Public Assessment Report Decentralised Procedure ...

1 PAR Zoledr onic Acid 4mg/5ml concentr ate for solution for infusion UK/H/5370/001/DC. Public Assessment Report Decentralised Procedure zoledronic Acid 4mg/5ml concentrate for solution for infusion ( zoledronic acid monohydrate). Procedure No: UK/H/5370/001/DC. UK Licence No: PL 20568/0045. Claris Lifesciences (UK) Limited 1. PAR Zoledr onic Acid 4mg/5ml concentr ate for solution for infusion UK/H/5370/001/DC. LAY SUMMARY. zoledronic Acid 4mg/5ml concentrate for solution for infusion ( zoledronic acid monohydrate, concentrate for solution for infusion, 4mg/5ml). This is a summary of the Public Assessment Report (PAR) for zoledronic Acid 4mg/5ml concentrate for solution for infusion (PL 20568/0045; UK/H/5370/001/DC). It explains how zoledronic Acid 4mg/5ml concentrate for solution for infusion was assessed and its authorisation recommended, as well as its conditions of use. It is not intended to provide practical advice on how to use zoledronic Acid 4mg/5ml concentrate for solution for infusion.

2 For practical information about using zoledronic Acid 4mg/5ml concentrate for solution for infusion, patients should read the package leaflet or contact their doctor or pharmacist. The product will be referred to as zoledronic Acid throughout the remainder of this Public Assessment Report . What is zoledronic Acid and what is it used for? zoledronic Acid is a generic medicine'. This means that zoledronic Acid is similar to a reference medicine' already authorised in the European Union (EU) called Zometa 4mg/5ml Concentrate for Solution for Infusion (Novartis Europharma Limited, UK). zoledronic Acid is used to: Prevent bone complications, fractures, in adult patients with bone metastases (spread of cancer from primary site to the bone). Reduce the amount of calcium in the blood in adult patients where it is too high due to the presence of a tumour. Tumours can accelerate normal bone change in such a way that the release of calcium from bone is increased.

3 This condition is known as tumour-induced hypercalcaemia (TIH). How does zoledronic Acid work? The active ingredient, zoledronic acid, belongs to a group of medicines called bisphosphonates. zoledronic acid works by attaching itself to the bone and slowing down the rate of bone change. How is zoledronic Acid used? The pharmaceutical form of this medicine is a concentrate for solution for infusion. The route of administration of this medicine is as a drip (infusion) into the patient's vein. The infusion should take at least 15 minutes and should be administered as a single intravenous solution in a separate infusion line. zoledronic Acid must only be given by healthcare professionals trained in administering bisphosphonates intravenously, through a vein. The patient's doctor will recommend that the patient drinks enough water before each treatment to help prevent dehydration. The patient should carefully follow all other instructions given to them by their doctor, nurse or pharmacist.

4 The usual single dose given is 4 mg. Patients with kidney problems, will be given a lower dose depending on the severity of their problem. Patients who are being treated for bone metastases will be given one infusion of zoledronic Acid every 2. PAR Zoledr onic Acid 4mg/5ml concentr ate for solution for infusion UK/H/5370/001/DC. three to four weeks. Patients who are being treated to reduce the amount of calcium in their blood will normally only be given one infusion of zoledronic Acid. Please read section 3 of the package leaflet for detailed information on dosing recommendations, the route of administration, and the duration of treatment. This medicine can only be obtained with a prescription. What benefits of zoledronic Acid have been shown in studies? No additional studies were needed as zoledronic Acid is a generic medicine that is given by infusion and contains the same active substance as the reference medicine, Zometa 4mg/5ml Concentrate for Solution for Infusion (Novartis Europharma Limited, UK).

5 What are the possible side effects of zoledronic Acid? Because zoledronic Acid is a generic medicine, its benefits and possible side effects are taken as being the same as the reference medicine. For the full list of restrictions, see the package leaflet. For the full list of all side effects reported with zoledronic Acid, see section 4 of the package leaflet available on the MHRA website. Why was zoledronic Acid approved? It was concluded that, in accordance with EU requirements, zoledronic Acid has been shown to have comparable quality and to be comparable to Zometa 4mg/5ml Concentrate for Solution for Infusion. Therefore, the MHRA decided that, as for Zometa 4mg/5ml Concentrate for Solution for Infusion, the benefits are greater than its risk and recommended that it can be approved for use. What measures are being taken to ensure the safe and effective use of zoledronic Acid? A risk management plan (RMP) has been developed to ensure that zoledronic Acid is used as safely as possible.

6 Based on this plan, safety information has been included in the Summary of Product Characteristics and the package leaflet for zoledronic Acid including the appropriate precautions to be followed by healthcare professionals and patients. Known side effects are continuously monitored. Furthermore new safety signals reported by patients/healthcare professionals will be monitored/reviewed continuously. Other information about zoledronic Acid Austria, Germany, France, Italy, Poland, Portugal and the UK agreed to grant a Marketing Authorisation for zoledronic Acid on 19 April 2015. A Marketing Authorisation was granted in the UK on 14 May 2015. The full PAR for zoledronic Acid follows this summary. For more information about treatment with zoledronic Acid, read the package leaflet, or contact your doctor or pharmacist. This summary was last updated in July 2015. 3. PAR Zoledr onic Acid 4mg/5ml concentr ate for solution for infusion UK/H/5370/001/DC.

7 TABLE OF CONTENTS. I Introduction Page 5. II Quality aspects Page 6. III Non-clinical aspects Page 8. IV Clinical aspects Page 8. V User consultation Page 10. VI Overall conclusion, benefit/risk Assessment and Page 10. recommendation 4. PAR Zoledr onic Acid 4mg/5ml concentr ate for solution for infusion UK/H/5370/001/DC. I INTRODUCTION. Based on the review of the data on quality, safety and efficacy, the Member States considered that the application for zoledronic Acid (PL 20568/0045; UK/H/5370/001/DC) could be approved. The product is a prescription-only medicine (POM) and is indicated for the treatment of: 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). The application was submitted using the Decentralised Procedure (DCP), with the UK as Reference Member State (RMS), and Austria, Germany, France, Italy, Poland and Portugal as Concerned Member States (CMS).

8 The application was submitted under Article of Directive 2001/83/EC, as amended, as a generic application. The reference medicinal product for this application is Zometa 4mg/5ml Concentrate for Solution for Infusion, which was originally authorised to Novartis Europharma Limited, UK (EU/1/01/176/04-06), on 24 March 2003 via the Centralised Procedure . zoledronic acid belongs to the class of bisphosphonates 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 anti- tumour properties that could contribute to its overall efficacy in the treatment of metastatic bone disease.

9 No new non-clinical studies were conducted, which is acceptable given that the application was based on being a generic medicinal product of an originator product that has been licensed for over 10 years. No new clinical data have been submitted and none are required for applications of this type. A. bioequivalence study was not necessary to support this application as both test and reference products are aqueous intravenous solutions at the time of administration. The RMS has been assured that acceptable standards of Good Manufacturing Practice (GMP) are in place at all sites responsible for the manufacture, assembly and batch release 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.

10 Certificates or satisfactory inspection summary reports as certification that acceptable standards of GMP. are in place at those non-Community sites. The RMS and CMS considered that the application could be approved at the end of Procedure (Day 210). on 19 April 2015. After a subsequent national phase, a licence was granted in the UK on 14 May 2015. 5. PAR Zoledr onic Acid 4mg/5ml concentr ate for solution for infusion UK/H/5370/001/DC. II QUALITY ASPECTS. Introduction Each ml of concentrate contains mg zoledronic acid corresponding to mg zoledronic acid monohydrate. One vial with 5 ml concentrate solution contains 4 mg zoledronic acid, corresponding to mg zoledronic acid monohydrate. Other ingredients consist of the pharmaceutical excipients mannitol, sodium citrate and water for injections. The finished product is packed into 5 ml clear glass vials with a bromobutyl rubber stopper with an aluminium cap with a plastic flip-off seal in pack sizes of 5 vials.