Beipackzettel, Nebenwirkungen, Wirkung, Anwendungsgebiete - Secretin Iberoinvesa Pharma, 100 klinische Einheiten (CU), Pulver und Lösungsmittel zur Herstellung einer Injektions- bzw. Infusionslösung
Decentralised Procedure
Secretin Iberoinvesa Pharma, 100 klinische Einheiten (CU), Pulver und Lösungsmittel zur Herstellung einer Injektions- bzw. Infusionslösung
Procedure-Number: DE/H/3553/001/DC
Active Substance:
Secretin hydrochloride (porcine)
Dosage Form:
Powder and solvent for solution for injection or infusion
Marketing Authorisation Holder in the RMS, Germany:
Iberoinvesa Pharma S.L.
Publication:
23.03.2022
This module reflects the scientific discussion for the approval of Secretin Iberoinvesa Pharma, 100 klinische Einheiten (CU), Pulver und Lösungsmittel zur Herstellung einer Injektions- bzw. Infusionslösung. The procedure was finalised on 21.01.2015.
TABLE OF CONTENTS
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ADMINISTRATIVE INFORMATION
| Proposed name of the medicinal product in the RMS | Secretin Iberoinvesa Pharma, 100 klinische Einheiten (CU), Pulver und Lösungsmittel zur Herstellung einer Injektions- bzw. Infusionslösung |
| INN (or common name) of the active substance(s): | Secretin hydrochloride |
| Pharmaco-therapeutic group (ATC Code): | V04CK01 |
| Pharmaceutical form(s) and strength(s): | Lyophilisate and Solvent |
| Reference Number(s) for the Decentralised Procedure | DE/H/3553/01/DC |
| Reference Member State: | DE |
| Member States concerned: | AT; BE; ES; IT; NL |
| Marketing Authorisation Holder (name and address) | Iberoinvesa Pharma S.L. Calle Zurbaran 18, 6 28010 Madrid Espana |
| Names and addresses of manufacturer(s) responsible for batch release in the EEA | Sanochemia Pharmazeutika AG Landeggerstrasse 7 2491 Neufeld/Leitha Austria |
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I. INTRODUCTION
Based on the review of the data on quality, safety and efficacy, the RMS considers that the application for Secretin Iberoinvesa Pharma, 100 klinische Einheiten (CU), Pulver und Lösungsmittel zur Herstellung einer Injektions- bzw. Infusionslösung. in the treatment of Diagnosis of exocrine pancreatic function and Diagnosis of Zollinger-Ellison syndrome
is approved.
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II. EXECUTIVE SUMMARY
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II.1 Problem statement
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II.2 About the product
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This mutual recognition/decentralised application concerns a generic version Secrelux, as licensed in Germany on 1982–10–06, under the trade name “Secretolin Diagnosticum”. In this Assessment Report, the name Secrelux is used as the name of the product was changed to Secrelux in 1999.
The originator product is Secrelux; Lyophilisat und Lösungsmittel zur Herstellung einer Injektionslösung by Sanochemia Diagnostics Deutschland GmbH.
With Germany as the Reference Member State in this Decentralized Procedure, Iveroinvesa Pharma S.L applied for the Marketing Authorisations for Secretin Iberoinvesa Pharma, 100 klinische Einheiten (CU), Pulver und Lösungsmittel zur Herstellung einer Injektions- bzw. Infusionslösung. in AT; BE; ES; IT; NL. Secretin Iberoinvesa is a synthetic porcine secretin.
The licensed indications for the originator product are currently the following:
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– Diagnosis of the exocrine function of the pancrease
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– Diagnosis of Zollinger-Ellison-Syndrome.
The revised proposal is as follows:
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– Stimulation of pancreatic secretions, including bicarbonate, to aid in the diagnosis of exocrine pancreas dysfunction.
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– Stimulation of gastrin secretion to aid in the diagnosis of Zollinger-Ellison-Syndrome
Both wordings are considered to need further revision.
The product will be marketed in only one strength, in vials containing 100 Clinical Units (CU). A 100 CU-vial contains 24.4 mg of the lyophilised dry substance with a content of secretin-pentahydrocholoride of 0.029 mg. The proposed clinical standard dose is 1 CU per kg body weight.
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II.3 General comments on the submitted dossier
This is a generic application of an i.v. administered compound. No additional studies were conducted, and this is considered fully adequate. The evaluation of PK, PD, efficacy and safety has been based on the available literature by the company. The company has presented a clinical overview, and clinical summaries to all aspects, although this would be considered not to be necessary in the case of a pure generic application. It is understood that the company takes account of the fact that the originator product is only licensed in a part of the CMSs involved, and tries to fully introduce the available data for the compound. This is acknowledged by the RMS. The dossier itself, in its clinical part is generally considered to be of good quality, including the technical features.
The dossier is of satisfying quality. The legal base of the application is a generic application according to Art. 10(1) of 2001/83/EC but not an informed consent application. However, it is very obvious that the applicant uses information and data from the originator and the reference product.
The active substance is not considered a new active substance.
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II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles.
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.
GCP issues are not concerned with this application, because no new studies have been conducted.
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III. SCIENTIFIC OVERVIEW AND DISCUSSION
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III.1 Quality aspects
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Drug Substance
Secretinhyrochloride (porcine) is a synthetic peptides consisting of 27 natural amino acids. All amino acids are in L-configuration. The counter ion hydrochloride is present in a non-stoichiometric ratio. It is bound mainly to positively charged functional groups in the peptide, e.g. the side chains of arginine and histidine.
The ASMF procedure is used and the synthesis of the drug substance is sufficiently described in the restricted part of the ASMF.
The combination of the techniques (amino acid analysis, elemental analysis, NSI-MS – nanospray ionisation mass spectrometry, NSI-MS-CAD-MS – nanospray ionization mass spectrometry collision activated dissociation mass spectrometry / sequence analysis and chiral GC-MS) used for characterising the drug substance is sufficient to elucidate the structure. The analysis by NSI-MS-CAD-MS gives information about the correct sequence of the peptide. Circular dichroism studies have been performed. Information about impurities resulting from the synthesis is provided. The proposed impurity limits are higher than required for synthetic peptide impurities in the Ph. Eur. monograph ‘Substances for pharmaceutical use’. However, the proposed limits are acceptable and have been justfied by the low dose of the drug product.
The specification consists of the following parameters: appearance, appearance of solution, identity by ESI-MS, identity by HPLC, identity by amino acid analysis, specific optical rotation, assay by elemental analysis, purity by HPLC, water content, chloride content by titration, acetic acid content by ion chromatography, residual organic solvent by gas chromatography, mass balance, bacterial endotoxins and microbial limit test. Analytical methods have been adequately described and are suitable for their intended use. Batch analysis data for five batches are provided in the dossier.
Reference standards and the container closure system have been adequately described.
Real time stability data are available for three batches manufactured in 2004. The batches have been stored at –20°C for up to 60 months and for up to 6 months at 5°C and 25°C / 60% RH. Stress testing was performed to provide data about the stability of the drug substance under potentially degradative conditions (e.g. elevated temperature, presence of moisture or oxidant, alkaline or acidic conditions). The stability-indicating power of the analytical procedures has been demonstrated.
Drug Product (Powder)
The drug product consists of one vial with lyophilisate containing 0.029 mg secretin pentahydrochloride, corresponding to 100 clinical units (CU) and one vial with reconstitution diluent containing 10 mL 0.9% sodium chloride solution.
The lyophilisate is filled into 15R clear tubular glass vials of Type I glass according to Ph. Eur. The vials are closed with bromobutyl rubber stoppers. The primary packaging material is sealed with aluminium snap caps with polypropylene plastic disc which is not in contact with the product.
The formulation is identical to the reference product.
However, in-process control testing for content is performed at different steps of the manufacturing process and a homogeneous solution is filled into the vials prior to lyophilisation.
An adequate description of the manufacturing process has been provided and critical steps of the manufacturing process for the drug product have been defined. An adequate process validation study was performed.
Haemaccel used as an excipient in the lyophilisate is an approved medicinal product in Germany. All other excipients are described in the Ph. Eur. The level of information on excipients is acceptable.
The release specification consists of the following parameters: appearance, appearance of solution, identity by HPLC, pH, residual moisture, assay by HPLC, uniformity of dosage unit, reconstitution time, particulate matter, sterility and bacterial endotoxins. Visual closure appearance (visual testing) is an additional parameter in the shelf-life specification whereas identity and uniformity of dosage units are not tested during stability. All limits in the shelf-life specification are identical to the release specification. As requested the specification has been amended. Specification limits for purity (individual impurities and sum of impurities) have been included in the release and shelf-life specification for the drug product. The description of the analytical methods is acceptable. From the stability data is becomes obvious that the results for purity and content are highly variable. No trend to degradation was observed. However, optimisation and/or revalidation of the analytical methods should be considered.
The results of the three process validation batches packaged as vials and results from five batches packaged as ampoules are provided. An additional batch was manufactured in 2013 and used in the photostability study.
The information on reference standards and container closure system is acceptable.
The process validation batches have been included in stability studies. Data for up to 36 months at four different storage conditions (2 – 8°C, 25°C/65% RH, 30°C/65% RH, and 40°C/75% RH) are available. Additionally, different batches of ampoules in commercial batch size are presented with stability data for three conditions (-18°C, 2 – 8°C, 25°C/65% RH).
The tested parameters are: appearance, appearance after reconstitution, pH, water, and assay. Sterility and endotoxines will be tested at selected time points. Reporting of the results for purity, reconstitution time and particulate matter starts with the 24 months time point. The results for assay and purity are highly variable as described above. However, no degradation or other negative trends has been observed. Therefore a shelf-life of 3 years if stored at 2 – 8°C in a refrigerator with the storage conditions ‘sensitive to light, keep vials in the outer carton’ is acceptable.
Drug Product (Solvent)
The information on manufacturing and control of the solvent (10 mL 0.9% sodium chloride solution) is acceptable. The expiry dates of the powder and the solvent have been synchronised.
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III.2 Non-clinical aspects
Pharmacodynamic, pharmacokinetic and toxicological properties of secretin are well known. As secretin is a well-known active substance with a long clinical diagnostic use , the Applicant has not provided additional studies and further studies are not required. Overview based on literature review is, thus, appropriate.
The non-clinical overview is dated January 2012 and based mainly on original data from studies of the reference product secrelux/secretolin of the innovator in Germany, Hoechst AG, and refers additionally 54 publications up to year 2004.
The non-clinical overview on the pre-clinical pharmacology, pharmacokinetics and toxicology is adequate.
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III.3 Clinical aspects
This is a generic application for a product administered as aequous solution via the i.v. route. No bioequivalence studies have been conducted. This is considered to be fully acceptable. The transfer of the data for safety and efficacy is in these cases assessed on the demonstration of adequate quality properties only.
Pharmacokinetics
The company is providing data from 5 pharmacokinetic studies.
The available human pharmacokinetic data of secretin demonstrate that the substance has a very short half-life and rapid metabolic clearance. As a consequence, biological effects exerted by bolus injections of secretin are only short lasting and can be well controlled. The presentation of the data on PK are deemed adequate. The data presented by the company show that a full characterisation of the PK of the compound is not available in the public domain. However, the conclusions drawn by the company, that the compound has a short half-life and rapid metabolic clearance are supported. However, the company will have to additionally address questions on use of the compound in certain patient populations at risk in more detail, and proposed adequate instructions for the SmPC.
Pharmacodynamics
Secretin is a 27-amino acid peptide, which has been isolated from several animal species including humans, pigs, dogs, rats, mice, goats, rabbits, guinea pigs, and chickens. Mammalian secretins are highly homologous,
The secretin receptor is a member of the glucagon-VIP-secretin receptor family, and is expressed in the pancreas, stomach, liver, kidney, colon, heart, lung, ovary, and brain. In the pancreas, secretin receptor is present in both the ductal and acinar cells.
Data comparing the effects of different secretins demonstrate that porcine secretin and the autologous secretin have comparable potency in the respective species. In the human situation porcine secretin proved to be slightly more potent than human secretin itself.
The well-established physiological actions of secretin include stimulation of pancreatic exocrine secretion of pancreatic fluid including peptides and bicarbonate, and inhibition of gastric acid secretion and motility.
Overall it can be shown that the published data from peer-reviewed journals demonstrate a very low species specificity of mammalian secretins and their corresponding receptors. Thus, the use of porcine secretin in humans is well justified. Synthetic porcine secretin is equipotent to natural porcine secretin in this case.
Secretin administered via the intravenous route stimulates pancreatic volume and bicarbonate secretion, and induces a significant dilatation of the main pancreatic duct over several minutes.
Basal serum gastrin levels are diagnostic for Zollinger Ellison Syndrome (ZES) only at both extreme ends of the spectrum and secretin based stimulation of gastrin secretion can give indication of the presence of a gastrin-secreting tumour.
Off-target effects of secretin encompass an influence on urinary volume, electrolyte secretion, and insulin levels, along with effects on portal venous blood flow. The clinical relevance of these effects is unknown. However, currently the applicant has to further discuss these problems with regard to appropriate amendments of the SmPC.
Clinical efficacy
The presentation of efficacy of the compound has been divided by the applicant into two sections focusing on the added value of secretin stimulation in the assessment of exocrine pancreatic function and the diagnosis of Zollinger-Ellison syndrome.
For the indication “exocrine pancreatic function testing” (or “diagnosis of exocrine pancreatic dysfunction” as proposed by the RMS), the company has provided a systematic review which has up to date not been published but was solely set up in support of this MAA. This review “The diagnostic value of exocrine pancreatic function testing using secretin” is part of the literature provided in the dossier.
For the indication “diagnosis of ZES”, the applicant presents a systematic review as of the year 2005, similar to the one presented for pancreatic function testing, which was also prepared especially for the purpose of this MAA.
The literature analysed confirms that a secretin stimulation test is an accurate diagnostic test to identify impaired exocrine pancreatic function. It is therefore well justified to use the secretin test as the gold standard to qualify other pancreas function test. However, the secretin-stimulated pancreatic function test cannot serve as a stand-alone test to diagnose the underlying pancreatic disease. Although it has a high predictive value for chronic pancreatitis, other pathological conditions (such as pancreatic carcinoma) may also result in reduced exocrine pancreatic function. Thus, a secretin stimulation test should always be combined with imaging to increase the accuracy of the applied diagnostic algorithm. The presentation of the company regarding the analysis of the efficacy data in the first indication (diagnosis of exocrine pancreatic function) is overall deemed adequate.
The literature analysed for the indication Zollinger-Ellison-Syndrome confirms that the secretin test has – at the dose of 2 CU/kg b.w. –a high diagnostic accuracy (>90%) when used with a diagnostic threshold of 120 pg/ml gastrin, which has been shown to be superior to previously advocated thresholds (e.g. 200 pg/ml, or 50% increase) which are partly still included in Gastroenterology textbooks. The presentation of the efficacy data regarding the indication ZES is considered fully adequate.
The company should include a brief summary of these data (of the two summaries of efficacy) into chapter 5.1. of the SmPC. Additionally – in order to prevent the ever increasing off-label use as an “enhancer” for diagnostic imaging, an appropriate statement to discourage this use is also warranted.
Clinical safety
The compound shows a relatively benign safety profile. Adverse events are rare, and restricted to rather mild AE’s, mostly related to the primary and secondary pharmacodynamic activities of the drug.
The company has not only evaluated the (limited) safety data available in the literature, but also the PSURs of the originator in the years 1992 to 2007.
During and after intravenous administration of secretin, there is frequently a rise in so-called “pancreatic enzymes” (amylase, lipase, trypsin) in the blood. These enzyme rises generally have no clinical importance. The use of secretin occasionally results in diarrhoea, which may be associated with cramp-like abdominal pain and/or nausea and vomiting. If injection is too rapid, flushing and faintness may occur.
Increased gastric juice volume and urinary urgency may be observed with infusion of secretin, as well as occasionally electrolyte disturbances. After intravenous injection and also with overdosing, a transient fall in blood sugar may occur in diabetic subjects. In some cases, administration of secretin may be followed by a fall in blood pressure, acidosis, or anaphylactoid reactions to the peptide, which may manifest as headache, changed blood pressure, tachycardia, itching of the skin, rash and urticaria. Overdoses of secretin have a blood pressure lowering effect.
Based on the data presented, and considering the only short-term (one-time) administration of the compound, there appear to be only minor adverse events occurring in a minority of patients, mostly related to the on-target pharmacodynamics effects of the compound.
The characterization of the safety profile of the compound is deemed to be overall adequate.
Further revisions of the SmPC and PL were requested and were fully overtaken by the applicant.
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
Secretin has generally an acceptable level of safety in the proposed indications for Secretin Iberoinvesa. Therefore, Secretin Iberoinvesa with the following proposed indications
- Diagnosis of exocrine pancreatic function
- Diagnosis of Zollinger-Ellison syndrome
does currently not require risk minimisation measures beyond the Product Information. No additional risk minimisation activities and no additional pharmacovigilance activities are currently required. A Risk Management Plan has therefore not been established for Secrelux and is also not considered necessary for Secretin Iberoinvesa. The proposed Eu-SmPC [with the additional recommended modifications] reflects the known safety profile of Secretin Iberoinvesa.
With regard to PSUR submission, the MAH should take into account the following:
- In accordance with the revised legislation on pharmacovigilance (Directive 2010/84/EU), the list of European Union Reference Dates (the EURD list) of PSURs has been established and published by EMA. Marketing authorisation holders shall continuously check the EMA webportal 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.
For medicinal products that do not fall within the categories waived of the obligation to submit routine PSURs by the revised pharmacovigilance legislation, the MAH should follow the DLP according to the EURD list.
Common Renewal Date
A proposed common renewal date of 5 years after finalisation of the procedure was accepted.
Legal Status
Medicinal product subject to medical prescription.
User Testing
The applicant will present a variation to introduce the user test (“readability test”).
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IV. BENEFIT RISK ASSESSMENT
This is a generic application for a product that is administered via the i.v. route. No bioequivalence data are deemed necessary for the possibility of transferring the clinical data on safety and efficacy to this product from the originator product, which has been on the market for 30 years.
The applicant has presented an adequate evaluation of the literature data available which were able to show that the compound possesses an acceptable level of diagnostic accuracy in the indications
proposed. The proposed doses have been adequately justified, and the PK and PD of the compound have also been adequately displayed.
The safety profile of the compound was presented based on the extensive evaluation of literature data, and the evaluation of 15 years of marketing surveillance by the MAH of the originator product, as presented in PSURs. The product has been shown to possess an acceptable level of safety, especially with respect to the only single-dose use of the product in the indications proposed for licensing.
The application is approved. For intermediate amendments, see the current product information.
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V. PROPOSED CONDITIONS FOR MARKETING
AUTHORISATION AND PRODUCT INFORMATION -
V. 1 Proposed list of follow-up measures and specific obligations in case of a positive