Public Assessment Report of the Norwegian Medicines Agency Scientific discussion Zoledronic acid Strides 4 mg/5 ml concentrate for solution for infusion Zoledronic acid NO/H/0228/001/DC Applicant: Strides Arcolab International Ltd EU- procedure number: NO/H/0228/001/DC Reg. number in Norway: 11/8757 Date: 16-Sep-2013 Pharmacotherapeutic group: drug affecting bone structure and mineralization, Bisphonates ATC code: M05BA08 Route of administration: intravenous Therapeutic indication: adult patients with tumour-induced hypercalcaemia (TIH) and for prevention of skeletal related events (pathological fractures, spinal compression, radiation or surgery to bone, or tumour-induced hypercalcaemia) in adult patients with advanced malignancies involving bone Prescription status: prescription only Date of authorisation in NO: 08 February 2013 Concerned Member States: Decentralised procedure with AT, DE, DK, ES, FI, FR, IT, PL, SE and UK Application type/legal basis: Directive 2001/83/EC, Article 10(1) This module reflects the scientific discussion for the approval of Zoledronsyre Strides. The procedure was finalised at 12-Dec-2012. For information on changes after this date please refer to the module ‘Update’. I. INTRODUCTION Based on the review of the quality, safety and efficacy data, the decentralised procedure for Zoledronic acid Strides 4 mg/5 ml concentrate for solution for infusion from Strides Arcolab International Ltd was approved on 12-Dec-2012. NO was acting as Reference Member State. AT, DE, DK, ES, FI, FR, IT, PL, SE and UK were Concerned Member States. Zoledronic acid belongs to the class of bisphosphonates (ATC code: M05 BA 08) and acts primarily on bone. It is an inhibitor of osteoclastic bone resorption. The selective action of bisphosphonates on bone is based on their high affinity for mineralised bone, but the precise molecular mechanism leading to the inhibition of osteoclastic activity is still unclear. In long-term animal studies, zoledronic acid inhibits bone resorption without adversely affecting the formation, mineralisation or mechanical properties of bone. In addition to being a potent inhibitor of bone resorption, zoledronic acid also possesses several antitumour properties that could contribute to its overall efficacy in the treatment of metastatic bone disease. Zoledronic acid has a well established efficacy and safety profile and no new clinical studies have been conducted and none is required for this application. The product is indicated for: - Prevention of skeletal related events (pathological fractures, spinal compression, radiation or surgery to bone, or tumour-induced hypercalcaemia) in adult patients with advanced malignancies involving bone. - Treatment of adult patients with tumour-induced hypercalcaemia (TIH). A comprehensive description of the posology in these indications is given in the SmPC. The marketing authorisation has been granted pursuant to Article 10(1) of Directive 2001/83/EC. 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 Zoledronic acid Strides is a product for parenteral use, it is exempted for biostudy (CPMP/EWP/QWP/1401/98 Rev. 1/Corr**). No new pre-clinical and clinical studies were conducted, which is acceptable for this abridged application. No scientific advice has been given to the MAH with respect to these products and no paediatric development programme has been submitted, as this is not required for a generic application. II. QUALITY ASPECTS II.1 Introduction The drug product is a concentrate for solution for infusion, containing zoledronic acid monohydrate corresponding to 4 mg/5 ml (0.8 mg/ml) zoledronic acid. The formulation contains the same excipients (mannitol, sodium citrate (as anhydrate), water for injections) as the reference product. The drug product is packaged in 5 ml clear, colourless glass vials closed with grey coated bromobutyl rubber PAR Scientific discussion – Zoledronsyre Strides – NO/H/0228/001/DC 2/5 stoppers and caps with red flip off lid. No accompanying reconstitution diluent is supplied with the drug product. II.2 2.2 Drug Substance The active substance Zoledronic acid monohydrate is manufactured by Natco Pharma Limited, India and holds an ASMF. There is no Ph.Eur. monograph available for this active substance. The manufacturing process consists of two synthetic steps from simple starting materials. The specifications are sufficient in order to ensure an adequate and consistent quality of the active substance. Three commercial batches of 3.5 kg have been manufactured and put on the stability study. Based on the stability data available which also includes supportive data from older batches, a retest period of 5 years is approved. II.3 Medicinal Product The drug product is manufactured by Agila Specialities Private Limited, India. The development of the product has been described, the choice of excipients is justified and their functions are explained. The excipients and packaging materials are usual for this type of dosage form, and are of pharmacopeia (Ph.Eur.) quality. Studies were performed to confirm the stability of the chosen formulation, the suitability of the container closure system and that the finished product can withstand terminal sterilisation by autoclaving. The manufacturing process includes the steps of preparation of bulk solution, filtration, filling and terminal sterilisation. Conventional manufacturing techniques are used. Data on process validation has been presented for two pilot scale batches, and a process validation protocol has been provided for three full scale batches. The commercial batch size is 20 l. The drug product specifications cover appropriate parameters with acceptable limits for this dosage form. Analytical methods validation has been presented for all relevant tests. Batch analytical data has been presented on two pilot scale batches, demonstrating compliance with the proposed release specification. Stability data has been presented for two pilot scale batches stored at 25°C/60% RH for 24 months and 40°C/75% RH for 6 months. The conditions used in the stability studies are according to the ICH stability guideline. All results are within the proposed specification. A shelf-life of 2 years can be approved. The three first production scale batches should be put on post-approval stability. Data has been provided demonstrating that the product remains stable for 24 hours following dilution with 5% glucose and 0.9% sodium chloride, when stored at 2 - 8°C. II.4 Discussion on chemical, pharmaceutical and biological aspects There was no discussion in the CMD(h). Agreement between member states was reached during a written procedure. The application is considered approvable from a quality point of view. III. NON-CLINICAL ASPECTS III.1 Introduction Pharmacodynamic, pharmacokinetic and toxicological properties of zoledronic acid are well known. As zoledronic acid is a widely used, well-known active substance, 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 refers 55 publications up to year 2012, and is considered acceptable. PAR Scientific discussion – Zoledronsyre Strides – NO/H/0228/001/DC 3/5 III.2 Pharmacology N/A III.3 Pharmacokinetics N/A III.4 Toxicology N/A III.5 Ecotoxicity/environmental risk assessment (ERA) No environmental risk assessment has been provided. The application concerns a generic and no new indications are added. It is therefore expected that Zoledronic Acid Strides will substitute parts of prescriptions of currently marketed drug. Consequently, no changes in the environment that are not already known for zoledronic acid are to be anticipated. III.6 Discussion on the non-clinical aspects Abridged applications avoid the need for repetitive tests on animals and humans. The submitted overview of literature references is deemed satisfactory. The application is considered approvable from a non-clinical point of view. IV. CLINICAL ASPECTS IV.1 Introduction Zoledronic acid is a well known substance. IV.2 Pharmacokinetics No new studies have been performed and none is required for this generic application. According to the CHMP Guideline on the Investigation of Bioequivalence, appendix II, Parenteral solutions (CPMP/EWP/QWP/1401/98 rev.1), a biowaiver for a parenteral solution can be accepted provided it is administered as an aqueous intravenous solution containing the same active substance as the medicinal product already approved. This criterion is fulfilled. The excipients are not considered to affect the pharmacokinetics of the active substance. Zoledronic Acid Strides can be considered essentially similar to the original product Zometa “Novartis”. IV.3 Pharmacodynamics N/A IV.4 Clinical efficacy The efficacy of zoldronic acid is well established and no clinical studies have been conducted and none were required for this generic application. PAR Scientific discussion