Australian Public Assessment Report for Tacrolimus Proprietary Product Name: Prograf-XL Submission No: PM-2008-03783-3-2 Sponsor: Janssen-Cilag Pty Ltd May 2010 Contents I. Introduction to Product Submission ..................................................................... 3 Submission Details.............................................................................................................. 3 Product Background ............................................................................................................ 3 Regulatory Status ................................................................................................................ 4 Product Information ............................................................................................................ 4 II. Quality Findings .................................................................................................... 4 Drug Substance (active ingredient) ...................................................................................... 4 Drug Product ...................................................................................................................... 4 Biopharmaceutics................................................................................................................ 5 Quality Summary and Conclusions...................................................................................... 7 III. Nonclinical Findings .............................................................................................. 7 Introduction ........................................................................................................................ 7 Pharmacokinetics ................................................................................................................ 7 Toxicology.......................................................................................................................... 7 Nonclinical Summary and Conclusions ............................................................................... 8 IV. Clinical Findings .................................................................................................... 8 Introduction ........................................................................................................................ 8 Pharmacokinetics ................................................................................................................ 8 Drug Interactions .............................................................................................................. 28 Pharmacodynamics ........................................................................................................... 31 Efficacy ............................................................................................................................ 35 Safety ............................................................................................................................... 56 Clinical Summary and Conclusions ................................................................................... 83 V. Pharmacovigilance Findings ............................................................................... 85 VI. Overall Conclusion and Risk/Benefit Assessment .............................................. 85 Quality .............................................................................................................................. 85 Nonclinical ....................................................................................................................... 85 Clinical ............................................................................................................................. 85 Risk-Benefit Analysis ....................................................................................................... 92 Outcome ........................................................................................................................... 93 Attachment 1. Product Information .......................................................................... 93 AusPAR Prograf-XL tacrolimus Janssen-Cilag Pty Ltd PM-2008-03783-3-2 Final 6 May 2010 Page 2 of 112 I. Introduction to Product Submission Submission Details Type of Submission New Dosage Form Decision: Approved Date of Decision: 19 March 2010 Active ingredient(s): Tacrolimus Product Name(s): Prograf-XL Sponsor’s Name and Janssen-Cilag Pty Ltd Address: Locked Bag 2070 North Ryde NSW 167 Dose form(s): Modified release capsules Strength(s): 0.5, 1 and 5 mg Container(s): Blister packs Pack size(s): 0.5 and 5 mg: 30, 50 1 mg: 30, 50, 60 & 100 Approved Therapeutic use: as an adjunct to liver, kidney, lung or heart allograft transplantation in adults and children. Route(s) of administration: Oral Dosage: Starting dose 0.075-0.30 mg/kg/day as a single morning dose Product Background Janssen-Cilag currently has registered tacrolimus (Prograf) immediate release (IR) capsules 0.5, 1 and 5 mg and concentrated injection 5 mg/1 mL. The present application seeks to register prolonged release (XL) capsules in the same dosage strengths as the IR capsules, for the same indications (adjunct to liver, kidney, lung or heart allograft transplantation). The total daily dose of the XL capsules is proposed to be the same as approved for the IR capsules, but the XL capsules will be given as a single morning dose, whereas the IR capsules are given in two divided doses (morning and evening). The starting dose is 0.075-0.30 mg/kg/day for adults and 0.15-0.30 mg/kg/day for children, corresponding, for example, to 5-20 mg/day for a 67 kg adult and 1.5-3.0 mg/day for a 10 kg child. Therapeutic drug monitoring is considered essential, with the aim of maintaining whole blood tacrolimus trough concentrations within specified 2 to 4-fold ranges (within the overall range 5-20 ng/mL) depending upon the type of transplant. Tacrolimus is currently registered in Australia in 2 different dosage forms, Prograf immediate release oral capsules (0.5, 1 and 5 mg) and Prograf concentrated injection for the use as an adjunct to liver, kidney, heart and lung allograft transplantation in adults and children. In this submission, the sponsors seek approval of the new dosage form, Prograf-XL prolonged release oral capsules (0.5 mg, 1 mg, 5 mg), administered once daily for the same indication. Prograf-XL can be initiated in de novo patients immediately following organ transplantation or by conversion from twice daily Prograf therapy on a 1mg:1mg conversion ratio. AusPAR Prograf-XL tacrolimus Janssen-Cilag Pty Ltd PM-2008-03783-3-2 Final 6 May 2010 Page 3 of 112 Regulatory Status The data for the established formulation of tacrolimus (Prograf capsules) provide the basis for the efficacy of the prolonged-release formulation of tacrolimus. Tacrolimus is currently approved by the TGA in 2 different dosage forms, Prograf immediate release oral capsules (0.5, 1 and 5 mg) and Prograf concentrated injection for use as an adjunct to liver, kidney, heart and lung allograft transplantation in adults and children. Both tacrolimus dosage forms were first registered on the Australian Register of Therapeutic Goods in July 1997. The first Marketing Authorisation for Prograf in the European Union (EU) was granted in 1994 by the United Kingdom. Subsequently, Prograf has been approved and marketed throughout the European Union except Estonia, Latvia and Lithuania. It is indicated for prophylaxis of transplant rejection in kidney, liver and heart allograft recipients and the treatment of allograft rejection resistant to treatment with immunosuppressive drugs. Prograf XL has been approved in various EU countries (for prophylaxis of transplant rejection in adult kidney or liver allograft recipients, and treatment of allograft rejection resistant to treatment with other immunosuppressive medicinal products in adult patients.) and Canada (for kidney transplant prophylaxis), as well as in Argentina, Brazil, Chile, Colombia, Costa Rica, El Salvador, Guatemala, Mexico, Paraguay, Peru, Uruguay, Hong Kong, Japan, Korea, Taiwan, Ukraine, Macau, Armenia, Dominica and Russia,. The data packages submitted in Australia, EU, Canada and USA are essentially identical. In addition to the clinical study reports for Prograf-XL submitted in all countries, the EU package submitted in this application also included past study reports of tacrolimus with other formulations such as tacrolimus intravenous formulation and Prograf. These data have been cross-referenced in the data package submitted in Canada and the USA. The US New Drug Applications (NDAs) for Prograf XL (tacrolimus extended release formulation) for prevention of rejection after solid organ transplantation was withdrawn by the US sponsor as of 30 January 2009, after considering the clinical challenges in performing additional studies necessary to meet FDA expectations to support approval. Product Information The approved product information current at the time this AusPAR was prepared is at Attachment 1. II. Quality Findings Drug Substance (active ingredient) The drug substance is identical to that used in the registered dose forms. Tacrolimus is practically insoluble in water (about 0.001%) but it is dissolved in ethanol during manufacture of the drug product, so particle size and polymorphic form are not relevant to the manufacture of the product. Drug Product Tacrolimus is mixed with ethylcellulose, hypromellose and lactose to form intermediate sustained release granules, which are milled to a specified