Zusammenfassung der Merkmale des Arzneimittels - Atosiban HYBIO 37.5 mg/5 ml Konzentrat zur Herstellung einer Infusionslösung
ADMINISTRATIVE INFORMATION
| Proposed name of the medicinal product(s) in the RMS | Atosiban HYBIO 37.5 mg/5 mL Konzentrat zur Herstellung einer Infusionslösung |
| Name of the drug substance (INN name): | Atosiban |
| Pharmaco-therapeutic group (ATC Code): | Other gynecologicals (G02CX01) |
| Pharmaceutical form(s) and strength(s): | Concentrate for solution for infusion |
| Reference Number(s) for the Decentralised Procedure | DE/H/5641/001/DC |
| Reference Member State: | DE |
| Member States concerned: | ES |
| Legal basis of application: | Generic Art 10.1 Dir 2001/83/EC |
| Marketing Authorisation Holder (name and address) | Hybio Pharmaceutical Germany GmbH c/o Bird & Bird LLP Maximiliansplatz 22 80333 München Germany |
| Names and addresses of all manufacturer(s) responsible for batch release in the EEA | Venus Pharma GmbH Am Bahnhof 1–3 59368 Werne Germany |
Based on the review of the data on quality, safety and efficacy, the RMS considers that the application for “Atosiban Hybio 37.5 mg/5 mL Konzentrat zur Herstellung einer Infusionslösung”,
to delay imminent pre-term birth in pregnant adult women
is approvable.
Conditions are given in section V.1. Please see also steps taken after the initial procedure (section V).
II.1 Problem statement
Not applicable, this is a generic application.
II.2 About the product
Atosiban is a synthetic peptide which acts as a competitive antagonist of oxytocin at human uterine oxytocin receptors. Oxytocin causes uterine contractions through a direct effect on membrane bound receptors in the uterus by increasing the concentration of intracellular calcium in the myometrial cells. It can also lead to cervical ripening by stimulating the release of prostaglandins in the decidual and fetal membranes. Atosiban has been shown to result in inhibition of uterine contractility and a decrease in prostaglandin release. This occurs rapidly, with a reduction in contractions being seen within ten minutes.
Pharmacotherapeutic group: Other gynecologicals
ATC code: G02CX01
Proposed indication:
Atosiban is indicated to delay imminent pre-term birth in pregnant adult women with:
regular uterine contractions of at least 30 seconds duration at a rate of ≥ 4 per 30 minutes; a cervical dilation of 1 to 3 cm (0–3 for nulliparas) and effacement of ≥ 50%; a gestational age from 24 until 33 completed weeks; a normal foetal heart rate.Proposed posology:
Treatment with atosiban should be initiated and maintained by a physician experienced in the treatment of pre-term labour.
Atosiban is administered intravenously in three successive stages: an initial bolus dose (6.75 mg), performed with atosiban 6.75 mg/0.9 ml solution for injection, immediately followed by a continuous high dose infusion (loading infusion 300 micrograms/min) of atosiban 37.5 mg/5 ml concentrate for solution for infusion during three hours, followed by a lower dose of atosiban 37.5 mg/5 ml concentrate for solution for infusion (subsequent infusion 100 micrograms/min) up to 45 hours.
The duration of the treatment should not exceed 48 hours. The total dose given during a full course of atosiban therapy should preferably not exceed 330.75 mg of atosiban.
Intravenous therapy using the initial bolus injection of atosiban 6.75 mg/0.9 ml solution for injection (see Summary of Product Characteristics of this product) should be started as soon as possible after Atosiban HYBIO 37.5 mg/5 mL
Konzentrat zur Herstellung einer Infusionslösung
DE/H/5641/001/DC Public Assessment Report Page 4/11
diagnosis of pre-term labour. Once the bolus has been injected, proceed with the infusion. In the case of persistence of uterine contractions during treatment with atosiban, alternative therapy should be considered.
The following table shows the full posology of the bolus injection followed by the infusion:
| Step | Regimen | Infusion rate | Atosiban dose |
| 1 | 0.9 ml intravenous bolus injection given over 1 minute | Not applicable | 6.75 mg |
| 2 | 3 hours mtravenous loading infusion | 24 ml hour (300 pg min) | 54 mg |
| 3 | Up to 45 hours subsequent mtravenous infusion | 8 ml hour (100 pg nun) | Up to 270 mg |
Re-treatment
In case a re-treatment with atosiban is needed, it should also commence with a bolus injection of atosiban 6.75 mg/0.9 ml, solution for injection followed by infusion with atosiban 37.5 mg/5 ml, concentrate for solution for infusion.
Patients with renal or hepatic impairment
There is no experience with atosiban treatment in patients with impaired function of the liver or kidneys. Renal impairment is not likely to warrant a dose adjustment, since only a small extent of atosiban is excreted in the urine. In patients with impaired hepatic function, atosiban should be used with caution.
Paediatric population
The safety and efficacy of atosiban in pregnant women aged less than 18 years have not been established. No data are available.
Method of administration
For instructions on preparation of the medicinal product before administration, see section 6.6.
II.3 General comments on the submitted dossier
This decentralised application concerns a generic version of atosiban. The European reference product is Tractocile 37.5 mg/5 ml concentrate for solution for infusion.The first marketing authorisation of Tractocile within the EU was granted through the central procedure in January 2000 to Ferring Pharmaceuticals A/S.
The legal basis for this submission is article 10.1 so called ‘generic application’.
With DE as the Reference Member State in this Decentralized Procedure, Hybio Pharmaceutical Germany GmbH c/o Bird & Bird LLP applied for the Marketing Authorisation for Atosiban Hybio 37.5 mg/5 ml in ES based on the reference product. In this Assessment Report, the name Atosiban Hybio 37.5 mg/5 ml is used.
The proposed product (Trade name: Atosiban HYBIO 37.5 mg/5 ml) is a solution for infusion and contains the same active substance in the same concentration as an approved solution for infusion (Reference product: Tractocile 37.5 mg/5 ml concentrate for solution for infusion). As per the CPMP/EWP/QWP/1401/98 Rev. 1/Corr **, since the proposed product is an aqueous intravenous solution at time of administration and contains the same active ingredient, the applicant is not required to submit a bioequivalence study.
The atosiban product submitted with this application is considered a generic of the reference medicinal product Tractocile 37.5 mg/5 ml concentrate for solution for infusion as it satisfies the criteria of having the same qualitative and quantitative composition in terms of active ingredients and the same pharmaceutical form.
Atosiban HYBIO 37.5 mg/5 mL
Konzentrat zur Herstellung einer Infusionslösung
DE/H/5641/001/DC Public Assessment Report Page 5/11
II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles
The RMS has been assured that acceptable standards of GMP are in place for these product types at all sites responsible for the manufacture and assembly of this product.
For manufacturing sites within the Community, the RMS has accepted copies of current manufacturer authorisations issued by inspection services of the competent authorities as certification that acceptable standards of GMP are in place at those sites.
For manufacturing sites outside the Community, the RMS has accepted copies of current GMP Certificates of satisfactory inspection summary reports, ‘close-out letters’ or ‘exchange of information’ issued by the inspection services of the competent authorities (or those countries with which the EEA has a Mutual Recognition Agreement for their own territories) as certification that acceptable standards of GMP are in place at those non-Community sites.
GMP active substance
Regarding the statement on GMP for the active substance a statement/declaration is provided from the manufacturer(s) responsible for manufacture of the finished product and batch release situated in the EU.
GCP
No clinical study or bioequivalence study was conducted for this application.
III.1 Quality aspects
The drug substance is atosiban acetate a synthetic cyclic nonapeptide. No Ph. Eur. monograph currently exists. The ASMF procedure is used and a letter of access by the ASMF holder has been provided.
The QP declaration has been presented.
The active substance atosiban is manufactured by a process consisting of four stages: synthesis of the linear peptide, oxidation reaction, cleavage and preparation of the crude peptide, purification and preparation of the active substance, drying and packaging. The intended commercial batch size is 3.5 mol or 1.75 kg. The drug substance manufacturing process has been described in sufficient detail. The proposed re-processing steps have been adequately justified. The proposed in-process controls are acceptable. Protected amino acid derivatives are used as starting material which is also acceptable. It is documented that a change in starting material suppliers will result in a variation. The specifications for the starting materials are acceptable. The manufacturing process has been validated. Changes during manufacturing process development have been described.
The confirmation of the chemical structure of atosiban acetate is based on the results of peptide sequence analysis, amino acid ratio analysis, and on the compliance of the MS-, NMR- and IR-spectrum. Product- and process-related impurities have been adequately addressed. The discussion on genotoxic impurities is acceptable.
The following attributes are included in the drug substance specification: appearance, hygroscopicity, solubility, specific rotation, identification by HPLC, identification by MS, pH, water content, acetic acid content, anions, amino acid analysis, related compounds, residual solvent, bacterial endotoxins, microbial limit and assay. The specification limits are acceptable. The analytical methods have been adequately described. Validation data have been provided and the methods are suitable for their intended use. Batch analysis data for 21 commercial batches have been provided. All results comply with the specifications.
Adequate information for reference standards and the container closure system has been provided.
Stability data for three drug substance batches stored for 48 months under real time conditions (-20°C) and 6 months under accelerated conditions 2 – 8°C) have been provided in the dossier. All results are within the specifications and only a very slight increase in the sum of impurities has been observed after 48 months under long term conditions. The proposed re-test period of 36 months is acceptable.
Atosiban Acetate Injection 37.5 mg/5.0 mL is a clear, colourless solution without particles for intravenous (IV) use. The excipients are mannitol, hydrochloric acid and water for injection. The container closure system consists of clear borosilicated (type I) sealed with grey siliconised bromobutyl rubber stopper, type I, and flip-off cap of polypropylene and aluminium. An overfill of 0.3 mL is added to each vial to allow withdrawal and administration of the nominal dose (5 ml). It is stated that qualitatively and quantitatively the same excipients as in the RMP (Tractocile) are used. For the formulation development commercial Tractocile samples serves as reference. Based on the analysis of reference product and a risk evaluation critical properties and the quality product profile were identified. All relevant aspects of the drug product manufacturing process were considered during manufacturing process development. The choice of aseptic processing for preparation of a sterile product has been justified by investigations of the influence of terminal sterilization on drug product quality. The amounts of total impurities significantly increased in the HPLC method (above the specification limit) and the assay results decreased, even though no out of specification results were obtained. Extractable studies with the vial and the rubber stopper material have proven that none of the identified and detected substances is likely to occur in the drug product solution. Collectively, the manufacturing process development has been adequately described.
The batch size is 10,000 vials and the manufacturing process consists of the following steps: preparation of dilute hydrochloric acid solution, preparation and filtration of mannitol solution, ultrafiltration of mannitol solution, preparation of bulk solution, sterile filtration, filling, capping, inspection, labelling, packaging and distribution.
An adequate description of the manufacturing process has been provided by the applicant. Validation data for three consecutive commercial-scale drug product batches have been provided. The information on process validation including media fill is acceptable.
The excipients are compendial.
The drug product specification includes the following attributes: physical appearance, identification by HPLC and MS, pH, visible particles, undissolved particles, volume of injection in containers, osmolality, bacterial endotoxins, sterility, related substances and assay. The specifications for drug product control generally are in line with the recommendations of ICH Q6A. Possible contamination of the drug product with elemental impurities has been discussed with sufficient detail. The analytical methods have been adequately described. Validation data have been provided and the methods are suitable for their intended use. Batch analysis results for the three validation batches (10,000 vials each) have been provided. All results comply with the specifications.
Sufficient information for reference standards and the container closure system is provided.
Stability studies were performed under long-term (2 – 8°C) and accelerated (25 ± 2°C/60% ± 5% RH) storage conditions.
The stability data of the three validation batches after 6 months of storage at accelerated and 18 months of storage at long-term storage conditions are available demonstrating that all test parameters remained within their specification limits. The proposed shelf-life of 24 months for the drug product is acceptable.
A commitment has been made by the applicant that the first three production-scale batches will be placed on stability studies and that at least one production lot will be added to the stability program each year.
Results of the photostability study indicated that the drug product is sensitive to light. Against that background the proposed storage condition for the drug product (2–8°C, light-resistant container) is considered adequate.
III.2 Non-clinical aspects
The pharmacodynamic, pharmacokinetic and toxicological properties of Atosiban are well known. As Atosiban is a widely used, well-known active substance, the applicant has not provided additional studies and further studies are not required. An overview based on a literature review is, thus, appropriate.
As requested, the applicant performed a ready biodegradation study with the active ingredient atosiban showing that atosiban is not readily biodegradable. Instead of providing a Phase II ERA the applicant calculated the PECsurface water by refining Fpen with prevalence data resulting in a PEC value being clearly below the action limit. Furthermore, a justification was provided for not submitting a Phase II environmental risk assessment.
The RMS would like to note again that atosiban is a potential endocrine disruptor. Therefore, the provision of a tailored Phase II ERA for the active ingredient atosiban is deemed necessary in compliance with the respective guidelines. The applicant provided a commitment on submitting additional information on the metabolism of atosiban in humans to further support, the argument that low concentrations of this active substance (atosiban) would reach the environment and therefore no further risk assessment would be required.
Summary of main study results
| Substance (INN/Invented Name): atosiban acetate | |||
| CAS-number (if available): 90779–64–4 | |||
| Phase I | |||
| Calculation | Value | Unit | Conclusion |
| PEC surface water , refined (e.g prevalence, literature) | 0.000476 | µg/L | > 0.01 threshold (N) |
| Other concerns (e.g. chemical class) | endocrine mode of action | (Y) | |
| Phase II Physical-chemical pro | perties and fate | ||
| Study type | Test protocol | Results | Remarks |
| Ready Biodegradability Test | OECD 301F | 53/49 % (d 28) kSTP (0 h-1) | not readily biodegradable |
At the time of the end of the procedure, a final conclusion on the environment could not be drawn. The RMS was waiting for fulfilling the post approval commitment within six months after approval. (see V.1). In the meantime, the post approval commitment was submitted (see VI).
III.3 Clinical aspects
The applicant has not conducted any clinical studies with atosiban and all the relevant clinical information is literature based. The clinical overview supports the indications and covers the pharmacology, efficacy and safety of the product.
This is a generic application for a solution for injection. According to the Guideline on the Investigation of Bioequivalence (CPMP/QWP/EWP/1401/98 Rev.1/Corr**), the Applicant is not required to submit a bioequivalence study if the product is to be administered as an aqueous solution containing the same active substance in the same concentration as the currently authorized reference product and excipients do not interact and/or otherwise affect the disposition of the drug substance.
All these conditions are fulfilled in the present application, as the formulation contains the same active substance in the same concentration and the same excipients in same amounts as the reference product.
Furthermore, “Atosiban HYBIO 37.5 mg/5mL” has the same indication, pharmaceutical form, strengths and route of administration as the reference medicinal product.
Pharmacokinetics
No new data have been submitted. None is required for this type of generic applications.
The pharmacokinetic claims in the SmPC are consistent with the reference product.
No new data have been submitted. None is required for this type of generic applications. The pharmacodynamics claims in the SmPC are consistent with the reference product.
No new efficacy or safety data have been submitted and none are required for this application.
The Applicant has submitted a signed Summary of the Applicant's and/or 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.
The MAH has submitted a risk management plan, in accordance with the requirements of Directive 2001/83/EC as amended, describing the pharmacovigilance activities and interventions designed to identify, characterise, prevent or minimise risks relating to the medicinal product(s) applied for authorisation.
Safety specification
According to the Applicant the safety specification is in full accordance with the current safety specification agreed and published for a similar product which is acceptable.
Pharmacovigilance Plan
Routine pharmacovigilance is suggested and no additional pharmacovigilance activities are proposed by the applicant, which is endorsed.
Risk minimisation measures
Routine risk minimisation is suggested and no additional risk minimisation activities are proposed by the applicant, which is endorsed.
Summary of the RMP
The submitted Risk Management Plan is considered acceptable.
The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in the Marketing Authorisation and any agreed subsequent updates of the RMP.
An updated RMP should be submitted:
– At the request of the RMS;
– Whenever the risk management system is modified, especially as the result of new
information being received that may lead to a significant change to the benefit/risk profile or as the result of 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.
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. 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.
The common renewal date is 09.09.2024.
Medicinal product subject to a medical prescription.
For the current DCP (DE/5641/001/DC) the Applicant submitted with the D106 Responses a bridging report comparing PIL for Atosiban HYBIO 37.5 mg/5 ml with PIL for Atosiban HYBIO 6.75mg/0.9 ml (DE/H5469/001/DC). Since the results of the User Testing on the PIL for Atosiban HYBIO 6.75mg/0.9 ml (DE/H5469/001/DC) were positive and the analysis in the current bridging report established that the leaflet text for Atosiban HYBIO 37.5 mg/5 ml concentrate for solution for infusion (Daughter PIL) is very similar to Atosiban HYBIO 6.75 mg/0.9 ml solution for injection (Parent PIL), no separate user testing is required and the PIL is considered acceptable.
All quality issues have been resolved.
The application contains an adequate review of published non-clinical and clinical data.
This is a generic application for a solution for injection. According to the Guideline on the Investigation of Bioequivalence (CPMP/QWP/EWP/1401/98 Rev.1/Corr**), the Applicant is not required to submit a bioequivalence study if the product is to be administered as an aqueous solution containing the same active substance in the same concentration as the currently authorized reference product and excipients do not interact and/or otherwise affect the disposition of the drug substance.
All these conditions are fulfilled in the present application, as the formulation contains the same active substance in the same concentration and the same excipients in same amounts as the reference product. Furthermore, “Atosiban HYBIO 37.5 mg/5 ml” has the same indication, pharmaceutical form, strengths and route of administration as the reference medicinal product.
There are no obstacles to approval from the quality, non-clinical and clinical point of view.
The application is approved. For intermediate amendments see current product information.
V.1 Final list of recommendations not falling under Article 21a/22 of Directive
2001/83 / positive benefit risk assessment
The applicant provided a commitment to support the argument that negotiable concentrations of this active substance (atosiban) would reach the environment. More detailed data on metabolism and elimination of Atosiban should be provided within six months post approval. In case a sound justification cannot be provided further action is deemed required, i.e. a tailored Phase II ERA should be prepared in consultation with the competent authority.