Mitoxantrone 2mg ml Concentrate For Solution For …

1 UKPAR Mitoxantrone 2mg/ml Concentrate for Solution for infusion PL20796/0001. Mitoxantrone 2MG/ML Concentrate FOR Solution . FOR infusion . PL 20796/0001. UKPAR. TABLE OF CONTENTS. Lay Summary Page 2. Scientific discussion Page 3. Steps taken for assessment Page 13. Steps taken after authorisation summary Page 14. Summary of Product Characteristics Page 15. Product Information Leaflet Page 22. Labelling Page 26. 1. UKPAR Mitoxantrone 2mg/ml Concentrate for Solution for infusion PL20796/0001. Mitoxantrone 2MG/ML Concentrate FOR Solution . FOR infusion . PL 20796/0001. LAY SUMMARY. The MHRA granted Pharmakal Limited a Marketing Authorisation (licence) for the medicinal product Mitoxantrone 2mg/ml Concentrate for Solution for infusion (PL. 20796/0001). This is a prescription-only medicine (POM) for the treatment of metastatic breast cancer, non-Hodgkin's lymphoma and leukaemia and to relieve symptoms in liver cancer when an operation is not suitable.

2 No new or unexpected safety concerns arose from this application and it was therefore judged that the benefits of taking Mitoxantrone 2mg/ml Concentrate for Solution for infusion outweigh the risks; hence a Marketing Authorisation has been granted. 2. UKPAR Mitoxantrone 2mg/ml Concentrate for Solution for infusion PL20796/0001. Mitoxantrone 2MG/ML Concentrate FOR Solution . FOR infusion . PL 20796/0001. SCIENTIFIC DISCUSSION. TABLE OF CONTENTS. Introduction Page 4. Pharmaceutical assessment Page 5. Preclinical assessment Page 7. Clinical assessment (including statistical assessment) Page 8. Overall conclusions and risk benefit assessment Page 12. 3. UKPAR Mitoxantrone 2mg/ml Concentrate for Solution for infusion PL20796/0001. INTRODUCTION. Based on the review of the data on quality, safety and efficacy, the UK granted a marketing authorisation for the medicinal product Mitoxantrone 2mg/ml Concentrate for Solution for infusion (PL 20796/0001) on 20th March 2009.

3 The product is a prescription-only medicine. This application was submitted according to Article 10(1) of EC Directive 2001/83, as amended, a generic product of Novantrone 2 mg/mL Concentrate for Solution for infusion , PL 00095/0088, granted license in the UK in June 1984. It was taken over by John Wyeth & Brother Limited, PL 00011/0276, in September 2003. The product contains the active ingredient Mitoxantrone hydrochloride, a DNA- reactive agent. Although its mechanism of action has not been determined it has a cytocidal effect on proliferating and non-proliferating cultured human cells, suggesting activity against rapidly proliferating and slow-growing neoplasms. 4. UKPAR Mitoxantrone 2mg/ml Concentrate for Solution for infusion PL20796/0001. PHARMACEUTICAL ASSESSMENT. DRUG SUBSTANCE. Mitoxantrone hydrochloride. INN: Mitoxantrone hydrochloride.

4 Chemical Name: Chemical name: 1,4-dihydroxy-5,8-bis[[2-[(2- hydroxyethyl)amino]ethyl]amino]anthracen e-9,10-dione dihydrochloride Structure: Molecular formula: C22H30Cl2N4O6. Molecular weight: Physical form: A dark blue, electrostatic powder, hygroscopic, sparingly soluble in water, slightly soluble in methanol, practically insoluble in acetone. All aspects of the manufacture and control of Mitoxantrone hydrochloride are supported by a European Directorate for the Quality of medicines and Healthcare (EDQM) Certificate of Suitability. This certificate is accepted as confirmation of the suitability of Mitoxantrone hydrochloride for inclusion in the medicinal product. The specification is in compliance with the pharmacopoeia monograph and Certificate of Suitability, with an additional test for residual solvents. The specification of the active substance is satisfactory.

5 Mitoxantrone hydrochloride is stored in appropriate packaging that has been evaluated in relation to the grant of the EDQM Certificate of Suitability. Batch analysis data are provided and comply with the proposed specification. Appropriate stability data have been generated showing the active substance to be a physically and chemically stable drug, and supporting an appropriate retest period. DRUG PRODUCT. Other ingredients Other ingredients consist of pharmaceutical excipients, namely sodium chloride, anhydrous sodium acetate, glacial acetic acid, and water for injections. All excipients used comply with their respective European Pharmacopoeial monograph. Satisfactory certificates of analysis have been provided for all excipients. 5. UKPAR Mitoxantrone 2mg/ml Concentrate for Solution for infusion PL20796/0001. None of the excipients used contain material of animal or human origin.

6 There were no novel excipients used and no overages. Impurity profiles Impurity profile for the drug product were found to be similar to those for the reference product. Manufacture A description and flow-chart of the manufacturing method has been provided. In-process controls are appropriate considering the nature of the product and the method of manufacture. Process validation has been carried out on three batches of every strength/vial size and the results are satisfactory. Finished product specification The finished product specification is satisfactory. Acceptance limits have been justified with respect to conventional pharmaceutical requirements and, where appropriate, safety. Test methods have been described and have been adequately validated, as appropriate. Batch data have been provided and comply with the release specification. Certificates of analysis have been provided for any working standards used.

7 Container Closure System Product is packaged in 5ml Type 1 glass vials filled to 5 ml, or 14 ml Type 1 glass vials filled to 10 or ml, or a 20 ml Type 1glass vial filled to 15ml. Each vial is sealed with a grey bromobutyl rubber stopper, aluminium seal and plastic flip-off cap. The 14 ml size containers are colour coded with blue plastic caps for the 10 ml fill and red for the ml fill. Mitoxantrone is presented in packs of 1 and certificates of analysis for all packaging types used have been provided. These are satisfactory. Stability Finished product stability studies have been conducted in accordance with current guidelines. Based on the results, a shelf-life of 24 months has been set, with the storages instructions Do not store above 25oC , which is satisfactory. Conclusion It is recommended that a Marketing Authorisation is granted for this application.

8 6. UKPAR Mitoxantrone 2mg/ml Concentrate for Solution for infusion PL20796/0001. PRECLINICAL ASSESSMENT. No new preclinical data have been supplied with this application and none are required for an application of this type. 7. UKPAR Mitoxantrone 2mg/ml Concentrate for Solution for infusion PL20796/0001. CLINICAL ASSESSMENT. 1. INTRODUCTION. This application is an abridged national Marketing Authorisation submitted under Article , of Directive 2001/83/EC claiming that Mitoxantrone 2mg/mL Concentrate for Solution for infusion is a generic medicinal product of Novantrone 2 mg/mL Concentrate for Solution for infusion , PL. 00095/0088, granted license in the UK in June 1984. It was taken over by John Wyeth & Brother Limited, PL 00011/0276, in September 2003. 2. BACKGROUND. Mitoxantrone is a synthetic anthracenedione exhibiting antineoplastic DNA- reactive effect.

9 It has been widely used for approximately 20 years as an alternative to anthracyclines for the treatment of various cancers including leukaemias. 3. INDICATIONS. Mitoxantrone is indicated in the treatment of metastatic breast cancer, non- Hodgkin's lymphoma and adult acute non-lymphocytic leukaemia. Mitoxantrone has also been used in the palliation of non-resectable primary hepatocellular carcinoma. 4. DOSE & DOSE SCHEDULE. Mitoxantrone should be given by intravenous infusion . For single use only. Any unused Solution should be discarded. Syringes containing this product should be labeled FOR INTRAVENOUS. USE ONLY'. Metastatic Breast Cancer, Non-Hodgkin's Lymphoma, Hepatoma: (a) Single Agent Dosage The recommended initial dosage of Mitoxantrone used as a single agent is 14. mg/m2 of body surface area, given as a single intravenous dose which may be repeated at 21-day intervals.

10 A lower initial dosage (12 mg/m2 or less) is recommended in patients with inadequate bone marrow reserves, due to prior chemotherapy or poor general condition. Dosage modification and the timing of subsequent dosing should be determined by clinical judgement depending on the degree and duration of myelosuppression. For subsequent courses the prior dose can usually be repeated if white blood cell and platelet counts have returned to normal levels after 21 days. The following table is suggested as a guide to dosage adjustment, in the treatment of metastatic breast cancer, non-Hodgkin's lymphoma and hepatoma according to haematological nadir (which usually occurs about 10 days after dosing). 8. UKPAR Mitoxantrone 2mg/ml Concentrate for Solution for infusion PL20796/0001. Nadir after Prior Dose WBC Platelets Time to Recovery Subsequent dose after (per mm3) (per mm3) adequate haematological recovery > 1,500 AND > 50,000 < 21 days Repeat prior dose after recovery or increase by 2.