Zusammenfassung der Merkmale des Arzneimittels - Enoxaparin Ledraxen 30.000 IE (300 mg)/3 ml Injektionslösung in Durchstechflasche
II.4 GENERAL COMMENTS ON COMPLIANCE WITH GMP, GLP, GCP AND AGREED
| Proposed name of the medicinal product in the RMS | Enoxaparin Ledraxen® 30.000 IE (300 mg)/3 ml, Injektionslösung in Durchstechflasche Enoxaparin Ledraxen® 50.000 IE (500 mg)/5 ml, Injektionslösung in Durchstechflasche |
| Name of the drug substance (INN name): | Enoxaparin Sodium |
| Pharmaco-therapeutic group (ATC Code): | B01AB05 |
| Pharmaceutical form(s) and strength(s): | Solution for injection in vial |
| Reference Number(s) for the Decentralised Procedure | DE/H/7190+7191/001/DC |
| Reference Member State: | DE |
| Concerned Member States: | LU |
| Legal basis of application: | Similar biological Art 10.4 Dir 2001/83/EC |
| Applicant (name and address) | Venipharm 4 Bureaux de la Colline 92210 SAINT-CLOUD Frankreich |
| Names and addresses of all manufacturer(s) responsible for batch release in the EEA | Centre Spécialités Pharmaceutiques (France) ZAC des Suzots 35 rue de la Chapelle F-63450 Saint-Amant Tallende France |
Based on the review of the data on quality, safety and efficacy, the RMS considers that the application for Enoxaparin Ledraxen 30.000 IE (300 mg)/3 ml [50.000 IE (500 mg)/5 ml], Injektionslösung in Durchstechflasche in the following indications:
Prophylaxis of venous thromboembolic disease in moderate and high risk surgical patients, inparticular those undergoing orthopaedic or general surgery including cancer surgery.
Prophylaxis of venous thromboembolic disease in medical patients with an acute illness (such asacute 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 torequire thrombolytic therapy or surgery.
Prevention of thrombus formation in extra corporeal circulation during haemodialysis. 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)
is approved.
II.1 Problem statement
For biosimilar application this section is not applicable.
II.2 About the product
Enoxaparin is a low-molecular-weight heparin (LMWH) obtained from unfractionated heparin (UFH). Enoxaparin binds to antithrombin III and accelerates antithrombin III activity, preferentially inhibiting the coagulation activity of factors Xa and IIa. The anticoagulant effect of enoxaparin is directly correlated with its inhibition of factor Xa activity. Factor Xa catalyses the conversion of prothrombin to thrombin; inhibition of this process by enoxaparin results in decreased thrombin concentration and the prevention of fibrin clot formation. Anti-Xa activity is used to monitor response to treatment with, and in vitro potency of, the LMWHs, including enoxaparin. The accurate determination of enoxaparin in blood or target tissues is difficult to achieve as LMWHs are mainly composed of glycosaminoglycans, which are normally present in biological tissues. Anti-Xa and anti-IIa activities are generally considered accepted pharmacodynamic (PD) surrogates to determine the pharmacokinetic properties and bioavailability of the LMWHs.
II.3 General comments on the submitted dossier
This decentralised application concerns Enoxaparin Ledraxen 30.000 IE (300 mg)/3 ml [50.000 IE (500 mg)/5 ml], Injektionslösung in Durchstechflasche, submitted as a similar biological application under article 10(4) of Directive 2001/83/EC, with reference to the originator Lovenox / Enoxaparin Venipharm 4,000 IU (40 mg)/0.4 mL, solution for injection in prefilled syringe (DCP duplicate application DE/H/7007/001/DC approved in 2021).
Venipharm in France as applicant and marketing authorisation holder has developed a biosimilar Product enoxaparin sodium, solution for injection in pre-filled syringes:
Enoxaparin Sodium 2,000 IU (20 mg)/0.2 mL solution for injection in pre-filled syringe
Enoxaparin Sodium 4,000 IU (40 mg)/0.4 mL solution for injection in pre-filled syringe
Enoxaparin Sodium 6,000 IU(60 mg) /0.6 mL solution for injection in pre-filled syringe
Enoxaparin Sodium 8,000 IU (80 mg)/0.8 mL solution for injection in pre-filled syringe
Enoxaparin Sodium10,000 IU (100 mg)/1 mL solution for injection in pre-filled syringe
These 5 Marketing Authorisation applications were initially submitted in December 2015 through a decentralised procedure as “similar biological applications” (i.e. based upon Article 10(4) of European Directive 2001/83/EC as amended). The Reference number of the procedure was UK/H/5936/01–05/DC.
Marketing authorisation was granted February 2019. In the following, the procedure was transferred to Germany as RMS with the reference number DE/H/6270/001–005.
Enoxaparin Venipharm, 4.000 IE (40 mg)/0,4 ml (DE/H/7007/001/DC ) is a duplicate application to UK/H/5936/01–05 / DE/H/6270/001–005. In the following, it is therefore referred to the assessment reports of procedure UK/H/5936/01–05.
Concerning information relating to orphan market exclusivity the applicant state that there is no orphan medicinal product the proposed therapeutic indications being applied for and for which a period of market exclusivity is in force in the European Union.
For further details, it is referred to the clinical overview, the assessment reports of procedure UK/H/5936/01–05/DC (annexed) and the submitted SPC.
II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles.
The RMS has been assured that acceptable standards of GMP are in place for these product types at all sites responsible for the manufacture and assembly of this product.
For manufacturing sites within the Community, the RMS has accepted copies of current manufacturer authorisations issued by inspection services of the competent authorities as certification that acceptable standards of GMP are in place at those sites.
For manufacturing sites outside the Community, the RMS has accepted copies of current GMP Certificates of satisfactory inspection summary reports issued by the inspection services of the competent authorities (or those countries with which the EEA has a Mutual Recognition Agreement for their own territories) as certification that acceptable standards of GMP are in place at those non-Community sites.
GMP active substance
The RMS has accepted copies of current GMP Certificates of satisfactory inspection summary reports issued by the inspection services of the competent authorities also for the manufacturer(s) responsible for manufacture of the finished product and batch release situated in the EU.
General Note on GMP certificates for AS and DP manufacturing sites: With a view to the Covid-19 pandemic situation and restrictions in China, the provided GMP certificates are accepted for the time being. Based on the revised “Notice to Stakeholders: Questions and answers on regulatory expectations for medicinal products for human use during the Covid-19 pandemic Rev 05– June 2022”, the validity of GMP certificates for manufacturing/importing sites of active substances and/or finished products in the EEA and outside the EEA can be extended until the end of 2023 without the need for further action from the holder of the certificate.
Seite 6 von 14 Based on the information provided the submitted pharmacodynamic study to demonstrate biosimilarity with the originator product was carried out according to GCP.
III.1 Quality aspects
This is an Extension application to Enoxaparin Venipharm 4.000 IE (40 mg)/0.4 ml, solution for injection in a pre-filled syringe (procedure number DE/H/7007/001/DC).
The Applicant claimed the following differences: “new strength/potency” and “Change or addition of a new pharmaceutical form” (see eAF section 1.3)
Enoxaparin Venipharm, 4.000 IE (40 mg)/0.4 ml, has been approved as a biosimilar under article 10(4) of Directive 2001/83/EC (procedure number DE/H/7007/001/DC), with reference to the originator Lovenox.
Venipharm in France as applicant and marketing authorisation holder has developed a biosimilar Product enoxaparin sodium, solution for injection in pre-filled syringes:
– Enoxaparin Sodium 2,000 IU (20 mg)/0.2 mL solution for injection in pre-filled syringe
– Enoxaparin Sodium 4,000 IU (40 mg)/0.4 mL solution for injection in pre-filled syringe
– Enoxaparin Sodium 6,000 IU(60 mg) /0.6 mL solution for injection in pre-filled syringe
– Enoxaparin Sodium 8,000 IU (80 mg)/0.8 mL solution for injection in pre-filled syringe
– Enoxaparin Sodium10,000 IU (100 mg)/1 mL solution for injection in pre-filled syringe
These 5 Marketing Authorisation applications were initially submitted in December 2015 through a decentralised procedure as “similar biological applications” (i.e. based upon Article 10(4) of European Directive 2001/83/EC as amended). The Reference number of the procedure was UK/H/5936/01–05/DC. Marketing authorisation was granted February 2019. In the following, the procedure was transferred to Germany as RMS with the reference number DE/H/6270/001–005.
Enoxaparin Venipharm, 4.000 IE (40 mg)/0.4 ml (procedure number DE/H/7007/001/DC) has been approved as a duplicate to UK/H/5936/01–05 / DE/H/6270/001–005.
The drug substance is not subject to this extension application and also according to the Applicant, there is no change in the dossier. Therefore no evaluation of the drug substance is provided as the drug substance is unchanged compared to the existing MA.
The active substance is enoxaparin sodiumfrom porcine resin-bound (crude) heparin. Pooled porcine mucosa is designated as the starting material. The manufacturing process for the drug substance has been acceptably described and the process is considered well-controlled.
The drug substance specification is considered to acceptably control the quality of the drug substance. The analytical methods have been suitably described and validated and batch data provided which demonstrate that the drug substance will meet the drug substance specification.
The finished products are Enoxaparin Ledraxen Venipharm, 30.000 IE (300 mg)/3 ml solution for injection and Enoxaparin Ledraxen Venipharm, 50.000 IE (500 mg)/5 ml solution for injection filled in glass vials closed with a bromobutyl rubber stopper. They are a line extension to Enoxaparin Venipharm 4.000 IE (40 mg)/0.4 ml, solution for injection in a pre-filled syringe (procedure number DE/H/7007/001/DC).
The finished products are manufactured a relatively simple fill-finish process consisting of dissolving the Seite 7 von 14 API, sterile filtration and aseptic filling into the glass vials.
The drug product manufacturing process is largely acceptably described and controlled and has been validated at the proposed commercial scales. Acceptable justification has been provided and meaningful risk mitigating measures have been included with respect to the omission of PUPSIT of the sterilising filter. The analytical methods have been acceptably described and validated. The finished product specification is considered acceptable to control the quality of the drug product. The proposed finished product is stable and a shelf-life of 24 months at 25°C/60 % RH conditions is proposed based on currently available data. Based on the data provided it is considered that this shelf life is acceptable. Updated in-use stability data have been provided to support the claimed in-use of 28 days at 25°C of the drug products.
III.2 Non clinical aspects
The applicant has provided a Non-clinical Overview which includes comparative studies conducted with batches of the proposed test enoxaparin sodium and approved reference enoxaparin sodium.
In accordance with the ICH guideline on non-clinical and clinical development of similar biological medicinal products containing low molecular-weight-heparins, in order to compare pharmacodynamic activity of the biosimilar and the reference low-molecular-weight heparin (LMWH), data from a number of comparative bioassays (based on state of the art knowledge about clinically relevant pharmacodynamic effects of LMWH and including, at least, evaluations of anti-FXa and anti-FIIa activity) should be provided. The applicant has provided this information. In addition, a discussion of impurities in the proposed product was provided. The Non-clinical Overview was revised during the original UK procedure to include the additional information.
The applicant has conducted 3 pharmacology studies:
1. An activated partial thromboplastin time (aPTT) test to evaluate the similarity of 12 batches of test enoxaparin and 12 batches of reference European enoxaparin sodium to quantify and compare clotting times.
2. A Heptest to evaluate the ability of enoxaparin to catalyse the inhibition of exogenous Factor Xa by antithrombin plasma. Six samples of test enoxaparin sodium from 3 batches were compared with 6 batches of EU sourced reference enoxaparin sodium and the fibrin clotting times compared.
3. A chromogenic test to evaluate low-molecular-weight heparin activity by measuring changes in colour at a specific wavelength after cleavage of synthetic substrates that are tagged with a specific chromophore for either Factor IIa or Factor Xa. The optical density is converted to a drug concentration using a drug-specific calibration curve.
In the aPTT test and Heptest, similarity of clotting time was detected between test and EU reference batches of enoxaparin sodium. The statistical analysis used to assess similarity were the Shapiro-Wilk test and the folded F-test. All p values were greater than 0.05 under the concentrations tested. The applicant suggested that the 95% confidence intervals (CIs) for the differences between the test and reference products at each concentration level contained “zero”, indicating no significant differences. In addition, for the aPTT and Heptest clotting tests, further information was provided to prove similarity. In general, the results provided appear similar for the batches of test and reference products. The p-values for the difference (derived using t-test) and the 95% confidence intervals were provided. A discussion of the derivation of the confidence intervals used was provided. The applicant agreed that for the Heptest analysis, APTT test and chromogenic test, no indication was given for 95% CI that should be read as Hodges-Lehmann 95% confidence limits or no indication was given for 95% CI that should be read as standard confidence intervals calculated with pooled standard error. A discussion on whether the confidence intervals exclude clinically relevant differences was also provided. From the data provided, the applicant claimed that the confidence intervals exclude clinically relevant differences in Heptest clotting time or APTT clotting time. For the Heptest clotting time, the initial statistical analysis used a nonparametric approach. It was deemed acceptable to run
a parametric analysis considering that unequal variances were only seen at the concentration 2.0 IU/mL. Seite 8 von 14 This parametric approach allowed the calculations of Cohen’s d effect sizes. The additional parametric analyses gave similar results in terms of p-values and widths of the respective 95% confidence intervals, suggesting that unequal variances at 2.0 IU/mL do not substantially affect the comparison.
The applicant stated that six different batches of the finished product enoxaparin sodium solution for injection manufactured from six different batches of the drug substance were compared with six new European reference product batches used in the aPPT test statistical analyses.
However, for the Heptest, three batches of drug substance appear to have been used to produce six batches of test NKF finished product. One batch of drug substance was used for the manufacture of 2 batches of finished product at the strength 2,000 IU/mL, one batch at the strength 8,000 IU/mL and one batch at the strength 10,000 IU/mL. These four products were considered “independent” in the former statistical analysis. However, it is not correct to assume independence of products. The applicant stated that there is no possibility of conducting additional experiments because the Heptest® Assay kit is no longer commercially available.
To address this issue, the applicant has conducted two sensitivity. However, the analyses performed by the applicant does not address the independence of the 4 finished products. Therefore, additional analyses were performed for the Heptest clotting time as to include only the independent batches of the finished NKF test product, i.e., each batch of the finished product being manufactured with a distinct batch of the drug substance. Four additional comparisons were undertaken, using the software JMP® ver 13.0. In case the assumption for equality of variances was rejected, the Welch’s t -test was run with 95% confidence interval using the Welch-Satterthwaite approximation to the degree of freedom. Otherwise, the independent group Student’s t-test was run with 95% confidence interval for the mean difference using the pooled standard error. These four additional sensitivity analyses of Heptest clotting time on reduced NKF datasets gave similar results to those obtained on the full dataset (test = 6 and reference = 6). Again, assumption of unequal variances was rejected at concentration 2.0 IU/mL but only in two sets of data. The applicant agreed that the hypothesis of “independence” of the four NKF finished products manufactured with the same batch of the drug substance is questionable. However, the additional analysis supports the claim that there is no substantial bias in the comparability exercise based on the full dataset.
In a chromogenic assay Anti-FXa activity, Anti-FIIa activity and ratios Anti-Xa/Anti-IIa were reported to be similar between 13 test and 17 reference batches of enoxaparin sodium. In a chromogenic study conducted to assess the combining capacity between enoxaparin and antithrombin, similarity was demonstrated between 6 test and 6 reference batches of enoxaparin sodium. For the chromogenic test, the validity of each assay was demonstrated by ANOVA evaluating the significance of linear regression and deviation from linearity and parallelism. 1) With a p-value 0.073, the hypothesis of non-linearity was rejected in favour of the hypothesis of linearity of the relationship between the dose and the response. 2) With a p-value of 0.651, the hypothesis of non-parallelism was also rejected in favour of the hypothesis of parallelism between the response of the Test and the Standard Reference. 3) All p-values were greater than 0.05 and all 95% CIs of mean difference (test – reference) at each concentration contained « zero ». The applicant suggested that this indicated strong evidence of similarity between test and reference products regarding the combining capacity to antithrombin.
While the standard curves for a test batch and reference batch of enoxaparin sodium obtained in the Anti-FXa activity and Anti-FIIa activity studies support a linearity of relationship between the dose and response, further information was requested to confirm whether similar results were obtained with other test and reference batches of enoxaparin sodium. Further information was subsequently provided on the details of the statistical results observed with all the test and reference batches, based on the p-values for regression, parallelism and linearity as well the potency and its 95% confidence interval. The parameters measured appear similar for the test and reference batches of enoxaparin. However, the applicant should clarify how the upper and lower specification limits were derived and justify their clinical relevance.
Seite 9 von 14 Immunotoxicity studies were also conducted by the applicant. In studies that assessed the interaction of enoxaparin with PF4, 3 batches of test enoxaparin sodium and 6 reference batches were used. The changes in the molecular structure of PF4 were assessed by circular dichroism (CD) spectroscopy, isothermal titration calorimetry (ITC) and enzyme linked immunosorbent assay (ELISA). Platelet activation induced by human PF4/heparin antibodies in the presence of enoxaparin was assessed by functional assays (heparin-induced platelet activation (HIPA) assays).
The applicant suggested that for the CD spectroscopy study, no significant difference between the 3 test and 6 reference batches of enoxaparin sodium was detected. Information was provided to show that in the CD spectroscopy study the size of differences was small enough to claim similarity between the NKF and RLD products of enoxaparin sodium regarding interactions with PF4. In the comparison for the CD spectroscopy study, the analysis of means (ANOM) was used. The ANOM provided a confidence interval formed between a lower decision line and an upper decision line, as determined using a specified formula.
For the ITC study, no significant difference between the test and reference batches of enoxaparin sodium was detected.
In a study using serum samples from heparin-induced thrombocytopenia patients to assess the binding of human PF4/heparin antibodies to PF4 enoxaparin complexes, 3 test and 6 reference batches of enoxaparin sodium were used. The applicant reported that the serum samples reacted similarly with the test and reference batches. This suggests similar interaction with PF4.
Information was also provided to show that with the exclusion of the reference batch no. 4LF31 the parameters measured for the test and reference batches were similar at enoxaparin concentrations of 3 μg or 4 μg. The overall mean optical density was almost 2-fold lower at 2 μg (OD = 0.844) compared to 3 μg (OD = 1.574) or 4 μg (OD = 1.557). This suboptimal ratio was considered to be possibly due to the large variability of the data. In addition, there was no evidence of a potentially clinically significant increase in immunogenicity of enoxaparin sodium with the test compared to the reference products.
For the HIPA assay, which is a sensitive functional assay for the detection of heparin-dependent antibodies, all contained IgG antibodies to PF4/heparin complexes. Of the 10 serum samples tested, 5 showed a strong reaction with heparin (defined as platelet aggregation occurring within 15 min) 2 showed a moderate-weak reaction with heparin (defined as platelet aggregation occurring after 15 min with heparin) and 3 sera did not activate platelets in the presence of heparin. The serum samples reactions were similar with all 3 enoxaparin batches and 6 reference batches, suggesting similar interaction with PF4.
Three test batches and 6 reference batches of enoxaparin sodium for injection were also assessed for: -Time course of T cell proliferation – proliferation of peripheral blood mononuclear cells (PBMC), from healthy donors, which were stimulated with either lipopolysaccharide (LPS) or keyhole limpet hemocyanin (KLH) or a clinical control (hA33).
– PBMC IL2 enzyme-linked immunosorbent spot (ELISPOT) assay – assessing the number of cells secreting human IL2.
– PBMC flow cytometry – to identify cell type and cell differentiation.
– Cytokine bead assay – to investigate various cytokine responses in the presence or absence of suboptimal concentrations of LPS.
In these tests, the applicant reported that no significant difference between the test and reference batches were detected. This is considered to be acceptable.
Studies were also conducted to quantify and compare the impurities (proteins, fatty acids, nucleic acid impurities) in 3 test and 3 reference batches of enoxaparin sodium. The test and reference batches were analysed. Batches were also analysed for package leachables. The levels of impurities and leachables were very low and similar in the test and reference batches of enoxaparin sodium. Thus, the applicant has provided
an adequate discussion of the impurities in the proposed products.
Sections 4.6 and 5.3 of the proposed SmPCs are considered to be acceptable.
III.3 Clinical aspects
The toxicology, and pharmacodynamic properties, efficacy and safety profile of enoxaparin are well established. As mentioned above, the accurate determination of enoxaparin in blood or target tissues is difficult to achieve. Anti-Xa and Anti-IIa activities are generally considered, under certain conditions, accepted PD surrogates to determine the pharmacokinetic properties and bioavailability of the LMWHs and enoxaparin.
As per the relevant CHMP guideline, the submission of a PD study (based primarily on Anti-Xa and Anti-IIa activity) only may be acceptable in exceptional circumstances if similar efficacy of the biosimilar and the reference product can be convincingly deduced from the comparison of their physicochemical characteristics, biological activity/potency, using sensitive, orthogonal and state-of-the-art analytical methods, and from comparison of their PD profiles. In terms of safety sufficient reassurance is needed that the biosimilar LMWH is not associated with any unexpected adverse reactions or with excessive immunogenicity compared to the reference product.
In support of the application, the Applicant submitted the findings of a single, randomized, open-label, single-dose, two-period, equivalence study. The primary objective of the study was to assess the pharmacokinetic and pharmacodynamic equivalence between the reference product Lovenox 10 000 IU/1 mL solution for injection in prefilled syringe and test formulation of Enoxaparin Venipharm 10 000 IU/1 mL solution for injection in prefilled syringe following subcutaneous administration in healthy male and female subjects using pharmacodynamic activities anti-Xa and anti-IIa as primary surrogate markers. The secondary objective was to assess additional biological effects of both the test and the reference formulations by measuring total Tissue Factor Pathway Inhibitor (TFPI) profile in plasma concentrations. In addition, the clinical and biological safety was monitored. The safety included serious and non serious adverse events, laboratory values, physical examination, ECG and vital signs.
A submitted clinical Overview provided a detailed discussion on the regulatory background, the development of the product and the submitted pharmacodynamic equivalence study. Also there is a discussion on the non-clinical tests to assess immunogenicity (see also Non-clinical part). The applicant has not performed any clinical therapeutic trials; therefore, the efficacy and safety discussion are for the most part restricted to published data with the innovator.
In terms of the need for additional clinical studies, it is argued that these are not necessary based on that:
– The similarity of the physicochemical and biological characterisation of the biosimilar drug product and the French reference drug product Lovenox has been demonstrated by means of appropriate studies included in the dossier.
– A comprehensive in vitro comparability study and an in vivo healthy human volunteer pharmacodynamic study (non-inferiority clinical trial) have been conducted. The pharmacodynamic study was designed to demonstrate PK/PD equivalence between biosimilar drug product and the French reference drug product Lovenox.
Pharmacodynamic Study
A monocentric, randomized, open-label, single-dose, two-period, crossover study to assess the pharmacokinetic and pharmacodynamic equivalence of Reference Product Lovenox® 10 000 IU/1 mL solution for injection in prefilled syringe and test formulation of Enoxaparin Venipharm 10 000 IU/1 mL solution for injection in prefilled syringe following subcutaneous administration in healthy subjects in fasting conditions.
This was a randomized, open-label, single-dose, two-period, crossover study in 60 (57 completing the trial) healthy male and female volunteers. Blood samples for determination of the pharmacodynamic parameters (primarily Anti-Xa and Anti-IIa activity) were obtained on Day 1 at time 0 (within 60 minutes pre-dose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 8, 12, 16, 20 and 24 hours post-dose in each period. There was a washout period of at least 7 days between periods. A detailed discussion on the methods is included in the Day 70 Non-Clinical and Clinical AR.
The results suggested similar profiles for the Anti-Xa and Anti-IIa activity between Test and Reference products.
The key pharmacodynamic data together with the findings of the new statistical analyses are summarised below.
Anti-Xa activity
PK/PD data for Anti-Xa activity:
| Pharmacokinetic/Pharmacodynamic Parameter : n = 56 | Arithmetic Means ± SD | |
| Test Product | Reference Product | |
| AUEC , (IU/mLxh) | 7.7921 ± 2.2232 | 7.1793 ± 1.9938 |
| AUEC(0-inf) , (IU/mLxh) | 8.7814 ± 2.3334 | 8.0131 ± 1.9439 |
| % AUEC extrapolation | 11.46 ± 7.59 | 10.56 ± 6.76 |
| Cmax , (IU/mL) | 0.7943 ± 0.2276 | 0.7444 ± 0.2341 |
| Tmax1, (hours) | 4.00 (1.00 ; 8.00) | 4.00 (1.50 ; 8.00) |
| Biological T1/2 , (hours) | 5.98 ± 2.06 | 5.46 ± 1.88 |
1 Median (Min ; Max)
Biosimilarity evaluation of Anti-Xa activity:
| Parameter | Geometric Mean Ratio (Test/Reference), % | 95% Confidence Interval, % | ∆, Acceptance range of biosmilarity1 |
| AUEC (0-t), IU/mL*h | 108.22 | [104.49 – 112.08] | 85.00% – 117.65% |
| AUEC (0-infinite), IU/mL*h | 109.02 | [105.27 – 112.91] | 85.00% – 117.65% |
| Cmax, IU/mL | 107.46 | [103.28 – 111.81] | 85.00% – 117.65% |
1∆ Acceptance range of biosimilarity derived from an equivalence margin of ± 15% on untransformed data
Anti-IIa activity
PK/PD data for Anti-FIIa activity:
| Pharmacokinetic/Pharmacodynamic Parameter : n = 55 | Arithmetic Means ± SD | |
| Test Product | Reference Product | |
| AUEC , (IU/mLxh) | 1.3153 ± 0.6939 | 1.3548 ± 0.7048 |
| Cmax , (IU/mL) | 0.2061 ± 0.0659 | 0.2147 ± 0.0755 |
| Tmax1, (hours) | 4.00 (2.00 ; 5.00) | 4.00 (3.00 ; 5.00) |
1 Median (Min ; Max)
Biosimilarity evaluation of Anti-IIa activity:
| Seite 12 von 14 | Parameter | Geometric Mean Ratio (Test/Reference), % | 95% Confidence Interval, % | ∆, Acceptance range of biosmilarity1 |
| AUEC (0-t), IU/mLxh | 96.74 | [90.71 – 103.17] | 75.00% – 133.33% | |
| Cmax, IU/mL | 96.59 | [92.45 – 100.91] | 75.00% – 133.33% |
1∆ Acceptance range of biosimilarity derived from an equivalence margin of ± 25% on untransformed data
TFPI
PK/PD supportive data for baseline corrected TFPI:
| Pharmacokinetic/Pharmacodynamic Parameter : n = 57 | Arithmetic Means ± SD | |
| Test Product | Reference Product | |
| AUC(0-t) , (ng/mLxh) | 145.224 ± 137.509 | 138.824 ± 80.353 |
| AUC(0-inf) , (ng/mLxh) | 158.716 ± 161.082 | 150.229 ± 85.159 |
| % AUEC extrapolation | 6.95 ± 10.41 | 6.92 ± 9.73 |
| Cmax , (ng/mL) | 24.940 ± 16.843 | 24.507 ± 12.027 |
| Tmax1, (hours) | 1.50 (0.50 ; 4.00) | 1.00 (0.50 ; 3.00) |
| Thalf , (hours) | 3.07 ± 1.43 | 2.83 ± 1.11 |
1 Median (Min ; Max)
Biosimilarity evaluation of TFPI (baseline-adjusted level):
| Parameter | Geometric Mean Ratio (Test/Reference), % | 95% Confidence Interval, % | ∆, Acceptance range of biosmilarity1 |
| AUC (0-t), hxng/mL | 97.06 | [91.82 – 102.59] | 80.00% – 125.00% |
| Cmax, ng/mL | 97.26 | [92.31 – 102.46] | 80.00% – 125.00% |
1∆ Acceptance range of biosimilarity based on standard ± 20% equivalence margin on untransformed data
The data from the study support the similarity between the proposed Enoxaparin Venipharm/Ledraxen and the originator Lovenox. From a Clinical perspective, the application could be approvable.
The Applicant/Proposed Future MAH has submitted a signed Summary of the Applicant's/Proposed Future MAH's Pharmacovigilance System. Provided that the Pharmacovigilance System Master File fully complies with the new legal requirements as set out in the Commission Implementing Regulation and as detailed in the GVP module, the RMS/Rapporteur considers the Summary acceptable.
The MAH has submitted separate risk management plans, 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:
Enoxaparin Ledraxen 30.000 IE (300 mg)/3 ml, Injektionslösung in Durchstechflasche (DE/H/7190/001/DC) and
Enoxaparin Ledraxen 50.000 IE (500 mg)/5 ml, Injektionslösung in Durchstechflasche
(DE/H/7191/001/DC).
Besides administrative information, the RMPs submitted for DE/H/7190/001/DC and DE/H/7191/001/DC seem to be identical. Therefore, the below assessment applies to both RMPs equally.
Safety specification
Table SVIII.1: Summary of safety concerns
| Important identified risks | Major haemorrhages 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 |
Pharmacovigilance Plan
Routine pharmacovigilance is suggested and no additional pharmacovigilance activities are proposed by the applicant.
Risk minimisation measures
Routine risk minimisation is suggested and no additional risk minimisation activities are proposed by the applicant.
Summary of the RMP
The summary of safety concern is endorsed.
There are no additional pharmacovigilance activities for the medicinal products under review, routine pharmacovigilance is considered sufficient. The applicant has established a specific adverse drug reaction follow-up form for the important identified risk of heparin-induced thrombocytopenia as a tool of routine pharmacovigilance, which is endorsed.
Routine risk minimisation measures are considered sufficient.
The submitted RMPs are considered acceptable.
The future MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in the dossier of the Marketing Authorisation and any agreed subsequent updates of the RMP.
An updated RMP should be submitted:
At the request of the RMS Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of animportant (pharmacovigilance or risk minimisation) milestone being reached.
With regard to PSUR submission, the MAH should take the following into account:
PSURs shall be submitted in accordance with the requirements set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and published on the European medicines web-portal. Marketing authorisation holders shall continuously check the European medicines web-portal for the DLP and frequency of submission of the next PSUR. For medicinal products authorized under the legal basis of Article 10(1) or Article 10a of Directive 2001/83/EC, no routine PSURs need to be submitted, unless otherwise specified in the EURD list. In case the active substance will be removed in the future from the EURD list because the MAs have been withdrawn in all but one MS, the MAH shall contact that MS and propose DLP and frequency for further PSUR submissions together with a justification.The common renewal date is 04.05.2028.
Medicinal product subject to medical prescription.
The results of this test indicate that the PIL is well structured and organised, easy to understand and written in a comprehensible manner. The test shows that the leaflet is readable and patients/users are able to act upon the information that it contains. This report also meets the legal requirements for Art. 59(3) of Directive 2001/83/EC (as amended).
ELC also confirms the report conforms to the study design, principles and success criteria featured in the European Commission's document „Guideline on the Readability of the Label and Package Leaflet of Medicinal Products for Human Use” (Revision 1, 12 January 2009).
Based on the above mentioned facts the package leaflet can be qualified as acceptable.
The applicant provided a statement that the results can be bridged to the PIL of Enoxaparin Ledraxen® 30,000 IU (300 mg)/3 mL, solution for injection in vial, which is considered acceptable.