Levitra Clinical Development

<table cellspacing="1" cellpadding="7" width="100%" border="1"> <tbody> <tr> <td valign="top" bgcolor="#ffffff" height="16"> <br /> <br /> <p> <b><font face="Times" color="#ff0000" size="5">Levitra Clinical Development</font></b> </p> </td> </tr> <tr> <td valign="top" bgcolor="#ffffff" height="16"> <p> <b><font face="Times" size="4">IND Chronology</font></b> </p> </td> </tr> </tbody> </table> <table cellspacing="1" cellpadding="7" width="100%" border="1"> <tbody> <tr> <td valign="top" width="27%" height="15"> <p> <b><font face="Helvetica Condensed" size="1">Date</font></b> </p> </td> <td valign="top" width="73%" height="15"> <p> <b><font face="Helvetica Condensed" size="1">Action</font></b> </p> </td> </tr> <tr> <td valign="top" width="27%" height="15"> <p> <font face="Helvetica Condensed" size="2">10/7/1998</font> </p> </td> <td valign="top" width="73%" height="15"> <p> <font face="Helvetica Condensed" size="2">Pre-IND meeting</font> </p> </td> </tr> <tr> <td valign="top" width="27%" height="15"> <p> <font face="Helvetica Condensed" size="2">3/17/2000</font> </p> </td> <td valign="top" width="73%" height="15"> <p> <font face="Helvetica Condensed" size="2">End-of-<i>Phase II</i> meeting</font> </p> </td> </tr> <tr> <td valign="top" width="27%" height="15"> <p> <font face="Helvetica Condensed" size="2">5/2/2001</font> </p> </td> <td valign="top" width="73%" height="15"> <p> <font face="Helvetica Condensed" size="2">Pre-NDA meeting</font> </p> </td> </tr> <tr> <td valign="top" width="27%" height="15"> <p> <font face="Helvetica Condensed" size="2">6/25/2001</font> </p> </td> <td valign="top" width="73%" height="15"> <p> <font face="Helvetica Condensed" size="2">Division of Reproductive &amp; Urologic Drug Products requests proprietary name review of <b><i>Nuviva</i>;</b> submission includes an independent analysis of the name</font> </p> </td> </tr> <tr> <td valign="top" bgcolor="#ffffff" colspan="2" height="16"> <p> <b><font face="Times" size="4">NDA Chronology (21-400)</font></b> </p> </td> </tr> <tr> <td valign="top" width="27%" height="15"> <p> <b><font face="Helvetica Condensed" size="1">Date</font></b> </p> </td> <td valign="top" width="73%" height="15"> <p> <b><font face="Helvetica Condensed" size="1">Action</font></b> </p> </td> </tr> <tr> <td valign="top" width="27%" height="15"> <p> <font face="Helvetica Condensed" size="2">9/24/2001</font> </p> </td> <td valign="top" width="73%" height="15"> <p> <font face="Helvetica Condensed" size="2">NDA submission</font> </p> </td> </tr> <tr> <td valign="top" width="27%" height="15"> <p> <font face="Helvetica Condensed" size="2">11/14/2001</font> </p> </td> <td valign="top" width="73%" height="15"> <p> <font face="Helvetica Condensed" size="2">First Division of Medication Errors &amp; Technical Support review of Nuviva tradename recommends against use due to confusion with <b><i>Norvasc</i></b> and <b><i>Navane</i></b></font> </p> </td> </tr> <tr> <td valign="top" width="27%" height="15"> <p> <font face="Helvetica Condensed" size="2">1/9/2002</font> </p> </td> <td valign="top" width="73%" height="15"> <p> <font face="Helvetica Condensed" size="2">FDA informs Bayer that Nuviva is not an acceptable tradename</font> </p> </td> </tr> <tr> <td valign="top" width="27%" height="15"> <p> <font face="Helvetica Condensed" size="2">1/23/2002</font> </p> </td> <td valign="top" width="73%" height="15"> <p> <font face="Helvetica Condensed" size="2">Four-month safety update</font> </p> </td> </tr> <tr> <td valign="top" width="27%" height="15"> <p> <font face="Helvetica Condensed" size="2">2/5/2002</font> </p> </td> <td valign="top" width="73%" height="15"> <p> <font face="Helvetica Condensed" size="2">Bayer requests a re-review of Nuviva tradename</font> </p> </td> </tr> <tr> <td valign="top" width="27%" height="15"> <p> <font face="Helvetica Condensed" size="2">3/29/2002</font> </p> </td> <td valign="top" width="73%" height="15"> <p> <font face="Helvetica Condensed" size="2">Second DMETS review of Nuviva recommends against tradename</font> </p> </td> </tr> <tr> <td valign="top" width="27%" height="15"> <p> <font face="Helvetica Condensed" size="2">4/3/2002</font> </p> </td> <td valign="top" width="73%" height="15"> <p> <font face="Helvetica Condensed" size="2">Teleconference to discuss Nuviva tradename</font> </p> </td> </tr> <tr> <td valign="top" width="27%" height="15"> <p> <font face="Helvetica Condensed" size="2">4/11/2002</font> </p> </td> <td valign="top" width="73%" height="15"> <p> <font face="Helvetica Condensed" size="2">FDA informs Bayer that it still finds Nuviva tradename unacceptable</font> </p> </td> </tr> <tr> <td valign="top" width="27%" height="15"> <p> <font face="Helvetica Condensed" size="2">4/18/2002</font> </p> </td> <td valign="top" width="73%" height="15"> <p> <font face="Helvetica Condensed" size="2">Teleconference to discuss Nuviva tradename; Bayer maintains it cannot provide a replacement name; Bayer agrees to submit proposal for "Nuviva Medication Error Risk Management Program"</font> </p> </td> </tr> <tr> <td valign="top" width="27%" height="15"> <p> <font face="Helvetica Condensed" size="2">6/13/2002</font> </p> </td> <td valign="top" width="73%" height="15"> <p> <font face="Helvetica Condensed" size="2">Teleconference to discuss QT prolongation, drug interactions, back pain and tradename</font> </p> </td> </tr> <tr> <td valign="top" width="27%" height="15"> <p> <font face="Helvetica Condensed" size="2">7/2/2002</font> </p> </td> <td valign="top" width="73%" height="15"> <p> <font face="Helvetica Condensed" size="2">DMETS finds <b><i>Levitra</i></b> tradename acceptable</font> </p> </td> </tr> <tr> <td valign="top" width="27%" height="15"> <p> <font face="Helvetica Condensed" size="2">7/3/2002</font> </p> </td> <td valign="top" width="73%" height="15"> <p> <font face="Helvetica Condensed" size="2">Teleconference to discuss QT prolongation, myalgia and back pain, and nitrate interaction; FDA asks for data on 50 patients reporting back pain</font> </p> </td> </tr> <tr> <td valign="top" width="27%" height="15"> <p> <font face="Helvetica Condensed" size="2">7/23/2002</font> </p> </td> <td valign="top" width="73%" height="15"> <p> <font face="Helvetica Condensed" size="2">"Approvable" letter</font> </p> </td> </tr> <tr> <td valign="top" width="27%" height="15"> <p> <font face="Helvetica Condensed" size="2">2/2003</font> </p> </td> <td valign="top" width="73%" height="15"> <p> <font face="Helvetica Condensed" size="2">Bayer submits patient package insert and risk management plan for Levitra</font> </p> </td> </tr> <tr> <td valign="top" width="27%" height="15"> <p> <font face="Helvetica Condensed" size="2">2/19/2003</font> </p> </td> <td valign="top" width="73%" height="15"> <p> <font face="Helvetica Condensed" size="2">Complete response to approvable letter</font> </p> </td> </tr> <tr> <td valign="top" width="27%" height="15"> <p> <font face="Helvetica Condensed" size="2">8/1/2003</font> </p> </td> <td valign="top" width="73%" height="15"> <p> <font face="Helvetica Condensed" size="2">FDA sends Bayer counterproposal for labeling that includes alpha blocker contraindication</font> </p> </td> </tr> <tr> <td valign="top" width="27%" height="15"> <p> <font face="Helvetica Condensed" size="2">8/7/2003</font> </p> </td> <td valign="top" width="73%" height="15"> <p> <font face="Helvetica Condensed" size="2">Bayer submits labeling proposal for a warning regarding concomitant use with alpha blockers and recommendation for dosing at 5 mg</font> </p> </td> </tr> <tr> <td valign="top" width="27%" height="15"> <p> <font face="Helvetica Condensed" size="2">8/8/2003</font> </p> </td> <td valign="top" width="73%" height="15"> <p> <font face="Helvetica Condensed" size="2">Bayer agrees to full contraindication for alpha blockers</font> </p> </td> </tr> <tr> <td valign="top" width="27%" height="15"> <p> <font face="Helvetica Condensed" size="2">8/13/2003</font> </p> </td> <td valign="top" width="73%" height="15"> <p> <font face="Helvetica Condensed" size="2">FDA requests hypotension study of 5 mg dose in combination with alpha blockers</font> </p> </td> </tr> <tr> <td valign="top" width="27%" height="15"> <p> <font face="Helvetica Condensed" size="2">8/15/2003</font> </p> </td> <td valign="top" width="73%" height="15"> <p> <font face="Helvetica Condensed" size="2">DMETS re-review confirms Levitra tradename is acceptable</font> </p> </td> </tr> <tr> <td valign="top" width="27%" height="15"> <p> <font face="Helvetica Condensed" size="2">8/2003</font> </p> </td> <td valign="top" width="73%" height="15"> <p> <font face="Helvetica Condensed" size="2">Bayer submits abbreviated report of requested hypotension study</font> </p> </td> </tr> <tr> <td valign="top" width="27%" height="15"> <p> <font face="Helvetica Condensed" size="2">8/19/2003</font> </p> </td> <td valign="top" width="73%" height="15"> <p> <font face="Helvetica Condensed" size="2">Approval</font> </p> </td> </tr> </tbody> </table>