PUBLIC ASSESSMENT REPORT

Decentralised Procedure

Enoxaparin Becat 10,000 IU (100 mg /1ml)

Enoxaparin Becat 15,000 IU (150 mg /1ml)

Enoxaparin Becat 12,000 IU (120 mg /0,8 ml)

Enoxaparin Becat 8,000 IU (80 mg /0,8 ml)

Enoxaparin Becat 6,000 IU (60 mg /0,6 ml)

Enoxaparin Becat 4,000 IU (40 mg /0,4 ml)

Enoxaparin Becat 2,000 IU (20 mg /0,2 ml)

DE/H/5020/001-007/DC
 Crusia
10,000 IU (100 mg /1ml)

Crusia
15,000 IU (150 mg /1ml)

Crusia
12,000 IU (120 mg /0,8 ml)

Crusia
8,000 IU (80 mg /0,8 ml)

Crusia
6,000 IU (60 mg /0,6 ml)

Crusia
4,000 IU (40 mg /0,4 ml)

Crusia
2,000 IU (20 mg /0,2 ml)

DE/H/5021/001-007/DC
 Active Substance:
Enoxaparin

Marketing Authorisation Holder in

the Reference Member State, Germany :
Laboratorios Farmacéuticos Rovi, S.A

Publication:
25.05.2018
 TABLE OF CONTENTS
I. RECOMMENDATION .............................................................................................................. 6
II. EXECUTIVE SUMMARY ..................................................................................................... 6
II.1 Problem statement................................................................................................................... 6
II.2 About the product ................................................................................................................... 6
II.3 General comments on the submitted dossier ........................................................................ 7
II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles. 7
III. SCIENTIFIC OVERVIEW AND DISCUSSION ................................................................. 7
III.1 Quality aspects ......................................................................................................................... 7
III.2 Non-clinical aspects ............................................................................................................... 10
III.3 Clinical aspects ...................................................................................................................... 13
IV. BENEFIT RISK ASSESSMENT ......................................................................................... 25

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 ADMINISTRATIVE INFORMATION

Enoxaparin Becat 10,000 IU (100 mg /1ml)

Proposed name of the medicinal
Enoxaparin Becat 15,000 IU (150 mg /1ml)
product(s) in the RMS
Enoxaparin Becat 12,000 IU (120 mg /0,8 ml)
Enoxaparin Becat 8,000 IU (80 mg /0,8 ml)
Enoxaparin Becat 6,000 IU (60 mg /0,6 ml)
Enoxaparin Becat 4,000 IU (40 mg /0,4 ml)
Enoxaparin Becat 2,000 IU (20 mg /0,2 ml)
DE/H/5020/001-007/DC

Crusia 10,000 IU (100 mg /1ml)

Crusia 15,000 IU (150 mg /1ml)
Crusia 12,000 IU (120 mg /0,8 ml)
Crusia 8,000 IU (80 mg /0,8 ml)
Crusia 6,000 IU (60 mg /0,6 ml)
Crusia 4,000 IU (40 mg /0,4 ml)
Crusia 2,000 IU (20 mg /0,2 ml)
DE/H/5021/001-007/DC

Enoxaparin Sodium
Name of the drug substance (INN
name):
B01AB05
Pharmaco-therapeutic group
(ATC Code):
Solution for injection in pre-filled syringe
Pharmaceutical form(s) and
strength(s):
DE/H/5020-5021/001-007/DC
Reference Number(s) for the
Decentralised Procedure
DE
Reference Member State:
AT, BE, BG, CZ, DK, EE, EL, ES, FI, FR, HR, HU, IE, IT,
Member States concerned:
LU, LV, NL, NO, PL, PT, RO, SE, SI, SK and UK
Legal basis of application: Similar biological Art 10.4 Dir 2001/83/EC
Applicant (name and address) LABORATORIOS FARMACÉUTICOS ROVI, S.A.
JULIÁN CAMARILLO, 35 - MADRID
Postcode: 28037
Country: SPAIN

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 RECOMMENDATION
Based on the review of the data and the Applicant’s response to the questions raised by RMS and
CMSs on quality, safety and efficacy, the RMS considers that the application for Enoxaparin Rovi 100
mg/ml; 150 mg/ml and/or Crusia 100 mg/ml; 150 mg/ml treatment and prophylaxis of
thromboembolic disorders,

is approved provided that the applicant commits to perform a number of post authorisation follow- up
measures and obligations to be reported back to the Member States within predefined timeframes.

I. EXECUTIVE SUMMARY
I.1 Problem statement

This is an application for two dose strengths (100 mg/mL and 150 mg/mL solution for injection) of an
enoxaparin-containing medicinal product claimed to be “biosimilar” to the European reference product
Clexane.

I.2 About the product

Enoxaparin is a low molecular weight heparin with a mean molecular weight of approximately 4,500
daltons (3,500-5,500). The drug substance is the sodium salt. Enoxaparin sodium belongs to
Antithrombotic Agents pharmacological class with ATC code: B01AB05 enoxaparin.
It is obtained by alkaline depolymerization of heparin benzyl ester derived from porcine intestinal
mucosa.
Enoxaparin binds to antithrombin III leading to inhibition of coagulation factors IIa and Xa.
The mechanism of action of enoxaparin is antithrombin-dependent. It acts mainly by accelerating the
rate of the neutralization of certain activated coagulation factors by antithrombin, but other
mechanisms may also be involved. Enoxaparin potentiates preferentially the inhibition of coagulation
factors Xa and IIa and only slightly affects other hemostatic mechanisms such as clotting time. The
antithrombotic effect of enoxaparin is well correlated to the inhibition of Factor Xa.

Therapeutic indications applied 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.
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).
The indications applied for are in accordance with the result of the article 30 Referral of Directive
2001/83/EC Procedure no: EMEA/H/A-30/1429 to harmonise the PI of enoxaparin across the EU.

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I.3 General comments on the submitted dossier

Laboratorios Farmacéuticos Rovi is applying for a marketing authorisation for Enoxaparin sodium 100
mg/mL and 150 mg/mL solution for injection.
The active substance enoxaparin sodium is not considered as a new active substance.
The application is submitted under the legal base of Similar Biological Medicinal Product referring to
Article 10.4 of Directive 2001/83/EC.
The chosen EU reference medicinal product for this application and used in the quality comparability
exercise is Clexane in all marketed strengths in solution for injection in pre-filled syringe produced in
France and sourced from the Spanish market.
For the German market reference is made to Clexane 100 mg / Injektionslösung.

The proposed biosimilar Enoxaparin Sodium solution for injection has been evaluated in a Single-
Dose, Randomized, Double-Blind, Two-Way Crossover pivotal Bioequivalence Study of Enoxaparin
(100 mg/mL) 100-mg Subcutaneous Injection Manufactured by ROVI, Spain, and Clexane (100
mg/mL) 100-mg Subcutaneous Injection manufactured by Sanofi-aventis France, Paris, France, in 46
Healthy Volunteers (Study# ROV-RO20-2015-01).

The applicant has submitted a risk management plan.

I.4 General comments on compliance with GMP, GLP, GCP and agreed ethical
principles.

GMP inspections in any of the manufacturing sites of Enoxaparin sodium drug substance and drug
product are not needed as valid GMP certificates have been submitted. Universidad Complutense is
confirmed as a registered subcontractor of Laboratorios Farmacéuticos Rovi, Granada.

GLP: All submitted non-clinical studies were performed according to GLP principles with the
exception of the in-vivo pilot PK/PD study in rabbits (study S41751) and the in-vitro characterisation
of the enoxaparin-PF4 complex.

GCP: The applicant stated that the bioequivalence study was conducted in accordance with GCP and
audited SOPs of the unit and internal quality assurance staff ensured compliance with GCP. The
analytical staff (PRA Health Sciences, Zuidlaren, The Netherlands) did not have access to the
randomization code before the pharmacokinetic analysis was performed. The study was also
conducted in accordance with GLP regulations. It was a single-dose, randomized, double-blind, 2-
period, 2-sequence crossover study.
Written approval from the investigator’s institutional review board (IRB) for ethical review of the
original study protocol was provided.

II. SCIENTIFIC OVERVIEW AND DISCUSSION

II.1 Quality aspects

Drug substance
Enoxaparin sodium is the sodium salt of a low molecular-mass heparin obtained by alkaline
depolymerisation of the benzyl ester derivative of heparin manufactured from porcine intestinal

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mucosa. Enoxaparin sodium is manufactured and released by Laboratorios Farmacéuticos ROVI, S.A.,
Parque Tecnológico de Ciencias de la Salud (PTS), Granada, Spain.
Manufacturing Process and Process Controls
The manufacturing process description starts from pooled porcine mucosae in accordance with the
classification of pooled porcine intestinal mucosae as starting material for heparin and heparin
derivatives (EMA/CHMPBWP/429241/2013). Detailed information on the manufacturing process of
heparin sodium has now replaced the initially limited information on this intermediate. This is
considered relevant as the manufacturing process of heparin sodium from pooled porcine mucosa is
considered to have significant impact on the quality attributes of heparin sodium and consequently on
those of enoxaparin sodium.

The conversion of heparin sodium to enoxaparin sodium is divided in four major steps comprising
formation of heparin benzethonium salt, formation of heparin benzyl ester, depolymerisation and
purification of the product to give enoxaparin sodium.

Control of Materials
Materials used in the manufacturing process are properly controlled

Control of Critical Steps and Intermediates

Critical steps and intermediates have been described and process controls are in place to deliver
intermediate product within predefined acceptance criteria.
Process Validation
Prospective validation was performed and data show that all CQAs have been followed.

Characterisation
The provided characterisation data include physico-chemical properties of Rovi’s enoxaparin such as
molecular weight distribution, UV- and IR spectrum, sodium content, molecular ratio of sulfate to
carboxylate ions and NMR fingerprints.

A number of process-related impurities are mentioned to be controlled in the DS specification which is

considered appropriate. Potential product-related impurities and degradants have also been considered.
To address this aspect, stress studies have been performed to identify both potential product-related
impurities and degradants and respective stability-indicating analytical methods.

Specification
The proposed DS specification combines tests required in the Ph. Eur. monographs “Enoxaparin” and
“Low molecular mass heparins” and tests, which are performed in accordance to in-house procedures.
The proposed DS specification complies largely with the requirements of the Ph. Eur. monographs.
The provided DS specification includes tests for appearance and solubility as well as identification by
13
C NMR, presence of 1,6-anhydro structure and sodium, anti FXa/ anti FIIa ratio and mass % of
chains of different ranges. Tests on solution appearance, pH, specific absorbance, content of benzyl
alcohol, sodium, nitrogen and heavy metals as well as on molar ratio of sulfate ions/ carboxylate ions,
loss on drying and bacterial endotoxins are also included. In addition, assay by determination of anti-
FXa and anti FIIa activity, Test on residual solvents and on microbial contamination are implemented
into the proposed DS specification.
Analytical methods are acceptable and sufficient detail has been provided.
Analytical data for exemplary commercial batches have been provided to demonstrate compliance
with the DS specification.

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Information regarding the reference standards used is sufficient.
Stability data are provided for three commercial scale batches and up to 24 months at long-term
conditions, 12 months at intermediate conditions and 6 months at accelerated conditions when stored
in a container representative for the commercial one. The initially proposed “re-test period” has been
converted to a shelf life in accordance with the principles of ICHQ5C.
On the basis of the data provided the proposed shelf-life for Enoxaparin Sodium was considered
acceptable.

Drug Product
Enoxaparin sodium drug product is formulated with water for injection only, without addition of any
excipients. The composition is identical with the reference product Clexane. The critical quality
attributes of Enoxaparin sodium Rovi drug product were evaluated to meet the relevant general
requirements of Ph. Eur. and the acceptance criteria described in the monograph ‘Enoxaparin sodium
for injection’ of the British Pharmacopoeia (BP).
For commercial drug product production, lyophilised Enoxaparin sodium is solved in water. After
sterile filtration, the bulk product solution is filled into the sterilized syringes and stoppered. The
specified ranges of the operational parameters implemented for the commercial production process are
supported by appropriate process development data. Process validation was adequately performed and
confirms that the commercial process is capable to consistently produce Enoxaparin Rovi drug
product.
The DP specification proposed is based on the BP monograph Enoxaparin Sodium Injection. The list
of test parameters to be controlled at release and during stability studies is considered adequate. As
regards justification of suitability of the drug product specification acceptance criteria derived from
the pharmacopoeias reference is made to the drug substance specification.
The final product is labelled by amount as well as by anti-factor Xa activity. The activity labelled is
verified at DP release for each batch. Batch analysis has been performed on a sufficient number of
batches of commercial size produced by utilizing different DS batches. A list of all DP batches
produced so far (including those introduced in the new biosimilarity studies) with details on their
production (date, scale, DS batch used for manufacture) and their purpose of use has been presented.
DP release data of the pilot scale batches and the newly produced batches for the new comparative
studies have been provided.
Packaging materials are described. For primary packaging materials, coming into contact with finished
product solution, compliance with the respective Ph. Eur. requirements is confirmed.
Potential extractables and leachables of the primary packaging material were thoroughly investigated
and found to be acceptable.
ICH conforming stability studies as well as adequate stress studies have been performed. The number
of batches included in the studies is sufficient and cover all strengths. The updated DP stability data
presented supports the claimed shelf life of 36 months. No significant quality changes could be
observed at the recommended storage temperature. The storage instructions indicated in the SPC are
justified and are in compliance with the relevant Guideline.
Adventitious Agents
Porcine mucosa is the starting material for manufacture of enoxaparin and can potentially contain
contaminating ruminant material.
Biosimilarity
Similarity of quality profiles between the test product and the reference product Clexane authorized in
the EEA can now be derived more reliably based on a significantly larger database with respect to

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number of batches investigated and representativeness of data obtained.
As documented the chosen test product batches were manufactured based on numerous different crude
heparin batch lots the quality data of which has been provided. Furthermore the use of different
heparin batches in manufacture of commercial enoxaparin batches further supports representativeness
of these batches used in the comparability exercise.
Remaining differences in quality attributes especially as regards biological activity have suggested the
need to adapt acceptance criteria for biological activity in crude heparin lots in order to further ensure
similarity with the reference product.
For the biosimilar comparability exercise acceptance criteria applied for comparison of specific quality
attributes between the test and the reference product have now been explained with more detail.
Information on the proposed statistical approaches and on transformation of the study data into
statistical data for the purpose of evaluation of similarity as well as deduction of biosimilarity
acceptance criteria have been explained in detail. Development and deduction of biosimilarity
acceptance criteria to the various categories of quality attributes has thus been addressed as requested.
Suitability of statistical models has been further supported by visualisation of data, as requested.

Conclusion on Quality

In conclusion, all outstanding issues have been adequately solved.

II.2 Non-clinical aspects

Pharmacology

The idea of biosimilarity is that due to the complexity of the active substance full prediction of the
biological effects may not be possible with pharmaceutical methods only. Hence, characterisation of
the primary action of the active substance in the organism is sought. The most important primary
action of enoxaparin is inhibition of the circulating activated coagulation factors (serine proteases)
FXa and FIIa.
The assay used by the Applicant for determining inhibition of these factors is appropriate, and several
enoxaparin doses have been tested, allowing construction of a reliable concentration-response
relationship curve. The shape of this curve provides much more information than only one value such
as EC50 or maximal inhibition. It is difficult to describe the whole concentration-response relationship
with statistical methods. Therefore, the non-clinical biosimilarity exercise mainly relies on visual
inspection of the results after suitable graphical representation. This revealed that Enoxaparin Rovi
and Clexane can be considered similar.

The Applicant also aimed to characterise an in-vitro concentration-response relationship by providing

IC50 values for elongation of thrombin time. However, this approach failed because beyond a certain
(relatively low) enoxaparin concentration, the outcome became an all-or-nothing response, preventing
meaningful calculation of IC50. This is not a concern since appropriate data on FXa and FIIa
inhibition using a chromogenic substrate were provided. The Applicant also followed an in-vivo
approach by measuring PK/PD parameters in rabbits. The results demonstrate high similarity between
Enoxaparin Rovi and the comparator Clexane. Nevertheless, in-vitro tests are in general preferred
because they measure the interaction of the active substance and its pharmacological target more
directly and their variability is often lower. Therefore, in-vivo tests are only required if suitable and
accurate in-vitro tests are not available.

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Anti-FXa and anti-FIIa activity in vivo

The Applicant also submitted a new bioequivalence study in rabbits to support the biosimilarity of
Enoxaparin Rovi and the reference product Clexane.

A dose of 517 aFXa IU/kg SC of test and reference product was injected in 12 male rabbits each in a
cross-over design; i.e. all 24 animals received each treatment, test and reference, with a wash-out
period of 7 days in-between. Blood was drawn at different time points up to 24 hours. Product
concentration in plasma was calculated by evaluating the capacity of Factor Xa and FIIa inhibition.
Moreover, APTT (Activated Partial Thromboplastin Time) were determined from the plasma
obtained. Pharmacokinetic parameters were calculated for the anti-Factor Xa and anti-Factor IIa
activities using WinNonlin® Professional Version 6.3 software (Pharsight Corporation).

The plasma anti FXa- and anti-FIIa-activity over time is shown graphically below.

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The time-course of FIIa and FXa inhibition after a single injection of enoxaparin was very similar for
Enoxaparin Rovi and Clexane. This is reassuring; however, measuring FXa and FIIa inhibition in vitro
is considered more accurate since in the whole organism several unknown factors can affect PK and
PD of enoxaparin, leading to higher variability than in vitro. This is reflected by the rather large error
bars shown in the figure above in case of FXa inhibition; FIIa inhibition has smaller error bars,

but the magnitude of the response is rather low and obviously close to the limit of quantification. In-
vitro measurements are preferred for demonstrating biosimilarity because of higher accuracy (less
fluctuation) of the data. Thus, these in-vivo findings are considered supportive.

Pharmacokinetics

PK analysis is not required for a biosimilar application. Furthermore, enoxaparin levels in plasma are
normally not measured directly but PD measurements are used to estimate and compare enoxaparin
plasma levels. An in-vivo PD study was performed in rabbits.

Toxicology

No general toxicity studies are required for biosimilar products unless there is specific concern, what
is not the case here. Hence, the Applicant has not performed toxicology studies what is endorsed.

Immunogenicity

A special aspect of biosimilar products is their immunogenicity which should not be larger than with
the comparator. In case of heparins, the most important consequence of immunogenicity is
development of HIT (heparin-induced thrombocytopenia). The molecular basis of this condition is the
formation of antibodies against a complex of the heparin with endogenous PF4 (platelet factor 4). The
antibodies, together with the heparin-PF4 complex, are able to activate and thereby consume
thrombocytes.

Hence, the Applicant characterised the enoxaparin-PF4 complex with several independent analytical
methods in direct comparison of Enoxaparin Rovi and the reference product Clexane.

No relevant differences between Enoxaparin Rovi and Clexane became obvious in all these
approaches.

Environmental Risk Assessment (ERA)

Since Enoxaparin Rovi is intended for biosimilar substitution, this will not lead to an increased
exposure to the environment. An environmental risk assessment is therefore not deemed necessary.

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II.3 Clinical aspects

Pharmacokinetics
Conventional PK studies cannot be performed for Low molecular weight heparins (LMWHs) due to
the heterogeneity in their physico-chemical characteristics.
Therefore, a medicinal product containing LMWH as active ingredient and claiming to be biosimilar
to a reference product needs to prove bioequivalence to the reference product on the basis of its PD
properties, according to the guideline on non-clinical and clinical development of similar biological
medicinal products containing LMWHs (EMEA / CHMP / BMWP / 118264 / 2007 Rev. 1, 17 January
2013), under the Directive 2001/83/EC Art 10(4).

Pharmacodynamics
Pivotal study (ROV-RO20-2015-01)

The applicant has conducted a single-dose, randomized, double-blind, two-way crossover

bioequivalence study of enoxaparin (100 mg/ml) 100-mg subcutaneous injection manufactured by
Rovi, Spain, and Clexane (100 mg/ml) 100-mg subcutaneous injection manufactured by Sanofi-
Aventis, EU, in healthy volunteers

Test and reference products

The applicant’s product [Enoxaparin (100 mg/mL)] 100-mg Subcutaneous Injection

manufactured by Rovi, Spain (batch No. L-05, Batch size (= production scale size) 30,000 pre-
filled syringes, Date of manufacture 21/06/2015, exp. date not provided) has been compared to
the reference product [Clexane (100 mg/mL)] 100-mg Subcutaneous Injection manufactured by
Sanofi-aventis France, Paris, France (Batch No: 5SA09 exp. date 12/2017).

Population(s) studied
A total of 33 male and 13 female subjects between 18 and 44 years of age and with a BMI
between 19.0 and 31.1 kg/m2 participated in the study.

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Results
Anti-Xa Activity

Statistical Analysis of Plasma Pharmacodynamic Parameters for Anti-Xa Activity (Pharmacodynamic

Population – ROV-RO20-2015-01)
Geometric Treatment 95% CI CV
Parameter Treatment Estimate
LS Means Comparison (lower-upper) (%)
A 0.974
Amax
A/B 100.1 94.6 - 105.9 13.0
(IU/mL) B 0.973

AUEC0-T A 8.05
A/B 103.8 99.8 - 108.0 9.1
(h*IU/mL) B 7.75
AUEC0-inf A 8.91
A/B 104.2 100.0 - 108.6 8.8
(h*IU/mL) B 8.55

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Anti-IIa Activity

Statistical Analysis of Plasma Pharmacodynamic Parameters for Anti-IIa Activity (Pharmacodynamic

Population– ROV-RO20-2015-01)
Geometric Treatment 95% CI CV
Parameter Treatment Estimate
LS Means Comparison (lower-upper) (%)
A 0.181
Amax
A/B 103.3 94.7 - 112.6 20.2
(IU/mL) B 0.175

AUEC0-T A 1.08
A/B 103.5 90.9 - 117.9 30.5
(h*IU/mL) B 1.04

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TFPI Activity

Statistical Analysis of Plasma Pharmacodynamic Parameters for Baseline-Adjusted TFPI Activity

(Pharmacodynamic Population– ROV-RO20-2015-01)
Geometric Treatment 95% CI CV
Parameter Treatment Estimate
LS Means Comparison (lower-upper) (%)
A 207
Amax (ng/mL) A/B 104.1 95.6 - 113.4 19.9
B 199
A 913
AUEC0-T
A/B 105.9 99.1 - 113.1 15.2
(h*ng/mL) B 863
A 910
AUEC0-inf
A/B 108.4 102.1 - 115.2 9.0
(h*ng/mL) B 839

Statistical Analysis of Plasma Pharmacodynamic Parameters RAUEC (Pharmacodynamic Population–

ROV-RO20-2015-01)

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 95% CI
Geometric Treatment CV
Parameter Treatment Estimate
LS Means Comparison (%)
(lower-upper)

A 7.46
RAUEC* A/B 100.3 87.9 - 114.5 31.1
B 7.44
CI=confidence interval; CV=coefficient of variation; LS=least squares
Treatment A: Enoxaparin (100 mg/mL) 100-mg SC injection, manufactured by Rovi (Spain)
Treatment B: Clexane® (100 mg/mL) 100-mg SC injection, manufactured by Sanofi (EU)
* RAUEC is the ratio of AUEC0-T of anti-FXa activity to anti-FIIa activity
Note: A linear mixed effects model was applied to the natural log-transformed PD parameters with sequence,
period and treatment as fixed effects and subject nested within sequence as a random effect

Supportive study (ROV-RO20-2011-01)

The applicant submitted a single-dose, randomized, double-blind, 2-period, 2-sequence crossover
study (ROV-RO20-2011-01) at one study site to compare the PD profile of enoxaparin (100 mg/ml)
100-mg subcutaneous (SC) injection manufactured by Rovi, Spain and Lovenox (100 mg/ml) 100-mg
SC injection manufactured by Sanofi-Aventis, USA, after single-dosing in fasted healthy volunteers.

Blood samples for determination of anti-Xa, anti-IIa and baseline-adjusted tissue factor pathway
inhibitor (TFPI) activity were collected before dosing and up to 36 hours after dosing. The treatment
periods were separated by a washout period of 7 days, which is considered adequate.

Plasma samples were analysed for factors anti-Xa and anti-IIa using chromogenic methodologies
developed at the Harlan Laboratories S.A. facility in Barcelona, Spain. Plasma samples were analysed
for TFPI at the Harlan Laboratories S.A. facility in Barcelona, Spain using a commercially available
kit. The analytical methods are acceptable, properly validated (pre-study and within study) and the
handling of samples was adequate.

The PD parameters AUEC0-inf, AUEC0-T, and peak effect for anti-Xa, anti-IIa, and baseline-adjusted
tissue factor pathway inhibitor (TFPI) activity (anti-Xamax, anti-IIamax, and TFPImax) from the test
treatment were compared with those from the reference treatment. The pharmacodynamic variables are
in agreement with the CHMP scientific advice and considered adequate.

The geometric mean ratio and 90% CI (and 95% CI in post hoc analysis in response to the CHMP
scientific advice) were calculated. Bioequivalence was concluded if the 95% CI of the ratio of the
geometric least squares (LS) means between the test treatment and the reference treatment for AUEC0-
inf, AUEC0-T, and anti-Xamax of anti-Xa activity were completely within the standard 80% to 125% BE
interval and AUEC0-T and anti-IIamax of anti-IIa activity were completely within the standard 80% to
125% BE interval. The statistical methods are acceptable and described adequately.

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Table 1: Post Hoc Statistical Analysis of Plasma Pharmacodynamic Parameters for
Anti-Xa Activity (Pharmacodynamic Population)
Parameter Treatmenta N Geometric Treatment Ratio (%) 95% CI of
(unit) Comparison of
LS Means the Ratio
Geometric
LS Means

AUEC0-inf A 40 14.829 100.1–

A/B 103.3
(h•aXaU/mL) B 40 14.358 106.6

AUEC0-T A 41 13.852
A/B 103.3 99.9– 106.7
(h•aXaU/mL) B 40 13.415
Anti-Xamax A 41 1.173
(aXaU/mL) A/B 101.1 96.1 – 106.4
B 40 1.160
Abbreviations: CI, confidence interval; LS, least squares.
Note: A linear mixed effects model was applied to the natural log-transformed pharmacodynamic
parameters with sequence, period, and treatment as fixed effects and subject nested within sequence as
a random effect.
a
Treatment A = Enoxaparin (100 mg/mL) 100-mg subcutaneous injection manufactured by Rovi,
Spain.
Treatment B = Lovenox (100 mg/mL) 100-mg subcutaneous injection manufactured by Sanofi-
Aventis, USA.

For anti-Xa, 40 or 41 subjects were included in the PD analyses. Two subjects were excluded from
the analyses (for all 3 PD parameters: AUEC0-inf, AUEC0-T, and anti-Xamax) for both enoxaparin
manufactured by Rovi and Lovenox because the anti-Xa baseline value was higher than the lower
limit of quantification (LLOQ) for anti-Xa. Another subject was excluded from AUEC0-inf for
enoxaparin manufactured by Rovi because the extrapolated AUEC was greater than 20%.

DE/H/5020-5021/001-007/DC Enoxaparin / Crusia Public Assessment Report Page 18/25

Table 2: Post Hoc Statistical Analysis of Plasma Pharmacodynamic Parameters for Anti-
IIa Activity (Pharmacodynamic Population)
Parameter Treatmenta N Geometric Treatment Ratio (%) 95% CI of
(unit) Comparison of
LS Means the Ratio
Geometric
LS Means
AUEC0-T A 39 0.840 89.4 –
A/B 96.3
(h•aIIaU/mL) B 38 0.873 103.7

Anti-IIamax A 39 0.134 90.1 –

A/B 96.2
(aIIaU/mL) B 38 0.139 102.8

Abbreviations: CI, confidence interval; LS, least squares.

Note: A linear mixed effects model was applied to the natural log-transformed pharmacodynamic
parameters with sequence, period, and treatment as fixed effects and subject nested within sequence as
a random effect.
a
Treatment A = Enoxaparin (100 mg/mL) 100-mg subcutaneous injection manufactured by Rovi,
Spain.
Treatment B = Lovenox (100 mg/mL) 100-mg subcutaneous injection manufactured by Sanofi-Aventis,
USA.

For anti-IIa, 38 or 39 subjects were included in the PD analyses. AUEC0-inf was not included in the
analysis because of the small sample size. Two subjects were excluded from the analyses for both
enoxaparin manufactured by Rovi and Lovenox because of unexpectedly low plasma levels of anti-IIa
(most of the plasma anti-IIa levels were below the LLOQ). Another subject was excluded from the PD
parameters (AUEC0-T and anti-IIamax) for Lovenox and one subject for both enoxaparin manufactured
by Rovi and Lovenox because the baseline values were equal to or higher than the LLOQ.

Two subjects were excluded from analyses due to baseline value > LLOQ.

DE/H/5020-5021/001-007/DC Enoxaparin / Crusia Public Assessment Report Page 19/25

Table 3: Post Hoc Statistical Analysis of Plasma Pharmacodynamic Parameters for
Baseline-Adjusted TFPI Activity (Pharmacodynamic Population)
Parameter Treatmenta N Geometric Treatment Ratio (%) 95% CI of
(unit) LS Means Comparison of the Ratio
Geometric
LS Means

AUEC0-inf A 29 342264.549 93.2 – 106.7

A/B 99.7
(h•pg/mL)
B 30 343221.084
AUEC0-T A 42 357184.769
A/B 102.3 93.8 – 111.5
(h•pg/mL) B 42 349186.342
TFPImax A 42 52620.662
A/B 97.0 91.8 – 102.6
(pg/mL) B 42 54222.649
Abbreviations: CI, confidence interval; LS, least squares.
Note: A linear mixed effects model was applied to the natural log-transformed pharmacodynamic
parameters with sequence, period, and treatment as fixed effects and subject nested within sequence as
a random effect.
a
Treatment A = Enoxaparin (100 mg/mL) 100-mg subcutaneous injection manufactured by Rovi,
Spain.
Treatment B = Lovenox (100 mg/mL) 100-mg subcutaneous injection manufactured by Sanofi-
Aventis,USA

All 42 subjects were included in the PD analysis for TFPI. AUEC0-inf was not estimated for 13 subjects
who received enoxaparin manufactured by Rovi and 12 subjects who received Lovenox because no
clear terminal elimination phase could be identified for these profiles.

DE/H/5020-5021/001-007/DC Enoxaparin / Crusia Public Assessment Report Page 20/25

Table 5: Post Hoc Statistical Analysis of ratio of AUEC0-T of anti-Xa to anti-IIa (RAUEC;
Pharmacodynamic Population)
Parameter Treatmenta N Geometric Treatment Ratio (%) 95% CI of
(unit) Comparison of
LS Means the Ratio
Geometric
LS Means
A 39 16.383 98.8 –
RAUEC A/B 107.1 116.1
B 38 15.297

Abbreviations: CI, confidence interval; LS, least squares.

Note: A linear mixed effects model was applied to the natural log-transformed pharmacodynamic
parameters with sequence, period, and treatment as fixed effects and subject nested within sequence as
a random effect.
a
Treatment A = Enoxaparin (100 mg/mL) 100-mg subcutaneous injection manufactured by Rovi,
Spain.
Treatment B = Lovenox (100 mg/mL) 100-mg subcutaneous injection manufactured by Sanofi-
Aventis, USA.

Pharmacodynamic conclusion

In study ROV-RO20-2015-01 bioequivalence between Enoxaparin Rovi and the EU reference product
Clexane manufactured by Sanofi has been shown appropriately. The study design is considered
acceptable.
The results from study ROV-RO20-2015-01 support bioequivalence. The large differences in the
absolute values observed are considered to be derived from the inter-subject variability.

It is agreed that separate clinical investigations using both concentrations (100 mg/ml or a 150 mg/ml)
are not necessary, as the only difference is the amount of API and no clinical impact is expected in
case the same dose is applied.

No additional data are required for approval of the intravenous administration route since
subcutaneous PD data are more sensitive to demonstrate PD equivalence. If PD biosimilarity is
concluded via the subcutaneous route, which is subject to a more complex pharmacokinetics than the
direct intravenous administration, a relevant difference via direct administration is not expected.

Clinical efficacy

The Guideline on non-clinical and clinical development of similar biological medicinal products
containing low-molecular-weight-heparins (EMEA/CHMP/BMWP/118264/2007 + Draft Rev. 1)
foresees a clinical trial comparing efficacy and safety of the biosimilar candidate and the reference
product unless convincing evidence for similar efficacy and safety 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.

The applicant did not perform an efficacy/safety study. However, based on the analytical, functional
and preclinical data provided, it is concluded that an efficacy/safety trial can be waived. A clinical

DE/H/5020-5021/001-007/DC Enoxaparin / Crusia Public Assessment Report Page 21/25

efficacy/safety trial is not considered to be the appropriate measure to generate the missing
information.

Clinical safety

There were no unexpected safety findings in the 98 healthy adult subjects participating in the single-
dose crossover biopharmaceutic studies. No serious AEs were reported.
Enoxaparin has a well-established safety and tolerability profile, as described in published literature.
The data do not indicate a higher frequency or more severe AEs with enoxaparin Rovi compared to the
EU or US reference product from Sanofi.

The Applicant did not submit safety data from a clinical trial in patients. However, based on the
analytical, functional and preclinical data provided, it is concluded that an efficacy/safety trial can be
waived. A clinical efficacy/safety trial is not considered to be the appropriate measure to generate the
missing information.

Summary Pharmacovigilance system

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 considers the Summary acceptable.

Risk Management Plan

At the start of this decentralised procedure the applicant submitted the first Risk Management Plan
(version 1.0, DLP and date of final sign off 31-Jul-2014) Enoxaparin solution for injection. This RMP
has been subsequently updated to version 2.0 (DLP 22-Dec-2016, date of final sign off 02-Jan-2017)
and further to version 3.0 (DLP and date of final sign off 08-Feb-2017) according to the comments
given at the Day120 and Day180 of this procedure.

The applicant has submitted this 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 Enoxaparin solution for
injection.

Safety specification
Important identified risks
Important potential risks
Missing information
• Bleeding
• Immune-mediated thrombocytopenia
• Allergic reactions including anaphylactoid and anaphylactic
reactions
• Liver injury
• Hyperkalaemia
• Valve thrombosis in patients with prosthetic heart valves
• Osteoporosis
• Use during pregnancy and lactation
• Use in paediatric patients
• Use in patients with hepatic impairment
• Use in in obese patients (BMI>30 kg/m2)
• Porcine DNA in crude heparin

DE/H/5020-5021/001-007/DC Enoxaparin / Crusia Public Assessment Report Page 22/25

Risk minimisation measures
Summary table of risk minimisation measures:
Safety concern Routine risk minimisation measures
Bleeding
Immune-mediated
thrombocytopenia
Allergic reactions
including
anaphylactoid and
anaphylactic reactions
Liver injury
Hyperkalaemia
Valve thrombosis in
patients with
prosthetic heart valves
Osteoporosis
DE/H/5020-5021/001-007/DC Enoxaparin / Crusia
Additional risk
minimisation
measures
Text in SmPC in sections 4.2, is stated that for None
prevention of thrombus formation in the extracorporeal
circulation during haemodialysis/haemofiltration
For patients at a high risk of bleeding the dose should
be reduced ; in section 4.3 is stated that enoxaparin is
contraindicated in patients with severe bleeding
disorders or conditions with a risk of uncontrolled
bleeding; in section 4.4 is described several medical
conditions with higher risk of bleeding; in section 4.8
are listed several bleeding events associated to
enoxaparin; section 4.9 describes treatment in case of
overdose
Text in PIL: sections 2 and 4
Text in SmPC in sections 4.3 is stated that the use of None
enoxaparin is contraindicated if the patient has history
or presence of
thrombocytopenia section 4.4 includes instruction for
monitoring of platelets and the use of enoxaparin in
patients with history of History or presence of
thrombocytopenia; section 4.8 list thrombocytopenia
as adverse reaction
Text in PIL: sections 2 and 4
Text in SmPC in section 4.3 contraindicate the use of None
enoxaparin in case hypersensitivity to enoxaparin, and
in section 4.8 are described several types of allergic
reactions
Text in PIL: section 4
Text in SmPC in sections 4.2, 4.4,4.8, 5.1 and 5.2 None
describe that precaution should be used in patient with
hepatic impairment
Text in PIL: section 4
Text in SmPC in sections 4.4 describe the risk of None
hyperkalaemia; section 4.5 is stated that drugs that
increased serum potassium should be use with medical
supervision; and section 4.8 list hyperkalaemia as
adverse reaction.
Text in PIL: section 4
Sections 4.4, describe that no adequate studies about None
the efficacy of enoxaparin in patients with prosthetic
heart valves.
Text in PIL: sections 2 and 4
Text in SmPC in section 4.8 describes that None
osteoporosis has been described following long-
therapy
Text in PIL: section 4
Public Assessment Report Page 23/25
Use during pregnancy
and lactation
Use in paediatric
patients
Use in patients with
hepatic impairment
Use in obese patients
(BMI>30kg/m2)
Text in SmPC in section 4.6 states that no adequate None
studies in pregnant women are available
Text in PIL: section 2
Text in SmPC in section 4.2 states that the efficacy and None
safety is not established in these paediatric patients
Text in SmPC in section 4.2 states that as in the None
absence of studies caution should be exercised.
Text in SmPC in sections 4.4 states that no consensus None
for dose adjustment is established and as the risk of
VTE is increased careful monitoring is recommended
Text in PIL: section 2

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 an important (pharmacovigilance or risk minimisation) milestone being
reached.

If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at the
same time, but via different procedures.

Periodic Safety Update Report (PSUR)

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.

Common renewal date

Include final proposal for a common renewal date (i.e. in general 5 years after the finalisation of the
procedure.

Legal status
Medicinal product subject to medicinal prescription

DE/H/5020-5021/001-007/DC Enoxaparin / Crusia Public Assessment Report Page 24/25

User Testing
The results of this Readability Test for the patient information leaflet of Enoxaparin Rovi are
considered satisfactory as at least 80% of the population interviewed found the information and
answered the questions correctly. In fact, all questions (14) were valid for 100% of the interviewees.
Additionally, the results confirmed that the design and contents of the package leaflet are good and the
information is easy to find and understand.
According to the overall results presented in this report, the package leaflet meets the readability
criteria as proposed by current guidelines; it is understandable, clear and easy to use.
Suggestions were made to highlight additional text; however, this was not incorporated in the layout
up to now

III. BENEFIT RISK ASSESSMENT

Biosimilarity has been demonstrated from a quality point of view.
The pivotal clinical PD study is considered acceptable.
Based on the analytical, functional and preclinical data provided, it is concluded that an efficacy/safety
trial can be waived. A clinical efficacy/safety trial is not considered to be the appropriate measure to
generate valuable information.

Biosimilarity was confirmed at non-clinical level by carefully studying the interaction of Enoxaparin
Rovi and its comparator Clexane with the primary pharmacological targets, FXa and FIIa.
Furthermore, immunogenicity was adequately addressed by extensively characterising the enoxaparin-
PF4 complex, being the most important antigen, for the Rovi product vs. Clexane. Sufficient
sensitivity of the assays used was demonstrated.

At a clinical level, biosimilarity was established at the PD level as desired by measuring anti-Xa, anti-
IIa and tissue factor pathway inhibitor (TFPI) activity in direct comparison of Enoxaparin Rovi and
the reference product Clexane; conventional PK studies are not possible due to the heterogeneous
nature of enoxaparin. The applicant has conducted a single-dose, randomized, double-blind, two-way
crossover study of Enoxaparin Rovi (100 mg/ml) and Clexane from EU (100 mg/ml) as100-mg
subcutaneous injection in healthy volunteers (Study ROV-RO20-2015-01). The study design is
considered acceptable. The safety evaluation did not reveal any unexpected findings. It is not
necessary to investigate both concentrations (100 mg/ml or a 150 mg/ml) as the only difference is the
amount of API and no clinical impact is expected in case the same dose is applied. The data provided
with SC administration also support IV dosing since subcutaneous PD data are considered more
sensitive.

The application is approved. For intermediate amendments see current product information.

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