Public Assessment Report Scientific discussion LOVENOX 2.000 IE (20 mg)/0,2 ml Injektionslösung in einer Fertigspritze LOVENOX 4.000 IE (40 mg)/0,4 ml Injektionslösung in einer Fertigspritze LOVENOX 6.000 IE (60 mg)/0,6 ml Injektionslösung in einer Fertigspritze LOVENOX 8.000 IE (80 mg)/0,8 ml Injektionslösung in einer Fertigspritze LOVENOX 10.000 IE (100 mg)/1 ml Injektionslösung in einer Fertigspritze LOVENOX 30.000 IE (300 mg)/3 ml Injektionslösung in einer Durchstichflasche LOVENOX 50.000 IE (500 mg)/5 ml Injektionslösung in einer Durchstichflasche LOVENOX 100.000 IE (1.000 mg)/10 ml Injektionslösung in einer Durchstichflasche LOVENOX 12.000 IE (120 mg)/0,8 ml Injektionslösung in einer Fertigspritze LOVENOX 15.000 IE (150 mg)/1 ml Injektionslösung in einer Fertigspritze LOVENOX 10.000 IE (100 mg)/10 ml Injektionslösung in einer Durchstichflasche LOVENOX 10 x 4.000 IE (10 x 40 mg) Injektionslösung im Fertigpen ENOXAPARIN SODIUM AT/H/0751/001-005 AT/H/0752/001-003 AT/H/0754/001-002 AT/H/0755/001 AT/H/0756/001 Date: 25.04.2019 This module reflects the scientific discussion for LOVENOX based on the current level of knowledge. For information on changes after the date of this PAR please refer to the module ‘Update’. LOVENOX was first authorised in AT on 21.04.1989. AT/H/0751-756 PAR 1/18 I. INTRODUCTION LOVENOX is indicated in adults for: - Prophylaxis of venous thromboembolic disease in moderate and high risk surgical patients, in particular those undergoing orthopaedic or general surgery including cancer surgery. - Prophylaxis of venous thromboembolic disease in medical patients with an acute illness (such as acute heart failure, respiratory insufficiency, severe infections or rheumatic diseases) and reduced mobility at increased risk of venous thromboembolism. - Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), excluding PE likely to require thrombolytic therapy or surgery. - Acute coronary syndrome: - Treatment of unstable angina and Non ST-segment elevation myocardial infarction (NSTEMI), in combination with oral acetylsalicylic acid. - Treatment of acute ST-segment elevation myocardial infarction (STEMI) including patients to be managed medically or with subsequent percutaneous coronary intervention (PCI). LOVENOX solutions for injection in pre-filled syringes or multi-dose vials are additionally indicated in adults for: - Prevention of thrombus formation in extracorporeal circulation during haemodialysis. A comprehensive description of the indications and posology is given in the SmPC. The marketing authorisations were granted pursuant to Article 8 (3) of Directive 2001/83/EC. II. QUALITY ASPECTS II.1 Introduction LOVENOX is a solution for injection presented in pre-filled syringes, multi-dose vials or pre- filled pens. II.2 Drug Substance The active substance in LOVENOX is enoxaparin sodium. The specification of the active substance meets the current scientific requirements. The adequate quality of the active substance has been shown by submitting the appropriate control data. The stability of the active substance has been tested under ICH conditions. The results of the stability studies support the established shelf-life. II.3 Medicinal Product LOVENOX pre-filled syringes contain the following excipients: water for injection LOVENOX 100 mg/ml multi-dose vials and pre-filled pens contain the following excipients: 15 mg/ml benzyl alcohol water for injection LOVENOX 10 mg/ml multi-dose vials contain the following excipients: 8,1 mg/ml sodium chloride water for injection The development of the product has been sufficiently made and deemed appropriate. The usage of all the excipients has been described. AT/H/0751-756 PAR 2/18 The release specification includes the check of all parameters relevant to this pharmaceutical form. Appropriate data concerning the control of the finished product support the compliance with the release specifications. The packaging of the medicinal product complies with the current legal requirements. Stability studies under ICH conditions have been performed and data presented support the shelf life claimed in the SmPC: LOVENOX 100 mg/ml pre-filled syringes: shelf life of 3 years when stored below 25°C and not frozen LOVENOX 150 mg/ml pre-filled syringes: shelf life of 2 years when stored below 25°C and not frozen LOVENOX 100 mg/ml multi-dose vials: shelf life of 2 years when stored below 25°C in-use stability of 28 days at 25°C LOVENOX 10 mg/ml multi-dose vials: shelf life of 3 years when stored below 25°C, not frozen and protected from light single use only LOVENOX pre-filled pen: shelf life of 2 years when stored below 25°C, not frozen and protected from light in-use stability of 28 days The pharmaceutical quality of LOVENOX has been adequately shown. II.4 Discussion on chemical, pharmaceutical and biological aspects Information on development, manufacture and control of active substance and medicinal product has been presented in a satisfactory manner. The results of tests carried out indicate satisfactory consistency and uniformity of important product quality characteristics. III. NON-CLINICAL ASPECTS III.1 Introduction Enoxaparin is a low molecular weight heparin (LMWH) with a mean molecular weight of approximately 4,500 daltons (3,800 – 5,000). The drug substance is the sodium salt. Enoxaparin sodium is an antithrombotic agent and belongs to the antithrombotic agents pharmacological class with ATC code: B01AB05 enoxaparin. It is obtained by alkaline depolymerisation of the benzyl ester derivative of heparin extracted from porcine intestinal mucosa. III.2 Pharmacology The effect of enoxaparin was evaluated in a series of specific pharmacological tests including the effect on thrombus formation, haemostasis and lipase activity. A standard commercial heparin was tested in parallel. Antithrombotic activity The antithrombotic effect of enoxaparin has been studied in different animal species including rabbit, hamster, dog and monkey following subcutaneous and intravenous administration and in vitro by the Chandler loop model. Pre-treated animals were protected against thrombus formation when challenged by known potent thrombogens (e.g. ADP). Enoxaparin inhibited thrombus formation in a dose-dependent manner and this effect was highly specific for factor Xa-induced thrombi. Administration of enoxaparin after the thrombogens inhibited further the development of an already formed thrombus in rabbits. The potency of the antithrombotic effect of enoxaparin was generally similar to that of heparin. However, the effect of enoxaparin was stronger and more sustained compared to heparin when administered subcutaneously. In AT/H/0751-756 PAR 3/18 contrast to heparin, enoxaparin exhibited only weak anti-IIa activity and the reduction in the number of platelets at the level of the thrombus was very slight. Anticoagulant activity Enoxaparin showed anticoagulant activity when administered by both the subcutaneous and intravenous routes to the rabbit, dog, monkey and rat. However, doses of enoxaparin required for anticoagulant activity are much higher than those required for antithro mbotic activity. The potency of the anticoagulant activity of enoxaparin was lower compared to that of heparin. Lipase activity Lipase activity was increased in rabbit plasma following administration of relatively high enoxaparin doses (1300 anti-Xa U/kg s.c.). Enoxaparin also led to an increase in plasma levels of nonesterified fatty acids, but did not influence plasma cholesterol, triglycerides or phospholipids. Fibrinolysis Enoxaparin had little or no fibrinolytic activity when given subcutaneously to rabbits, however some fibrinolytic activity was apparent following intravenous injections to rabbits and monkeys. Enoxaparin had no fibrinolytic activity in human plasma in vitro, but did increase t- PA in human volunteers following repeated s.c. injections of 7500 and 12,500 anti-Xa U/day. III.3 Pharmacokinetics Pharmacokinetic studies were performed by the subcutaneous route at 0.7, 0.8, 1, 1.5 and 2 mg/kg in dogs in order to determine the clinical conditions of use in veterinary medicine (Lunsford et al., 2009). In this study, a 6-hour dosing interval of enoxaparin 0.8 mg/kg by the subcutaneous route maintained target levels of the anti-Xa activity (0.5 to 2 IU/mL) without evidence of haemorrhagic complications. III.4 Toxicology Repeat-dose toxicity Subacute and chronic toxicity studies were conducted in rats, dogs and monkeys. There were no species differences in the toxicity of enoxaparin. Changes in hematology values and organ weights were observed in all animal species, reflecting the physiological adaptation of animals to long term anticoagulant treatment and resulting haemorrhage. Besides the anticoagulant effects of enoxaparin sodium, there was no evidence of adverse effects at 15 mg/kg/day in the 13-week SC toxicity studies both in rats and dogs and at 10 mg/kg/day in the 26-week SC and IV toxicity studies both in rats, and monkeys. Mutagenicity Enoxaparin sodium has shown no mutagenic activity based on in vitro tests, including the Ames test, mouse lymphoma cell forward mutation test, and no clastogenic activity based on an in vitro human lymphocyte chromosomal aberration test, and the in vivo rat bone marrow chromosomal aberration test. Fertility and Reproduction Reproductive performance was evaluated in 26 male and 26 female sexually mature rats. Enoxaparin, when given in doses of up to 20 mg/kg/day subcutaneously throughout a complete gametogenic cycle, pregnancy and lactation exerted