C B G
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`PUBLIC ASSESSMENT REPORT
`of the Medicines Evaluation Board
`in the Netherlands
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`Epirubicine hydrochloride 2 mg/ml, solution for injection or infusion
`Pharmachemie B.V., the Netherlands
`
`epirubicin hydrochloride
`
`This assessment report is published by the MEB pursuant Article 21 (3) and (4) of Directive 2001/83/EC. The report
`comments on the registration dossier that was submitted to the MEB and its fellow –organisations in all concerned EU
`member states.
`It reflects the scientific conclusion reached by the MEB and all concerned member states at the end of the evaluation
`process and provides a summary of the grounds for approval of a marketing authorisation.
`This report is intended for all those involved with the safe and proper use of the medicinal product, i.e. healthcare
`professionals, patients and their family and carers. Some knowledge of medicines and diseases is expected of the
`latter category as the language in this report may be difficult for laymen to understand.
`
`This assessment report shall be updated by a following addendum whenever new information becomes available.
`
`General information on the Public Assessment Reports can be found on the website of the MEB.
`
`To the best of the MEB’s knowledge, this report does not contain any information that should not have been made
`available to the public. The MAH has checked this report for the absence of any confidential information.
`
`
`EU-procedure number: NL/H/1250/001/DC
`Registration number in the Netherlands: RVG 101490
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`27 August 2009
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`Pharmacotherapeutic group:
`ATC code:
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`Route of administration:
`Therapeutic indication:
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`anthracyclines and related substances
`L01DB03
`intravenous or intravesical use
`breast carcinoma; gastric carcinoma; papillary transitional cell
`carcinoma of
`the bladder; carcinoma
`in-situ;
`intravesical
`prophylaxis of recurrence of superficial bladder carcinoma
`following transurethral resection.
`prescription only
`17 February 2009
`Decentralised procedure with AT, BE, BG, CZ, DE, DK, EE, EL,
`ES, FI, FR, HU, IE, IT, LT, LU, LV, NO, PL, PT, RO, SE, SI, SK,
`UK
`Directive 2001/83/EC, Article 10(3)
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`Prescription status:
`Date of authorisation in NL:
`Concerned Member States:
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`Application type/legal basis:
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`For product information for healthcare professionals and users, including information on pack sizes and
`presentations, see Summary of Product Characteristics (SPC), package leaflet and labelling.
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`INTRODUCTION
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`I
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`Based on the review of the quality, safety and efficacy data, the member states have granted a marketing
`authorisation for Epirubicine hydrochloride 2 mg/ml, solution for injection or infusion, from Pharmachemie
`B.V.. The date of authorisation was on 17 February in the Netherlands.
`
`In European countries epirubicin hydrochloride, as generic substance, has obtained marketing
`authorization for a diversity of therapeutic indications. The therapeutic indications approved for this
`oncolytic substance vary per application (of the innovator and generics) and also per country. The MAH
`claimed several indications that could not be granted. Refer to section II.3 for a discussion of these
`indications.
`
`The product is indicated for the treatment of a range of neoplastic conditions including:
`• Breast carcinoma
`• Gastric carcinoma
`
`When administered intravesically, epirubicin has been shown to be beneficial in the treatment of:
`• Papillary transitional cell carcinoma of the bladder
`• Carcinoma in-situ
`Intravesical prophylaxis of recurrence of superficial bladder carcinoma following transurethral
`•
`resection.
`
`
`Epirubicine hydrochloride 2 mg/ml can be used in polychemotherapy schedules.
`
` A
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` comprehensive description of the indications and posology is given in the SPC.
`
`
`Epirubicin belongs to the group of anthracyclins. The working mechanism of epirubicin depends on its
`ability to form complexes with DNA. Experimental studies with cell cultures have shown that epirubicin
`rapidly penetrates the cell and is recovered in the nucleus where it inhibits the nucleic acid synthesis and
`the mitosis. The activity of epirubicin was established on many experimental tumours, amongst which
`leucaemias L1210 and P388, the sarcoma SA 180 (solid and ascetic form), the B16 melanoma, the breast
`carcinoma, the lung carcinoma of Lewis and the colon carcinoma 38, furthermore an effect was also
`shown on human tumours that were transplanted in athymic nude mice (melanoma and mammary, lung,
`prostate and ovarian carcinoma).
`
`Epirubicin is not orally absorbed. After iv administration, highest concentrations are found in the liver,
`spleen, kidney, and the small intestines. It is metabolized mainly in the liver, but also in other tissues, into
`epirubicinol which is also active. Biliary excretion is the major route of elimination (40%). The benefits of
`anthracyclines (doxorubicin, daunorubicin, epirubicin and idarubicin) in the treatment of malignant disease
`are known for decades. However, a major limitation to the use of anthracyclinesis cardiotoxicity that limits
`its use from a cumulative dose, irrespective of any favourable effect. Therefore the use is mitigated after
`heart function compromising radiotherapy or – chemotherapy. Contraidications are founded in (pre
`existing) cardiovascular disease and hepatic dysfunction.
`During the eighties attempts to modify the ‘core’ anthracycline molecule in order to minimize anthracycline
`induced cardiotoxicity without decreasing efficacy have not been very successful: Although epirubicin is
`less toxic than doxorubicin, compared to doxorubicin it is however also less biologically active.
`
`This decentralised procedure concerns a hybrid application claiming essential similarity with the innovator
`product Farmorubicin 2 mg/ml injektionsvätska which has been registered in Sweden by Pfizer AB since
`1989. In the Netherlands, Farmorubicine R.T.U. 2 mg/ml (NL RVG 14943), oplossing voor intraveneuze
`infusie has been registered since 1992. The differences of the product at issue compared to the reference
`medicinal product are a change in therapeutic indications and a change in route of administration. In
`addition, reference is made to Farmorubicin authorisations in the individual member states (reference
`product).
`
`The marketing authorisation is granted based on article 10(3) of Directive 2001/83/EC.
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`No new pre-clinical and clinical studies were conducted, which is acceptable for this abridged application.
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`This type of application refers to information that is contained in the pharmacological-toxicological and
`clinical part of the dossier of the authorisation of the reference product. A reference product is a medicinal
`product authorised and marketed on the basis of a full dossier, i.e. including chemical, biological,
`pharmaceutical, pharmacological-toxicological and clinical data. This information is not fully available in
`the public domain. Authorisations for generic products are therefore linked to the ‘original’ authorised
`medicinal product, which is legally allowed once the data protection time of the dossier of the reference
`product has expired. As Epirubicine hydrochloride 2 mg/ml is a product for parenteral use in an aqueous
`solution, it is exempted for biostudy (NfG CPMP/EWP/QWP 1401/98). The current product can be used
`instead of its reference product.
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`No scientific advice has been given to the MAH with respect to these products.
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`No paediatric development programme has been submitted.
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`II
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`II.1 Quality aspects
`
`Compliance with Good Manufacturing Practice
`The MEB has been assured that acceptable standards of GMP (see Directive 2003/94/EC) are in place for
`this product type at all sites responsible for the manufacturing of the active substance as well as for the
`manufacturing and assembly of this product prior to granting its national authorisation.
`
`Active substance
`
`General information
`The active substance is epirubicin hydrochloride, an established active substance described in the
`European Pharmacopoeia (Ph.Eur.*). The active substance is soluble in water and methanol, slightly
`soluble in ethanol an practically insoluble in acetone.
`Epirubicin hydrochloride precipitates at the beginning as a crystal, incorporating the crystallization solvent.
`The crystalline elementary structure is well defined and characterized by univocal diffraction lines. The
`presence of the solvent ensures its crystallographic stability. During the drying, the crystallization solvent
`is removed from the crystalling element, leaving an amorphous-like powder with some traces of the
`original crystalline structure.
`
`The Active Substance Master File (ASMF) procedure is used for the active substance. The main objective
`of the ASMF procedure, commonly known as the European Drug Master File (EDMF) procedure, is to
`allow valuable confidential intellectual property or ‘know-how’ of the manufacturer of the active substance
`(ASM) to be protected, while at the same time allowing the applicant or marketing authorisation holder
`(MAH) to take full responsibility for the medicinal product, the quality and quality control of the active
`substance. Competent Authorities/EMEA thus have access to the complete information that is necessary
`to evaluate the suitability of the use of the active substance in the medicinal product.
`
`Manufacturing process
`The MAH submitted a reaction scheme including the reagents and solvents as well as a summary of the
`two step manufacturing process. A detailed description of the manufacturing process was submitted.
`Control of materials, critical steps and intermediates as well as the process validation and manufacturing
`process development were included.
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`Quality control of drug substance
`The drug substance specification is in line with the Ph. Eur. with additional requirements for residual
`solvents and microbiological quality. Acetone which is listed in the monograph is not used in the
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`SCIENTIFIC OVERVIEW AND DISCUSSION
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`manufacturing process and therefore not included in the specifications. The specification is acceptable in
`view of the route of synthesis and the various European guidelines.
`Batch analytical data demonstrating compliance with the drug substance specification have been provided
`for three full scaled batches.
`
`Stability of drug substance
`Stability data on the active substance have been provided by the ASMF-holder for four full scaled batches
`stored at 25°C/60% RH (six months) and 5°C±3°C (36 months). When stored at 5°C the water content
`demonstrates a maximum increase of 2.4% (from 1.3% to 3.7%) but remains within the specification. The
`other parameters do not change. For the batches stored at 25°C comparable results are obtained,
`however, the water content shows a more pronounced increase after 6 months of storage.
`Based on the submitted stability data the re-test period of 12 months claimed by the MAH could be
`granted, when stored between 2-8°C in the original package.
`
` Ph.Eur. is an official handbook (pharmacopoeia) in which methods of analysis with specifications for
`substances are laid down by the authorities of the EU.
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`Medicinal Product
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`Composition
`Epirubicine hydrochloride 2 mg/ml contains as active substance 2 mg of epirubicin hydrochloride per
`millilitre, and is a clear red solution.
`
`The solution for injection or infusion is packed in a colourless type I glass vial with a bromobutyl rubber
`cap, aluminium closing and snap-cap containing 5 ml, 10 ml, 25 ml, 75 ml and 100 ml of epirubicine
`hydrochloride as a sterile, preservative-free solution. No overage is applied.
`
`The excipients are: sodium chloride, hydrochloric acid (for pH adjustment), water for injections
`The excipients and packaging are usual for this type of dosage form. The excipients comply with the
`Ph.Eur. with additional specifications for sodium chloride concerning mesophilic count and for water for
`injections regarding silicates. These specifications are acceptable.
`
`Pharmaceutical development
`The development of the product has been described, the choice of excipients is justistied and their
`functions explained. No clinical trials have been carried out since the solution is a generic product for
`parenteral infusion. The pharmaceutical development of the product has been adequately performed.
`Compatibility studies demonstrated compatibility with sodium chloride 0.9%, glucose 5% and water for
`injection in infusion bags.
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`Manufacturing process
`Epirubicine HCl is dissolved in part of the water for injections under nitrogen purging. The solution of
`sodium chloride is added. Water for injections is added to reach the final weight and homogenized. The
`solution was filtered into a sterile collecting vessel. The sterilised vials are then aseptically filled with the
`solution under nitrogen overlay. The vials are closed with the sterilised stoppers and copped. The vials are
`washed and sleeved.
`The manufacturing process has been validated according to relevant European guidelines. Process
`validation data on the product have been presented for three full scaled batches. The MAH committed to
`provide validation data of two additional batches post authorisation.
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`Compatibility
`Epirubicin HCl, solution for infusion 2 mg/ml will be injected into a running infusion and will be used for
`intravesical administration, therefore dilution studies have been performed. The drug product has been
`added to sodium chloride 0.9% and to glucose 5% infusion bags in concentrations of 0.6 and 1.6 mg/ml. It
`has also been diluted with sodium chloride 0.9%, with glucose 5% and with water for injections in 5 ml
`polypropyleen syringes in the same concentrations. The infusion bags as well as the syringes were all
`stored at two temperatures (2-8°C and 15-25°C) and sampled during four weeks. It was tested on
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`appearance, pH, particulate matter, related substances and assay. No differences were observed during
`the four weeks. Compatibility with polypropylene syringes and Viaflex® infusion bags has been
`demonstrated. Argumentation is given that the product is compatible with the regular lining of infusion
`systems.
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`Quality control of drug product
`The product specification includes tests for appearance, identity, assay, closure intergrity, extractable
`volume, particulate contamination (visible and sub-visible), pH, related substances, sterility and
`endotoxins. The release and shelf-life specifications are overall the same with the exception of the
`limitations on related substances. Limits in the specification have been justified and are considered
`appropriate for adequate quality control of the product. The analytical methods have been adequately
`described and validated. Batch analytical data from the proposed production site have been provided on
`ten full scaled batches, demonstrating compliance with the release specification. The MAH committed to
`perform compatibility and dilution studies in PVC free bags on samples near the expiration date and
`submit the results to the RMS and all CMS countries. The MAH also committed to place the highest size
`batches under stability studies and provide real time data up to 24 months for reassessment of the assay
`lower end limit 92.5%. If real time results are within 95-105%, the MAH committed to provide readjustment
`of the shelf-life specification by a variation.
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`Container closure system
`As a primary container colourless glass vials of hydrolytic class I were chosen. The quality of the material
`meets the specifications of the Ph.Eur. The sizes of the vials for individual packages are 10.0 ml, 13.5 ml,
`36.0 ml and 119.0 ml. The used bromobutyl rubber stoppers comply with the Ph.Eur.
`
`Stability tests on the finished product
`Stability data on the product has been provided for two production scale batches of each volume stored at
`5°C (24 months) and 25°C± 2°C/ 60% RH ± 5% RH (six months). The conditions used in the stability
`studies are according to the ICH stability guideline. The batches were stored in colourless glass vials,
`hydrolytic class I, with bromobutyl rubber cap and aluminium fixing shell.
`In all batches a slight increase in assay is observed versus a slight decrease in total related substances at
`5°C over a 24 month period. An increase of particulate contamination was also observed. Under
`accelerated conditions a significant decrease in assay within three months was observed. A shelf life was
`granted of 2 years. The labelled storage conditions are ’Store in the refrigerator (2-8°C)’, ‘Store and
`transport refrigerated’ and ‘Do not freeze’.
`
`Specific measures concerning the prevention of the transmission of animal spongiform encephalopathies
`There are no substances of ruminant animal origin present in the product nor have any been used in the
`manufacturing of this product, so a theoretical risk of transmitting TSE can be excluded.
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`II.2 Non clinical aspects
`
`Pharmacodynamic, pharmacokinetic and toxicological properties of epirubicine hydrochloride are well
`known. As epirubicine hydrochloride is a widely used, well-known active substance, no further studies are
`required and the applicant provides non. A non-clinical overview is based on literature review only is
`appropriate.
`
`Environmental risk assessment
`The product is intended as a substitute for other identical products on the market. The approval of this
`product will not result in an increase in the total quantity of epirubicin hydrochloride released into the
`environment. It does not contain any component, which results in an additional hazard to the environment
`during storage, distribution, use and disposal.
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`II.3 Clinical aspects
`
`Epirubicine hydrochloride is a well-known active substance with established efficacy and tolerability.
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`Epirubicine hydrochloride 2 mg/ml, solution for injection or infusion is a parenteral formulation and
`therefore fulfils the exemption mentioned in the Note for Guidance on bioequivalence “5.1.6 parenteral
`solutions”, which states that a bioequivalence study is not required if the product is administered as an
`aqueous intravenous solution containing the same active substance in the same concentration as the
`currently authorized reference medicinal product (NfG CPMP/EWP/QWP 1401/98). The quantitative
`composition of Epirubicine hydrochloride 2 mg/ml is entirely the same as the originator. Therefore, it may
`be considered as therapeutic equivalent, with the same efficacy/safety profile as known for the active
`substance of the reference medicinal product. The current product can be used instead of its reference
`product.
`
`
`Clinical efficacy
`In European countries epirubicin hydrochloride, as generic substance, has obtained marketing
`authorization for a diversity of therapeutic indications. The therapeutic indications approved for this
`oncolytic substance vary per application (of the innovator and generics) and also per country.
`
`For Epirubicine hydrochloride 2 mg/ml, the MAH requested a marketing authorisation for the following
`indications:
`
`
`•
`leukaemia (acute lymphatic leukaemia, acute non-lymphatic leukaemia)
`• malignant lymphoma (Hodgkin and non-Hodgkin lymphoma)
`• mammary carcinoma
`•
`soft tissue sarcoma
`• ovarian carcinoma
`•
`stomach carcinoma
`•
`lung carcinoma
`•
`colorectal carcinoma
`• multiple myeloma
`•
`Intravesical administration has appeared beneficial for the treatment of superficial bladder
`carcinoma and prophylaxis of recurrrence after transurethral resection.
`Epirubicin hydrochloride 2 mg/ml can be used in polychemotherapy schedules.
`
`In support of the proposed indications the MAH submitted a clinical overview, summarizing the clinical
`results obtained with epirubicin in various neoplastic conditions since the product was marketed.
`
`All indications sought for epirubicin in this application are commentated upon in view of the therapeutic
`indications for Epirubicin hydrochloride Mayne 2 mg/ml that were approved in 2006 following a MRP
`procedure UK/H/868/001 in Estonia, Norway, Sweden and the Netherlands (NL RVG 33726).
`
` •
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` Leukaemia: The usual remission induction regimens in acute myeloid leukemia (AML) encompass
`cytarabine, daunorubicin or idarubicin. Epirubicin is not considered a standard component in treatment
`regimen.
`In acute lymphatic leukemia (ALL) anthracyclins as daunorubicin, doxorubicin and zorubicin are
`applied in remission induction. However, epirubicin is currently not considered an standard. The
`indication was not supported by up to data scientific literature data. In view of the current standard
`therapy regimen for leukaemia’s, and in line with the SPC of Epirubicin Mayne 2 mg/ml. Therefore the
`indication leukaemia’s for epirubicin was considered not approvable.
`
` •
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` Malignant lymphoma:
`-
`Hodgkin lymphoma
`Member states considered that ‘favourable prognosis Hodgkin’s disease’ may not be founded
`robustly enough to justify this as an established indication, therefore it was decided to delete this
`indication. Furthermore, besides the fact that this indication for epirubicin is not generally
`accepted within the EU, to date there is no data to justify the use of epirubicin in the standard
`treatment modalities for this disease.
`Non-Hodgkin lymphoma (NHL)
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`Epirubicin is not a part of standard polychemotherapy regimens in non-Hodgkin lymphoma. Some
`reports suggest modest advantages for epirubicin containing regimen in the elderly with
`aggressive NHL (Sung et al. Br J Haematol 2006 134:45-53, Merli et al. Hematologica 2004
`89:973-2224). Nevertheless, the indication non Hodgkin’s lymphoma as such is not broadly
`supported by up to date literature. Therefore, in line with the SPC of Epirubicin Mayne 2 mg/ml,
`the indication NHL was considered not approvable.
`
` Mammary carcinoma/Breast cancer: The most widely used adjuvant regimens have been
`cyclophosphamide, methotrexate and 5-FU (CMF), anthracycline-based regimens, such as AC
`(doxorubicin plus cyclophosphamide) with or without a taxane, CAF (cyclophosphamide, doxorubicin, 5
`FU), and FEC/ CEF (cyclophosphamide, epirubicin, and 5-FU), By now the advantage of using
`anthracycline-containing versus non-anthracycline (ie, CMF-type) regimens has been proven in
`comparative studies (See: Lancet, 2005, 365:1687). To date the use of epirubicin as part of
`polychemotherapy regimens is considered established therapy in breast cancer.
`
` Soft tissue sarcoma (STS): The highest response rates have been achieved observed with doxorubicin
`and ifosfamide-containing combinations, but the toxicity of such a combined approach is considerable.
`Also for this reason, two trials have directly compared epirubicin with single agent doxorubicin for STS.
`One EORTC trial randomly assigned 334 patients with untreated metastatic sarcoma to doxorubicin, or
`high dose epirubicin on one of two different schedules. The epirubicin schedule was worse (Nielsen et
`al. Br J Cancer 1998;78:1634). In an other report, also mentioned by the MAH in the Clinical Overview,
`210 patients received either epirubicin or doxorubicin once every three weeks (Moouridsen HT et al.
`Euro J Cancer Clin Oncol 1987; 23: 1477). There was a slight trend toward a lower response rate with
`epirubicin (18 versus 25 percent), but duration of response and median survival were similar. To date,
`the standard therapy of STS does not encompass the application of epirubicine. Epirubicine
`hydrochloride Mayne 2 mg/ml is not authorised for the indication STS in NL and the indication is not
`supported by up to date scientific literature. Therefore, the indication STS was considered not
`approvable.
`
` Ovarian carcinoma: Since the adoption of the platinum-plus-taxane combination as the standard nearly
`worldwide, clinical trials have demonstrated increased toxic effects but no advantage of adding
`epirubicin to the carboplatin plus paclitaxel doublet (Kristensen et al. Int J Gynecol Cancer 2003, 13
`(Suppl 2): 172-177). There may be a small role for epirubicin in salvage chemotherapeutic treatment
`(Zanaboni et al. Gynecol Oncol 1991, 43:24-28). Others also considered that addition of epirubicin to
`standard regimen (platin/taxane) did not improve survival or time to treatment failure in patients with
`advanced epithelial ovarian cancer (du Bois et al. J Clin Oncol 2006, 24:1127-1135), therefore,
`epirubicin cannot be recommended for clinical use in this population. Epirubicin hydrochloride Mayne 2
`mg/ml is not authorised for the indication ovarian cancer in NL and the indication is not supported by
`up to date scientific literature. Therefore, the indication advanced ovarian cancer was not approved.
`
` Gastric carcinoma/stomach carcinoma: Currently the combination treatment with epirubicin, ciplatin
`and 5-FU (ECF) appears the most effective. In NL this regimen is considered the standard (palliative)
`treatment modality. Ample scientific information corroborates this strategy. Therefore, the indication
`gastric carcinoma was considered approvable.
`
` Small cell lung carcinoma (SCLC): To date the combination therapy with a platin compound with a
`(third generation) chemotherapeutic is the standard approach. The combination of cisplatin with
`etoposide is currently the preferred combination and CDDP/epirubicin can also be applied with
`comparable results (PFS, OS) albeit with slightly higher toxicity and lesser compliance (Artel Cortes et
`al. clin Lung Cancer 2004, 6:175-183). The combination of epirubicin plus cisplatin is not a standard
`regimen for the treatment of patients with SCLC. Therefore, the indication SCLC is considered not
`approvable.
`
` Colorectal carcinoma: Currently there are no standard treatment modalities that involve the application
`of epirubicin. Furthermore, the reference product has not been authorised for the indication colorectal
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`carcinoma in NL and also the indication is not supported by up to date scientific literature. Therefore,
`the indication colorectal cancer was considered not approvable.
`
` Bladder cancer:
`Superficial bladder cancer: Epirubicin has been reported to be of value in the chemotherapeutic
`-
`treatment of carcinoma in situ of bladder cancer (Oosterlink et al. J Urol 1993, 149:749-752),
`albeit that, despite improvement of recurrence rate and recurrence free survival, there seems a
`limited impact on overall survival (Oosterlinck et al. J Urol 1993, 149:749-752). Although the result
`obtained from BCG instillation in superficial bladder cancer are still superior to those from
`epirubicin, the application of epirubicin is currently considered an acceptable other treatment
`option (for those not suitable to receive live attenuated mycobacteria).
`Profylaxis of recurrence of superficial bladder cancer: For prophylaxis of recurrences of primary
`superficial bladder cancer the instillation of single dose epirubicin seems effective, although no
`data on the risk on invasive disease and OS are known yet (Rajala et al. J Urol 2002 Sep; 168(3);
`981-985.). Results have been confirmed by Liu et al (Cancer Invest 2006, 24:160-163). Earlier,
`others found that the application did not result in preventing tumour recurrence and, conversely,
`epirubicin may even promote tumourprogression in bladders with dysplastic mucosal changes
`(Igawa et al. Br J Urol 1996, 78: 662). This indication is included in the listing of therapeutical
`indications for Epirubicin Mayne 2 mg/ml, therefore the application for epirubicin in treatment and
`prophylaxis of superficial bladder cancer can be considered acceptable.
`
`-
`
` Multiple Myeloma
`Although the introduction of several new components has constituted an important advance in the
`treatment of multiple myeloma (for instance bortezomib, lenalidomide), to date patient survival remains
`unsatisfactory. Therefore, many combinations of chemotherapeutic agents have been tried. Examples
`of antineoplastic agents are those from the M2 protocol (vincristine, carmustine (BCNU), melphalan,
`cyclophosphamide, and prednisone) and the ABCM regimen (adriamycin, BCNU, cyclophosphamide,
`and melphalan). According to current standards epirubicin does not constitute a useful tool in the
`systemic treatment of MM. Therefore, and also in line with the SPC of Epirubicin Mayne 2 mg/ml, the
`indication MM was considered not approvable.
`
` •
`
` •
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`
`At the end of the MRP, the following indications were approved by all member states:
`• Breast carcinoma
`• Gastric carcinoma
`When administered intravesically, epirubicin has been shown to be beneficial in the treatment of:
`• Papillary transitional cell carcinoma carcinoma of the bladder
`• Carcinoma in-situ
`Intravesical prophylaxis of recurrence of superficial bladder carcinoma following transurethral
`•
`resection.
`
`
`However, the MAH was requested to submit a type II variation within 2 months after finalisation of the
`DCP in order to justify the intravesical administration of epirubicin (in the treatment of: Papillary
`transitional cell carcinoma of the bladder, carcinoma in situ and intravesical prophylaxis of recurrences of
`superficial bladder carcinoma following transurethral resection) by providing relevant data. The MAH
`committed not to place the product on the market in France until finalisation of the type II variation
`indicated (NL/H/1250/001/II/001). On 27 January 2009 the MAH has submitted this type II variation, which
`was approved on 10 June 2009.
`
`Risk management plan
`Epirubicin was first approved in 1982, and there is now more than 10 years post-authorisation experience
`with the active substance. The safety profile of epirubicin can be considered to be well established and no
`product specific pharmacovigilance issues were identified pre- or postauthorisation which are not
`adequately covered by the current SPC. Additional risk minimisation activities have not been identified for
`the reference medicinal product. The MAH has a pharmacovigilance system at their disposal, which is
`based on the current European legislation. Routine pharmacovigilance activities are sufficient to identify
`actual or potential risks and a detailed European Risk Management Plan is not necessary for this product.
`8 of 14
`
`
`
`Ex. 1059-0008
`
`

`
`C B G
`M E B
`
`
`
`
`
`
`Product information
`
`SPC
`The content of the SPC approved during the decentralised procedure is in accordance with the accepted
`wording in procedures UK/H/868/MR, PT/H/172/MR, DK/H/426/MR, DK/H/1124/DC, NL/H/1084/DC and
`UK/H/1123/DC.
`
`Readability test
`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 questions covered the following areas sufficiently:
`traceability, comprehensibility and applicability. The readability test has been sufficiently performed.
`The questionnaire consisted of 11 questions (all existing of two sub-questions) specific to Epirubicine
`hydrochloride 2 mg/ml solution for injection or infusion and the format of the package leaflet, and two
`questions to obtain general feedback on the user friendliness of the package leaflet. Adults of either sex
`were recruited. The demographics, e.g. sex, age, occupation and highest educational achievement, of the
`test population were provided. A first test was performed with 10 participants. The following areas for
`attention with regard to improving the patient information leaflet were identified during the study: sections
`“Do not use Epirubicine”, “Use in combination with other medicines”, and “Possible adverse events”.
`Several modifications were implemented. Based on the results of the second test round, the patient
`information leaflet’s readability was 91%. Following this round, the package leaflet was not adapted.
`
`
`
`
`9 of 14
`
`Ex. 1059-0009
`
`

`
`
`OVERALL CONCLUSION AND BENEFIT-RISK ASSESSMENT
`
`C B G
`M E B
`
`
`
`III
`
`Epirubicine hydrochloride 2 mg/ml solution for injection or infusion, is considered a hybrid of the reference
`medicinal product Farmorubicine R.T.U. 2 mg/ml, already marketed in different European countries, i.e. it
`satisfies the criteria of having the same qualitative a