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“Revolade is indicated for adult chronic immune (idiopathic) thrombocytopenic purpura (ITP)splenectomised patients who are refractory to other treatments (e.g. corticosteroids,immunoglobulins). Revolade may be considered as second line treatment for adultnon-splenectomised patients where surgery is contraindicated”.A Paediatric Investigation Plan (PIP) for the condition idiopathic thrombocytopenic purpura (ITP)has been agreed by the PDCO. The subset of the paediatric population concerned by the paediatricdevelopment included children from 1 year to less than 18 years. Newborns and infants from birth toless than 1 year have been waived on the grounds that ITP does not occur in this paediatric subset.The paediatric plan included the development of new a powder formulation for oral suspension infixed single-dose sachets and a clinical study to investigate the safety, tolerability and efficacy ofeltrombopag in patients diagnosed with ITP from 1 year to less than 18 years old. A deferral hasbeen granted for completion of the quality study and for the initiation and completion of the clinicalstudy.Revolade is a small molecule for oral administration that increases platelet production throughactivation of the TPO-R. The recommended initial dose for eltrombopag is 50 mg once dailyadministered orally. If after 2 to 3 weeks of initial therapy, the platelet counts are below the clinicallyindicated levels (e.g. 50,000/μL); the dose may be increased to a maximum of 75 mg once daily. Adose reduction is recommended for patients with platelet counts between 150,000 and 250,000/μL.Once the platelet count is 100,000/μL, therapy should be reinitiated at a reduced daily dose.Eltrombopag treatment should only be initiated by a physician experienced in the treatment ofthrombocytopenia. The diagnosis of ITP in adults and elderly patients should have been confirmedby the exclusion of other clinical entities presenting with thrombocytopenia. Consideration should begiven to performing a bone marrow aspirate and biopsy over the course of the disease and treatment,particularly in patients over 60 years of age, those with systemic symptoms or abnormal signs.2.2 Quality aspectsIntroductionRevolade is presented in the form of film-coated tablets containing 31.9 mg or 63.8 mg ofeltrombopag olamine equivalent to 25 mg or 50 mg of eltrombopag respectively. The tablets arepackaged in blisters composed of polyamide / aluminium foil / polyvinyl chloride (PVC) laminatesealed with aluminium foil lidding with a vinyl acrylic seal coating.Other excipients in the product are listed in Section 6.1 of the SPC.Active SubstanceEltrombopag is an orally bioavailable, small molecule TPO-R agonist present in the form of the bismonoethanolamine (olamine) salt.It is a crystalline solid, red/brown, sparingly soluble in water. The molecule does not containasymmetric centres although it exists as the6/79

Z - conformer in the solid state. It is thermally stable up to about 125 C. One solid state form (Form1), is consistently obtained by the synthetic process described, and this is the form that appears in theproduct. The active substance is milled to produce a consistent particle size distribution. ManufactureThe manufacturing process is correctly described, and specifications for reagents, solvents andauxiliary materials used in the process are satisfactory. All critical in-process controls parameters arewell established and justified. The isolated intermediate is controlled by well described and validatedmethods. A single route of synthesis has been used throughout the chemical development ofeltrombopag olamine. Based on knowledge gained during development of the process, together withtools such as a Parameter Attribute Matrix (PAM) and FMEA risk assessment, the processparameters most likely to have the greatest impact on API quality have been identified.The chemical structure is well characterised by the usual range of spectroscopic and physicochemicalstudies. All relevant characteristics of this substance have been studied and established.Concerning the impurities likely to arise during the synthesis, a reasoned discussion has beenprovided according to ICH Q3A (R2) Guideline, including their origin according to themanufacturing process described and the main degradation pathways. SpecificationIn general, the specification proposed is suitable to control the quality of the drug substance. Inaddition to the potential impurities, those impurities routinely found to arise during the synthesis ofthe active substance have been identified and controlled using validated methodology. Furthermore,the specified limits have been justified with reference to toxicology studies. Results of over 30batches used in clinical, non-clinical and stability studies were provided during the evaluation phaseand all recent batches at the intended commercial scale complied with the agreed specification. StabilityThe drug substance is stored in HDPE containers lined with anti-static LDPE bags and sealed withplastic ties. The main degradation pathways of eltrombopag olamine have been defined.The stability studies and conditions are in agreement with ICH Q1A Guideline and the testsperformed are considered stability indicating. Based on the accumulated stability data so far, asuitable and practical retest period has been defined.Medicinal ProductThe tablets have been formulated to contain the following excipients: Microcrystalline cellulose,mannitol, povidone K-30, sodium starch glycolate, magnesium stearate and Opadry White YS-17706-G or Opadry Brown 03B26716. The Opadry White film coat consists of hypromellose,macrogol 400, polysorbate 80 and titanium dioxide (E171). The Opadry Brown film coat consists ofhypromellose, macrogol 400, titanium dioxide (E171), Iron oxide Yellow (E-172) and Iron oxideRed (E-172). The excipients and packaging are usual for this type of dosage form. Pharmaceutical DevelopmentThe pharmaceutical development of the product has been adequately performed and the choice ofexcipients is justified and their functions explained. Appropriate multivariate experimental planswere designed based on the prior knowledge and the risk analysis. Based on the multivariate designof experiments, a design space for the manufacturing process parameters has been defined. Theprocess inputs and the Critical Quality attributes are clearly defined in the design space. The choiceof the packaging is justified. The composition of the batches used for clinical studies are similar tothe final drug product.7/79

Manufacture of the ProductThe manufacturing process covers dry mixing of ingredients, granulation, wet milling, drying,milling blending (pre-lubrication and lubrication), compression, coating and packaging. Amanufacturing process flow diagram and a description of the manufacturing operations areprovided. There is evidence of a significant level of manufacturing experience obtained duringdevelopment, scale-up, and production of clinical supplies. Product SpecificationThe product specifications cover appropriate parameters for this dosage form and include specificreferences to PhEur where applicable. The analytical methods have been adequately described andvalidated. The analytical methods used are a combination of traditional methods and methodsdeveloped using Quality by Design (QbD) principles. Batch analytical data from the proposedproduction site have been provided, demonstrating compliance with the release specifications. Stability of the ProductResults of long-term and accelerated primary stability studies when stored at 30 C/65% RH or40 C/75% RH, respectively, have been provided. At submission, twenty-four months’ data wereprovided for these batches stored under long term condition, and 6 months’ data provided for thebatches stored under accelerated condition. All results from both primary stability and supportivestability batches comply with the limits and no significant changes and trend were observed in all thetested parameters. , generated from market image packs or supporting data from other presentations.Forced degradation studies and photostability studies have also been carried out.Discussion on chemical, pharmaceutical and biological aspectsThe pharmaceutical development of this sparingly-soluble drug product has been performed in asatisfactory way. Attention has focussed on the physical state of the active substance, in particularthe particle size, in order to obtain consistent bioavailability. A risk-based approach is applied to thedevelopment of the active substance (in the synthesis process of eltrombopag free acid and thesynthesis of eltrombopag olamine) in order to establish the design space and control strategy for theprocess parameters. Concerning pharmaceutical development of the product, the design intent was todevelop an oral formulation, with a minimal number of tablets per dose. A risk based approach(FMEA and BRITEST) was utilised during development, to identify and mitigate risks by dosageform design, the manufacturing process and controls where appropriate.Therefore the synthesis of the active substance and the manufacture of the product are under controland can deliver a consistently high quality active substance or product, controlled from batch tobatch by relevant and validated test methodology and specification limits.2.3 Non-clinical aspectsIntroductionA range of in vitro and in vivo studies have been conducted to investigate the primary and secondarypharmacology of eltrombopag, including a battery of safety pharmacology studies. Absorption,distribution, metabolism and excretion studies have been performed with eltrombopag to assess thesuitability of the animal species used during toxicological evaluation.As claimed by the applicant, all safety pharmacology studies, a number of pharmacokinetic studiesand all pivotal toxicity studies (including the toxicokinetic investigat

Protocol Assistance: The applicant received Protocol Assistance from the CHMP on 24 March 2006. The Protocol Assistance pertained to clinical aspects of the dossier. Licensing status: Revolade has been given a Marketing Authorisation in the United States of America on 2