Public Assessment Report Scientific Discussion

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 no significant adverse effects on reproductive performance of treated animals or on the growth and reproduction of their untreated offspring.

Teratology

AT/H/0751-756 PAR 4/18 Teratogenic effects of enoxaparin was evaluated in female rats and rabbits who received enoxaparin by subcutaneous injection in doses of 0, 3, 10 and 30 mg/kg/day from Days 6 to 15 (rats)/18 (rabbits) of gestation. Subcutaneous administration of enoxaparin up to 30 mg/kg/day to pregnant rats or rabbits did not reveal any evidence of teratogenic effects or foetotoxicity.

Local Tolerance An investigation of local tolerance was done, after intravenous, intramuscular, intra-arterial, subcutaneous and paravenous administration, in beagle dogs. Single high dose subcutaneous injections of 0.6 mL enoxaparin injection solution (equivalent to an anti-Xa activity of approximately 100 mg) were well tolerated by 6 Beagle dogs, with no signs of local irritation or allergic potential. Local tolerance after subcutaneous route was also investigated in rabbits.

Additionally, in the context of the STEMI indication a toxicology study was performed to confirm the local tolerance of the multidose vial MDV (100 mg/mL and 1.5% benzylic alcohol) (Robles et al 2009). In this study local tolerance was investigated in rabbits after intravenous, intramuscular, subcutaneous, perivenous and intra-arterial administration of the MDV. Results of the study support the overall local tolerance of the MDV formulation notably via the new IV route. Additionally it should be noted that for the STEMI indication in clinical practice intravenous injection of the product is performed through a perfusion line.

III.5 Ecotoxicity/environmental risk assessment (ERA) According to Directive 2001/83/EC, carbohydrates are exempted from an ERA, because they are unlikely to result in a significant risk to the environment.

III.6 Discussion on the non-clinical aspects The non-clinical testing program as performed by the applicant is acceptable and supports the human use of LOVENOX.

IV. CLINICAL ASPECTS

IV.1 Introduction The first approval for enoxaparin was obtained in France on 03 APR 1987. Enoxaparin was licensed in Austria on 21 APR 1989. Enoxaparin is approved in more than 130 countries worldwide.

IV.2 Pharmacokinetics The pharmacokinetic parameters of enoxaparin sodium have been studied primarily in terms of the time course of plasma anti-Xa activity and also by anti-IIa activity, at the recommended dosage ranges after single and repeated SC administration and after single IV administration. The quantitative determination of anti-Xa and anti-IIa pharmacokinetic activities was conducted by validated amidolytic methods.

Absorption The absolute bioavailability of enoxaparin sodium after SC injection, based on anti-Xa activity, is close to 100%. The mean maximum plasma anti-Xa activity level is observed 3 to 5 hours after SC injection and achieves approximately 0.2, 0.4, 1.0 and 1.3 anti-Xa IU/mL following single SC administration of 2,000 IU, 4,000 IU, 100 IU/kg and 150 IU/kg (20 mg, 40 mg, 1 mg/kg and 1.5 mg/kg) doses, respectively. A 3,000 IU (30 mg) IV bolus immediately followed by a 100 IU/kg (1 mg/kg) SC every 12 hours provided initial maximum anti-Xa activity level

AT/H/0751-756 PAR 5/18 of 1.16 IU/mL (n=16) and average exposure corresponding to 88% of steady-state levels. Steady-state is achieved on the second day of treatment.

After repeated SC administration of 4,000 IU (40 mg) once daily and 150 IU/kg (1.5 mg/kg) once daily regimens in healthy volunteers, the steady-state is reached on day 2 with an average exposure ratio about 15% higher than after a single dose. After repeated SC administration of the 100 IU/kg (1 mg/kg) twice daily regimen, the steady-state is reached from day 3 to 4 with mean exposure about 65% higher than after a single dose and mean maximum and trough anti- Xa activity levels of about 1.2 and 0.52 IU/mL, respectively.

Injection volume and dose concentration over the range 100-200 mg/mL does not affect pharmacokinetic parameters in healthy volunteers. Enoxaparin sodium pharmacokinetics appears to be linear over the recommended dosage ranges. Intra-patient and inter-patient variability is low. Following repeated SC administration no accumulation takes place.

Plasma anti-IIa activity after SC administration is approximately ten-fold lower than anti-Xa activity. The mean maximum anti-IIa activity level is observed approximately 3 to 4 hours following SC injection and reaches 0.13 IU/mL and 0.19 IU/mL following repeated administration of 100 IU/kg (1 mg/kg) twice daily and 150 IU/kg (1.5 mg/kg) once daily, respectively.

Distribution The volume of distribution of enoxaparin sodium anti-Xa activity is about 4.3 litres and is close to the blood volume.

Biotransformation Enoxaparin sodium is primarily metabolized in the liver by desulfation and/or depolymerization to lower molecular weight species with much reduced biological potency.

Elimination Enoxaparin sodium is a low clearance drug with a mean anti-Xa plasma clearance of 0.74 L/h after a 150 IU /kg (1.5 mg/kg) 6-hour IV infusion. Elimination appears monophasic with a half- life of about 5 hours after a single SC dose to about 7 hours after repeated dosing. Renal clearance of active fragments represents about 10% of the administered dose and total renal excretion of active and non-active fragments 40% of the dose.

IV.3 Pharmacodynamics In the in vitro purified system, enoxaparin sodium has a high anti-Xa activity (approximately 100 IU/mg) and low anti-IIa or antithrombin activity (approximately 28 IU/mg), with a ratio of 3.6. These anticoagulant activities are mediated through anti-thrombin III (ATIII) resulting in antithrombotic activities in humans.

Beyond its anti-Xa/IIa activity, further antithrombotic and anti-inflammatory properties of enoxaparin have been identified in healthy subjects and patients as well as in non-clinical models. These include ATIII-dependent inhibition of other coagulation factors like factor VIIa, induction of endogenous Tissue Factor Pathway Inibitor (TFPI) release as well as a reduced release of von Willebrand factor (vWF) from the vascular endothelium into the blood circulation. These factors are known to contribute to the overall antithrombotic effect of enoxaparin sodium. When used as prophylactic treatment, enoxaparin sodium does not significantly affect the aPTT. When used as curative treatment, aPTT can be prolonged by 1.5- 2.2 times the control time at peak activity.

AT/H/0751-756 PAR 6/18

IV.4 Clinical efficacy Prevention of venous thromboembolic disease associated with surgery  Extended prophylaxis of venous thromboembolism (VTE) following orthopaedic surgery In a double blind study of extended prophylaxis for patients undergoing hip replacement surgery, 179 patients with no venous thromboembolic disease initially treated, while hospitalized, with enoxaparin sodium 4,000 IU (40 mg) SC, were randomized to a post- discharge regimen of either enoxaparin sodium 4,000 IU (40 mg) (n=90) once a day SC or to placebo (n=89) for 3 weeks. The incidence of DVT during extended prophylaxis was significantly lower for enoxaparin sodium compared to placebo, no pulmonary embolism (PE) was reported. No major bleeding occurred. The efficacy data are provided in the table below.

In a second double-blind study, 262 patients without VTE disease and undergoing hip replacement surgery initially treated, while hospitalized, with enoxaparin sodium 4,000 IU (40 mg) SC were randomized to a post-discharge regimen of either enoxaparin sodium 4,000 IU (40 mg) (n=131) once a day SC or to placebo (n=131) for 3 weeks. Similar to the first study the incidence of VTE during extended prophylaxis was significantly lower for enoxaparin sodium compared to placebo for both total VTE (enoxaparin sodium 21 [16%] versus placebo 45 [34.4%]; p=0.001) and proximal DVT (enoxaparin sodium 8 [6.1%] versus placebo 28 [21.4%]; p=<0.001). No difference in major bleeding was found between the enoxaparin sodium and the placebo group.

 Extended prophylaxis of DVT following cancer surgery A double-blind, multicenter trial, compared a four-week and a one-week regimen of enoxaparin sodium prophylaxis in terms of safety and efficacy in 332 patients undergoing elective surgery for abdominal or pelvic cancer. Patients received enoxaparin sodium (4,000 IU (40 mg) SC) daily for 6 to 10 days and were then randomly assigned to receive either enoxaparin sodium or placebo for another 21 days. Bilateral venography was performed between days 25 and 31, or sooner if symptoms of venous thromboembolism occurred. The patients were followed for three months. Enoxaparin sodium prophylaxis for four weeks after surgery for abdominal or pelvic cancer significantly reduced the incidence of venographically demonstrated thrombosis, as compared with enoxaparin sodium prophylaxis for one week. The rates of venous thromboembolism at the end of the double-blind phase were 12.0 % (n=20) in the placebo group and 4.8% (n=8) in the enoxaparin sodium group; p=0.02. This difference persisted at three months [13.8% vs 5.5% (n=23 vs 9), p=0.01]. There were no differences in the rates of bleeding or other complications during the double-blind or follow-up periods.

AT/H/0751-756 PAR 7/18 Prophylaxis of venous thromboembolic disease in medical patients with an acute illness expected to induce limitation of mobility In a double blind multicenter, parallel group study, LOVENOX injection 20 mg or 40 mg once a day s.c. was compared to placebo in the prophylaxis of VTE in medical patients with severely restricted mobility during acute illness. This study included patients with heart failure (NYHA Class III or IV); acute respiratory failure or complicated chronic respiratory insufficie ncy (not requiring ventilatory support); acute infection (excluding septic shock); or acute rheumatic disorder [acute lumbar or sciatic pain, vertebral compression (due to osteoporosis or tumor), acute arthritic episodes of the lower extremities]. A total of 1102 patients were enrolled in the study, and 1073 patients were treated. A number of 866 patients were assessed for the incidence of venous thromboembolism. Patients ranged in age from 41 to 97 years (mean age 73.55 years) with 50.35% men and 49.65% women. Treatment continued for a maximum of 14 days (median duration 7 days), and patients were followed-up at day 90. The efficacy data are provided in the table below.

At approximately 3 months following enrolment, the incidence of VTE remained significantly lower in the enoxaparin sodium 4,000 IU (40 mg) treatment group versus the placebo treatment group. The occurrence of total and major bleeding were respectively 8.6% and 1.1% in the placebo group, 11.7% and 0.3% in the enoxaparin sodium 2,000 IU (20 mg) group and 12.6% and 1.7% in the enoxaparin sodium 4,000 IU (40 mg) group.

Treatment of deep vein thrombosis with or without pulmonary embolism The safety and efficacy of enoxaparin in the treatment of DVT with or without PE has been evaluated in 2 clinical trials involving 1401 patients.

In a multicenter, parallel group study, 900 patients with acute lower extremity DVT with or without PE were randomized to an inpatient (hospital) treatment of either (i) enoxaparin sodium 150 IU/kg (1.5 mg/kg) once a day SC, (ii) enoxaparin sodium 100 IU/kg (1 mg/kg) every 12 hours SC, or (iii) heparin IV bolus (5,000 IU) followed by a continuous infusion (administered to achieve an aPTT of 55 to 85 seconds). A total of 900 patients were randomized in the study and all patients were treated. All patients also received warfarin sodium (dose adjusted according to prothrombin time to achieve an International Normalized Ratio (INR) of 2.0 to 3.0), commencing within 72 hours of initiation of enoxaparin sodium or standard heparin therapy, and continuing for 90 days. Enoxaparin sodium or standard heparin therapy was administered for a minimum of 5 days and until the targeted warfarin sodium INR was achieved. Both enoxaparin sodium regimens were equivalent to standard heparin therapy in reducing the

AT/H/0751-756 PAR 8/18 risk of recurrent venous thromboembolism (DVT and/or PE). The efficacy data are provided in the table below.

Major bleeding were respectively 1.7% in the enoxaparin sodium 150 IU/kg (1.5 mg/kg) once a day group, 1.3% in the enoxaparin sodium 100 IU/kg (1mg/kg) twice a day group and 2.1% in the heparin group.

The second study was a multicenter, open-label, parallel group study, patients with acute proximal DVT were randomized to LOVENOX injection or heparin. Patients who could not receive outpatient therapy were excluded from entering the study. Outpatient exclusion criteria included the following: inability to receive outpatient heparin therapy because of associated co- morbid conditions or potential for non-compliance and inability to attend follow-up visits as an outpatient because of geographic inaccessibility. Eligible patients could be treated in the hospital, but only LOVENOX injection patients were permitted to go home on therapy (72%). A total of 501 patients were randomized in the study and all patients were treated. Patients ranged in age from 19 to 96 years (mean age 57.8 years) with 60.5% men and 39.5% women. Patients were randomized to either LOVENOX injection 1 mg/kg every 12 hours SC or heparin IV bolus (5000 units) followed by a continuous infusion administered to achieve an aPTT of 60 to 85 seconds (in-patient treatment). All patients also received warfarin sodium as described in the previous study. LOVENOX injection or standard heparin therapy was administered for a minimum of 5 days. The efficacy data are provided in the table below.

AT/H/0751-756 PAR 9/18 Treatment of unstable angina and non ST elevation myocardial infarction In a large multicenter study, 3,171 patients enrolled at the acute phase of unstable angina or non-Q-wave myocardial infarction were randomized to receive in association with acetylsalicylic acid (100 to 325 mg once daily), either SC enoxaparin sodium 100 IU/kg (1 mg/kg) every 12 hours or IV unfractionated heparin adjusted based on aPTT. Patients had to be treated in hospital for a minimum of 2 days and a maximum of 8 days, until clinical stabilization, revascularization procedures or hospital discharge. The patients had to be followed up to 30 days. In comparison with heparin, enoxaparin sodium significantly reduced the combined incidence of angina pectoris, myocardial infarction and death, with a decrease of 19.8 to 16.6% (relative risk reduction of 16.2%) on day 14. This reduction in the combined incidence was maintained after 30 days (from 23.3 to 19.8%; relative risk reduction of 15%). There were no significant differences in major haemorrhages, although a haemorrhage at the site of the SC injection was more frequent.

Treatment of acute ST-segment elevation myocardial infarction (STEMI) In a large multicenter study, 20,479 patients with STEMI eligible to receive fibrinolytic therapy were randomized to receive either enoxaparin sodium in a single 3,000 IU (30 mg) IV bolus plus a 100 IU/kg (1 mg/kg) SC dose followed by an SC injection of 100 IU/kg (1 mg/kg) every 12 hours or IV unfractionated heparin adjusted based on aPTT for 48 hours. All patients were also treated with acetylsalicylic acid for a minimum of 30 days. The enoxaparin sodium dosing strategy was adjusted for severe renally impaired patients and for the elderly of at least 75 years of age. The SC injections of enoxaparin sodium were given until hospital discharge or for a maximum of eight days (whichever came first). 4,716 patients underwent percutaneous coronary intervention (PCI) receiving antithrombotic support with blinded study drug. Therefore, for patients on enoxaparin sodium, the PCI was to be performed on enoxaparin sodium (no switch) using the regimen established in previous studies i.e. no additional dosing, if last SC administration given less than 8 hours before balloon inflation, IV bolus of 30 IU/ kg (0.3 mg/kg) enoxaparin sodium, if the last SC administration given more than 8 hours before balloon inflation.

Enoxaparin sodium compared to unfractionated heparin significantly decreased the incidence of death from any cause or myocardial re-infarction in the first 30 days after randomization (composite primary endpoint) [9.9 percent in the enoxaparin sodium group, as compared with 12.0 percent in the unfractionated heparin group] with a 17 percent relative risk reduction (p<0.001).

The treatment benefits of enoxaparin sodium, evident for a number of efficacy outcomes, emerged at 48 hours, at which time there was a 35 percent reduction in the relative risk of myocardial re-infarction, as compared with treatment with unfractionated heparin (p<0.001). The beneficial effect of enoxaparin sodium on the primary end point was consistent across key subgroups including age, gender, infarct location, history of diabetes, history of prior myocardial infarction, type of fibrinolytic administered, and time to treatment with study drug. There was a significant treatment benefit of enoxaparin sodium, as compared with unfractionated heparin, in patients who underwent percutaneous coronary intervention within 30 days after randomization (23 percent reduction in relative risk) or who were treated medically (15 percent reduction in relative risk, p=0.27 for interaction). The rate of the 30 day composite endpoint of death, myocardial re-infarction or intracranial haemorrhage (a measure of net clinical benefit) was significantly lower (p<0.0001) in the enoxaparin sodium group (10.1%) as compared to the heparin group (12.2%), representing a 17% relative risk reduction in favour of treatment with enoxaparin sodium.

AT/H/0751-756 PAR 10/18 The incidence of major bleeding at 30 days was significantly higher (p<0.0001) in the enoxaparin sodium group (2.1%) versus the heparin group (1.4%). There was a higher incidence of gastrointestinal bleeding in the enoxaparin sodium group (0.5%) versus the heparin group (0.1%), while the incidence of intracranial haemorrhage was similar in both groups (0.8% with enoxaparin sodium versus 0.7% with heparin).

The beneficial effect of enoxaparin sodium on the primary endpoint observed during the first 30 days was maintained over a 12 month follow-up period.

Several substudies of the Extract-Timi 25 study were published:

 Sabatine MS, Morrow DA, Dalby A, et al. (2007) Efficacy and safety of enoxaparin versus unfractionated heparin in patients with ST‐ segment elevation myocardial infarction also treated with clopidogrel. J Am Coll Cardiol 49:2256‐ 2263  White HD, Braunwald E, Murphy SA, et al. (2007) Enoxaparin vs. unfractionated heparin with fibrinolysis for ST‐ elevation myocardial infarction in elderly and younger patients: results from ExTRACT‐ TIMI 25. Eur Heart J 28:1066‐ 1071  Fox KA, Antman EM, Montalescot G, et al. (2007) The impact of renal dysfunction on outcomes in the ExTRACT‐ TIMI 25 trial. J Am Coll Cardiol 49:2249‐ 2255  Scirica BM, Morrow DA, Sadowski Z, et al. (2007) A strategy of using enoxaparin as adjunctive antithrombin therapy reduces death and recurrent myocardial infarction in patients who achieve early ST‐ segment resolution after fibrinolytic therapy: the ExTRACT‐ TIMI 25 ECG study. Eur Heart J 28:2070‐ 2076  Giraldez RR, Nicolau JC, Corbalan R, et al. (2007) Enoxaparin is superior to unfractionated heparin in patients with ST elevation myocardial infarction undergoing fibrinolysis regardless of the choice of lytic: an ExTRACT‐ TIMI 25 analysis. Eur Heart J 28:1566‐ 1573  Morrow DA, Antman EM, Murphy SA, et al. (2007) Effect of enoxaparin versus unfractionated heparin in diabetic patients with ST‐ elevation myocardial infarction in the Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment‐ Thrombolysis In Myocardial Infarction study 25 (ExTRACTTIMI 25) trial. Am Heart J 154:1078‐ 1084, 1084 e1071  Gibson CM, Murphy SA, Montalescot G, et al. (2007) Percutaneous coronary intervention in patients receiving enoxaparin or unfractionated heparin after fibrinolytic therapy for ST‐ segment elevation myocardial infarction in the ExTRACT‐ TIMI 25 trial. J Am Coll Cardiol 49:2238‐ 2246  Giraldez RR, Wiviott SD, Nicolau JC, et al. (2009) Streptokinase and enoxaparin as an alternative to fibrin‐ specific lytic‐ based regimens: an ExTRACT‐ TIMI 25 analysis. Drugs 69:1433‐ 1443

Hepatic impairment Based on literature data the use of enoxaparin sodium 4,000 IU (40 mg) in cirrhotic patients (Child-Pugh class B-C) appears to be safe and effective in preventing portal vein thrombosis. It should be noted that the literature studies may have limitations. Caution should be used in patients with hepatic impairment as these patients have an increased potential for bleeding (see SmPC section 4.4) and no formal dose finding studies have been performed in cirrhotic patients (Child Pugh class A, B nor C).

IV.5 Clinical safety The safety has been evaluated in more than 15,000 patients who received enoxaparin in clinical trials. These included 1,776 for prophylaxis of deep vein thrombosis following orthopaedic or

AT/H/0751-756 PAR 11/18 abdominal surgery in patients at risk for thromboembolic complications, 1,169 for prophylaxis of deep vein thrombosis in acutely ill medical patients with severely restricted mobility, 559 for treatment of DVT with or without PE, 1,578 for treatment of unstable angina and non-Q- wave myocardial infarction and 10,176 for treatment of acute STEMI. Enoxaparin sodium dosing regimen administered during these clinical trials varies depending on indications. In clinical studies, haemorrhages, thrombocytopenia and thrombocytosis were the most commonly reported reactions.

The safety profile of enoxaparin sodium was further established through published literature and post-marketing experience including PSUR data. During the renewal no new safety information has been revealed which alter the known risk profile of enoxaparin sodium.

IV.6 Risk Management Plan The MAH has submitted a risk management plan, in accordance with the requirements of Directive 2001/83/EC as amended, describing the pharmacovigilance activities and interventions designed to identify, characterise, prevent or minimise risks relating to LOVENOX Injektionslösung.

- Summary table of safety concerns as approved in RMP Important identified risks Major hemorrhages Heparin-induced thrombocytopenia Important potential risks Medication error (in relation to the double strength expression) Missing information Use in patients with hepatic impairment

Use in pregnant women and lactating women

Use in children and adolescents

- Summary of Safety Concerns and Planned Risk Minimisation Activities as approved in RMP

Safety Concern Routine Risk Minimisation Additional Risk Measures Minimisation Measures

Important Identified Risks Major hemorrhages Routine risk minimization Routine pharmacovigilance measures: activities beyond adverse Labeled in sections 4.2, 4.3, 4.4, reactions reporting and signal 4.5, 4.6, 4.8 and 5.1of SmPC detection: None Labeled in sections 2, 3 and 4 of PL Additional pharmacovigilance activities: Additional risk minimization None measures: None Heparin-induced Routine risk minimization Routine pharmacovigilance thrombocytopenia measures: activities beyond adverse Labeled in sections 4.3, 4.4 and reactions reporting and 4.8 of SmPC signal detection: None

AT/H/0751-756 PAR 12/18 Safety Concern Routine Risk Minimisation Additional Risk Measures Minimisation Measures Labeled in section 2 of PL Additional pharmacovigilance Additional risk minimization activities: measures: None None Important Potential Risks Medication error (in relation Routine risk minimization Routine pharmacovigilance to the double strength measures: activities beyond adverse expression) The quantity in mg reactions reporting and signal corresponding to IU given aside detection: throughout the SmPC None

Additional risk minimization Additional pharmacovigilance measures: activities: DHPC ANNEX 6 None

Missing Information Use in patients with hepatic Routine risk minimization Routine pharmacovigilance impairment measures: activities beyond adverse Labeled in sections 4.2, 4.4, 5.1 reactions reporting and and 5.2 of SmPC signal detection: None Labeled in sections 2 and 4 of PL Additional pharmacovigilance activities: Additional risk minimization None measures: None Use in pregnant women and Routine risk minimization Routine pharmacovigilance lactating women measures: activities beyond adverse Labeled in sections 4.4 and 4.6 reactions reporting and signal of SmPC detection: None Labeled in section 2 of PL Additional pharmacovigilance Additional risk minimization activities: measures: None None Use in children and Routine risk minimization Routine pharmacovigilance adolescents measures: activities beyond adverse Labeled in sections 4.2, 4.3, 4.4 reactions reporting and and 4.8 of SmPC signal detection: None Labeled in section 2 and 3 of PL Additional pharmacovigilance Additional risk minimization activities: measures: None None

Additional risk minimization measures in relation with the important potential risk of medication error consecutive to the implementation of the harmonized strength expression in European Economic Area (EEA):

AT/H/0751-756 PAR 13/18 Direct healthcare professional communication (DHPC): • DHPC to inform the healthcare professionals about the potential risk of medication error as enoxaparin sodium strength is now being expressed both in International Unit (IU) of anti-Xa activity and mg.

• The key message is as follows: Enoxaparin strength will now be expressed both in IU of anti-Xa activity and in mg: One mg of enoxaparin sodium is equivalent to 100 IU anti-Xa activity. For example, for pre-filled syringes of 0.4 ml, the strength will appear as: 4000 IU (40 mg)/0.4 ml solution for injection.

• Target audience and planned distribution path: DHPC to be disseminated to the targeted healthcare professionals (general practitioners, orthopedics, internists, cardiologists, hematologists, surgeons, pharmacists, nurses [or other as per national health care system]).

• Plans to evaluate the effectiveness of the interventions and criteria for success: Routine pharmacovigilance (number and severity of cases reported).

IV.7 Discussion on the clinical aspects The efficacy and safety of LOVENOX has been sufficiently demonstrated in numerous clinical trials and case reports available in published literature and submitted data support the use of LOVENOX in the approved indications and regimens.

V. USER CONSULTATION

The package leaflet has been evaluated via a user consultation study in accordance with the requirements of Articles 59(3) and 61(1) of Directive 2001/83/EC. The language used for the purpose of user testing the PIL was English.

The test consisted of: a pilot test with two participants, followed by two rounds with 10 participants each. The questions covered the following areas sufficiently: traceability, comprehensibility and applicability.

The results show that the package leaflet meets the criteria for readability as set out in the Guideline on the readability of the label and package leaflet of medicinal products for human use.

VI. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION

The pharmaceutical quality of LOVENOX has been adequately shown. From a nonclinical and clinical point of view, the benefit-risk ratio of LOVENOX is considered positive.

AT/H/0751-756 PAR 14/18

Public Assessment Report

Update

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

This module reflects the procedural steps and scientific information after the finalisation of the public assessment report’s scientific discussion.

Procedure Scope Product Date of end of Approval/ number* Information procedure non approval affected AT/H/XXXX/ harmonise the quality dossier and the pharmaceutical sections Yes 08.04.2019 approved WS/036 of the SmPC

AT/H/XXXX/ This variation aims to upgrade and harmonise the registration no 26.07.2018 Approved WS/044 files across member states with Environmental Risk Assessment (exemption claim), Risk Management Plan and Summary of Pharmacovigilance System prior to Repeat Uses to register some strengths or duplicates in additional EU countries. AT/H/XXXX/ No 22.09.2018 Approved WS/052 Addition of Nanjing King Friend Biochemical Pharmaceutical Co. Ltd (NKF) as an alternate supplier for crude heparin sodium used in the manufacture of heparin sodium, intermediate of enoxaparin sodium drug substance. AT/H/XXXX/ This variation is submitted in support of a change in batch size No 19.08.2018 Approved WS/053 and increase of holding times for enoxaparin sodium solution for injection in pre-filled syringes 6,000 IU (60 mg)/0.6 ml; 8,000 IU (80 mg)/0.8 ml and 10,000 IU (100 mg)/1.0 ml manufactured at the following site:

AT/H/0751-756 PAR 15/18 Chinoin Pharmaceutical and Chemical Works Private Co. Ltd, Hungary

AT/H/XXXX/ This variation aims to submit the results of assessments Yes 01.09.2018 Approved WS/043 carried on target patient groups in order to comply with Article 59(3) of Directive 2001/83/EC and any resulting change to the Package Leaflet. AT/H/XXXX/ The purpose of this type II variation application is to register No 10.01.2019 Approved WS/061 an additional recovery process to be implemented at the last drying step of the manufacturing process of Enoxaparin sodium active substance. AT/H/XXXX/ Addition of the Singapore site for testing the AntiXa/IIa No 08.01.2019 Approved WS/063 activities in pure heparin sodium for the Sanofi Chimie Ploermel site.

AT/H/XXXX/ The purpose of this type II variation application is to add 4 No 04.04.2019 Approved WS/068 initial pooled porcine mucosa processing sites for Hepalink Shenzhen Pharmaceutical Co. LTD, approved supplier of crude heparin sodium intermediate. AT/H/XXXX/ Addition of Rovi Contract Manufacturing as a drug product No 26.04.2019 Approved WS/069 manufacturing and primary packaging site for the 40mg/0.4mL pre-filled syringe presentation.

AT/H/XXXX/ Addition of Bioiberica GmbH, Rheda-Wiedenbrueck, No 12.04.2019 Approved WS/058 Germany as an additional initial processing site using an alternative extraction process for the production of heparin complex (early stage intermediate that is further processed to crude heparin sodium intermediate). Bioiberica also proposes the addition of new sourcing countries for pigs which include Chile, Colombia (South America), Mexico and Canada (North America) in an effort to guarantee supply of pooled porcine mucosa (starting material). AT/H/XXXX/ Deletion of Yibin Lihao Bio-technology Co. LTD China as an No 09.04.2019 Approved WS/080 initial processing site (raw heparin workshop) for Shenzhen Hepalink Pharmaceutical Co. LTD

AT/H/XXXX/ The purpose of this variation is to update section 3.2.P.7 with No 26.04.2019 Approved WS/082 the appropriate drawings to show that the adhesive comes into contact with the product for the 100mg/mL and 150mg/mL pre-filled syringe presentations. AT/H/XXXX/ The purpose of this variation is to register a batch size increase No 11.02.2020 Approved WS/098 of pure heparin sodium manufactured in the (P2)-process without process change. Currently, the pure heparin batch size is of 33-76 kg. and the increased batch size proposed is of 33- 270 kg. AT/H/XXXX/ The purpose of this type II variation application is to submit Yes 06.05.2020 Approved WS/100 changes to the product information to adapt to the results of the repeat use procedure (AT/H/0754/001-002/E/001)

AT/H/XXXX/ The purpose of this variation is: No 08.05.2020 Approved WS/102 - To delete 3 raw heparin and 1 crude heparin workshop for Welding which are shut down due to urban construction planning from government; not for quality reason; o Chongqing Santeng Food Co., Ltd., Chongqing, Zhejiang CN (raw heparin); o Jiangxi Ruifeng Biological Technology Co., Ltd., Shanggao County, Jiangxi CN (raw heparin); o Anhui Jinxin Biotech Co., Ltd., Huaining County, Anhui Province CN (raw heparin) o Nanjing Kaiyang Biotech Co., Ltd., Gaochun District, Nanjing, Jiangsu Province CN (crude heparin)

- And to add raw heparin workshop to increase the production capability to secure the sourcing in heparin and ensure the supply chain of Lovenox. o Changshu Xingrui Casing technology Co., Ltd., Suzhou city, Jiangsu CN AT/H/XXXX/ Type IB B.II.b.3.z Change in the manufacturing process of the No 28.04.2020 Approved WS/103 finished product - Follow-Up Measure 003 to provide studies concerning possible volatile and semi-volatile extractables and leachables from the filters

AT/H/0751-756 PAR 16/18 Type IB B.II.f.z Stability - Follow-Up Measure 005 – Addition of in-use study with a batch close to the end of shelf life.

AT/H/XXXX/ The purpose of this Type IB Grouping is to regularize minor No 01.04.2020 Approved WS/107 discrepancies in the 3.2.S Part following Regulatory Compliance checking in order to align on current site practices already in place: · B.I.a.3.e variation application submitted herewith is to register: - a minimum input batch size from 72 kg to 36 kg of pure heparin engaged into Step 1 of Enoxaparin sodium at Singapore site; - a maximum input batch size increased from 208 kg to 232 kg of crude benzyl ester of heparin engaged into Step 3 of Enoxaparin sodium at Singapore site (and an adjustment from 22 to 21 kg for the minimum input); - an adjustment of the minimum input batch size from 29 to 27 kg of crude enoxaparin engaged into final stage 5 of Enoxaparin sodium at Singapore site · B.I.b.1.z change in the specification parameters and/or limits of an intermediate used in the manufacturing process of the active substance: - skip-testing for esterified benzyl alcohol & free benzyl alcohol assay of Enoxaparin sodium intermediate stage 3 AT/H/XXXX/ The purpose of this variation is to propose a new common No 23.07.2020 Approved WS/106 alternative extraction process to be used by both crude heparin manufacturing sites and their initial processing sites.

AT/H/XXXX/ The purpose of this variation is to propose the use of MnCl2 No 02.06.2020 Approved WS/111 tetrahydrate as an alternate raw material to MnCl2 monohydrate to prepare the MnCl2 solution used in the manufacturing process to produce pure heparin by the approved Aspen supplier. AT/H/XXXX/ Type IB Variation: B.II.b.3.z Change in the manufacturing No 28.07.2020 Approved WS/116 process of the finished product, including an intermediate used in the manufacture of the finished product. The purpose of this variation is to add two alternative filter references for the bioburden reduction filtration (AB1NF7PH4) and sterilizing filtration (KA2NFP1) steps. Type IB Variation: B.II.b.5.z Change to in-process test(s) or limits applied during the manufacture of the finished product. The purpose of this variation is to propose a change in the filter integrity test. AT/H/XXXX/ The purpose of this variation is to register an additional No 10.10.2020 Approved WS/121 alternative testing site to perform the 1H NMR testing performed for routine release on Pure Heparin Sodium intermediate and the 13C NMR testing performed on Enoxaparin Sodium Drug Substance (in case of major process change only). AT/H/XXXX/ Addition of DCW casing LLC as an additional crude heparin No 02.10.2020 Approved WS/122 sodium supplier

AT/H/XXXX/ A.7. Deletion of manufacturing sites for an active substance, No 20.01.2021 Approved WS/143 intermediate or finished product, packaging site, manufacturer responsible for batch release, site where batch control takes place, or supplier of a starting material, reagent or excipient (when mentioned in the dossier)* B.I.a).1. e) The change relates to a biological active substance or a starting material/reagent/intermediate used in the manufacture of a biological/immunological product

The purpose of the Type II B.I.a.1.e is to add the five (5) workshops performing the initial processing of the pooled porcine mucosae for obtaining complex heparin or raw heparin for NKF (two workshops) and Hepalink (three workshops), respectively. These early stages are used to manufacture crude heparin sodium. The purpose for the Type IA A7 is to delete Suqian Jiahui, an initial processing site of Hepalink, this deletion is due to urban construction planning by the Chinese government which forced its closure, and not for quality reasons “accelerated timetable”.

AT/H/0751-756 PAR 17/18 AT/H/XXXX/ B.I.e).2. Introduction of a post approval change management No 31.08.2021 Approved WS/165 protocol related to the active substance

The purpose of this Type II B.I.e.2 variation application submitted herewith is for the introduction of a post approval management protocol related to the active substance. The written protocol submitted herewith describes the following proposed changes: 1. New site performing the initial processing steps of the pooled porcine mucosae, also called “workshops”, to obtain an early stage intermediate used in crude heparin sodium intermediate manufacture, 2. New country of origin for the collect of porcine material. Both changes can be submitted either independently or linked when new workshops are collecting mucus in new countries. Both changes are currently submitted through the same variation classification (type & number). Therefore, it deems meaningful to have a common and simultaneous review of both changes under one single protocol. AT/H/XXXX/ C.I.6. a) Addition of a new therapeutic indication or Yes 11.09.2021 Approved WS/108 modification of an approved one

The application concerns a single type II variation for an extended indication in Cancer-Associated Thrombosis (CAT) patients for the enoxaparin Sodium products. The MAH is proposing to modify the pre-existing indication of the treatment of deep vein thrombosis (DVT) with the addition of the “Extended treatment of venous thromboembolism (VTE) and prevention of its recurrence in adult patients with active cancer”.

AT/H/0751-756 PAR 18/18