European Medicines Agency Pre-authorisation Evaluation of Medicines for Human Use
London, 26 June 2008 Doc. Ref: EMEA/CHMP/316130/2008
WITHDRAWAL ASSESSMENT REPORT FOR AQUILDA
International Nonproprietary Name: satavaptan
Procedure No. EMEA/H/C/873
Day 120 Assessment Report as adopted by the CHMP with all information of a commercially confidential nature deleted.
This should be read in conjunction with the “Question and Answer” document on the withdrawal of the application: the Assessment Report may not include all available information on the product if the CHMP assessment of the latest submitted information was still ongoing at the time of the withdrawal of the appli- cation.
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TABLE OF CONTENTS
I. RECOMMENDATION...... 3 II. EXECUTIVE SUMMARY...... 3 II.1 Problem statement...... 3 II.2 About the product ...... 4 II.3 The development programme/Compliance with CHMP Guidance/Scientific Advice...... 5 II.4 General comments on compliance with GMP, GLP, GCP...... 6 II.5 Type of application and other comments on the submitted dossier...... 6 III. SCIENTIFIC OVERVIEW AND DISCUSSION ...... 7 III.1 Quality aspects...... 7 III.2 Non clinical aspects...... 9 III.3 Clinical aspects ...... 13 IV. ORPHAN MEDICINAL PRODUCTS ...... 46 V. BENEFIT RISK ASSESSMENT ...... 47 V.1 Benefits ...... 47 V.2 Risks...... 49 V.3 Balance...... 49 V.4 Conclusions...... 51
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I. RECOMMENDATION
Based on the CHMP review of the data on quality, safety and efficacy, the CHMP considers that the ap- plication for AQUILDA in the treatment of euvolemic and hypervolemic dilutional hyponatremia, is not approvable since "major objections" have been identified, which preclude a recommendation for market- ing authorisation at the present time.
The major objections precluding a recommendation of marketing authorisation pertain to the following principal deficiencies: • Pre-Clinical • Clinical Efficacy • Clinical Safety
Questions to be posed to additional experts
None
Inspection issues
No inspections issues are identified during the assessment of the application.
II. EXECUTIVE SUMMARY
II.1 Problem statement
This is an application for satavaptan 5 and 25 mg film-coated tablets. The claimed indication is treatment of euvolemic and hypervolemic dilutional hyponatraemia.
Serum sodium accounts for nearly all of the osmotic activity of the plasma and is the primary extracellular electrolyte to which osmoreceptors respond. The antidiuretic hormone (ADH) arginine-vasopressin (AVP) maintains the balance of water that keeps the serum sodium concentration in the normal range between 135 and 145 mmol/L. The primary physiologic role of AVP is to act as a water-retaining hormone. In the absence of AVP, large volumes of maximally diluted urine are excreted (water diuresis). If AVP is present in excess, solute-free water is reabsorbed in the collecting ducts of the kidney, resulting in the excretion of small volumes of concentrated urine. Clinical symptoms of hyponatremia are primarily of neurological nature and are related to the osmotic water shift leading to increased intracellular volume, which is of special concern in the brain (cerebral oe- dema). Symptoms ranging from headache and nausea to disorientation, confusion, and focal neurological deficits appear with decreasing sodium. The severity of the symptoms depends on the rapidity and magni- tude of the decrease in serum sodium concentration. In cases with severe hyponatremia or a very rapid change in serum sodium concentration, stupor, seizures and coma may occur. Acute, severe hypoosmo- lality, although less common, is associated with substantial morbidity, and mortality rates of up to 50%.
In general, hyponatremia is defined as follows: Mild Serum sodium concentration 130 - <135 mmol/L Moderate Serum sodium concentration 125 - <130 mmol/L Severe Serum sodium concentration <125 mmol/L
Furthermore, hyponatremia can be classified according to the volume status of the patient as euvolemic, hypervolemic or hypovolemic:
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