of in accordance with local requirements. MARKETING AUTHORISATION HOLDER
Mitsubishi Pharma Europe Ltd, Jupiter House, Triton Court, 14 Finsbury Square, London EC2A 1BR, United Kingdom. MARKETING AUTHORISATION NUMBER(S)
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
DATE OF REVISION OF THE TEXT

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