CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`022255Orig1s000
`
`RISK ASSESSMENT and RISK MITIGATION
`REVIEW(S)
`
`
`
`
`
`
`

`

`Department of Health and Human Services
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Surveillance and Epidemiology
`
`
`
`April 20, 2010
`Russell Katz, MD, Director
`Division of Neurology Products (DNP)
`Claudia Karwoski, PharmD, Director
`Division of Risk Management (DRISK)
`Mary Dempsey BS, Risk Management Programs
`Coordinator, DRISK
`Jessica Diaz, RN, BS, Patient Labeling Reviewer, DRISK
`Vimpat Oral Solution proposed REMS ; Vimpat Tablets and
`Injection proposed REMS Modification
`Vimpat (lacosamide)
`NDA 022255 Vimpat Oral Solution
`NDA 022253/S-006 Vimpat Tablets
`NDA 022254/S-003 Vimpat Injection
`Schwarz Biosciences, Inc., a member of the UCB Group of
`Companies
`2009-1540
`
`Date:
`To:
`
`Through:
`
`From:
`
`Subject:
`
`Drug Name(s):
`Application
`Type/Number:
`
`Applicant/sponsor:
`
`OSE RCM #:
`
` Background
`
` 1
`
`
`The Division of Neurology Products (DNP) requested the Division of Risk Management
`(DRISK) review the Vimpat (lacosamide) Oral Solution proposed Medication Guide and
`Risk Evaluation Mitigation Strategy (REMS). DRISK was also requested to review the
`proposed Medication Guide and proposed Risk Evaluation Mitigation Strategy (REMS)
`modification for Vimpat (lacosamide) Tablets and Vimpat (lacosamide) Injection.
`
`The proposed REMS (NDA 022255) is for a new commercial Vimpat oral solution and
`the proposed REMS modification (NDA 022253 and NDA 022254) is for the Vimpat
`Tablets and Injection. All Vimpat formulations will share the same package insert (PI),
`Medication Guide (MG) and Risk Evaluation Mitigation Strategy (REMS).
`The REMS for Vimpat Tablets and Injection was approved October 28, 2008. The REMS
`consists of the following elements:
`
`
`
`
`
`1
`
`

`

`• Medication Guide
`• Timetable for Assessment
`
`
`2 Material Reviewed
`
`
` •
`
`
`
`• October 28, 2008 Vimpat Tablets and Injection approved REMS
`• August 21, 2009 proposed Vimpat Tablets and Injection REMS modification to
`include a comprehensive Medication Guide
`
`January 21, 2010 Jessica Diaz’ DRISK Review of Patient Labeling (Medication
`Guide), Proposed Risk Evaluation and Mitigation Strategy, and REMS
`Supporting Document Amendment
`
` •
`
` March 19, 2010 REMS information request to make the elements of the REMS
`the same for the three Vimpat formulations
`
`
`
`
`
` 3
`
`• March 31, 2010 proposed comprehensive Medication Guide for the three Vimpat
`formulations
`
` •
`
` April 13, 2010 proposed REMS for Vimpat Oral Solution; proposed REMS
`modification for Vimpat Tablets and Injection
`
`• April 19, 2010 proposed REMS for the three Vimpat formulations.
`
` Proposed REMS Elements
`
`
`The Vimpat March 31, 2010 submission includes the proposed Medication Guide which
`incorporated the Vimpat Tablets, Injection, and Oral Solution formulations into one
`comprehensive Medication Guide.
`
`The Vimpat April 19, 2010 submission includes the proposed REMS which incorporates
`the Vimpat Tablets, Injection, and Oral Solution formulations into one REMS.
`
`FDA Information Request of March 19, 2010 states the following:
`
`“The timetable for submission of assessments in the REMS approved on October
`
`28, 2008, for Vimpat (lacosamide) Tablets and Injection requires an April 2010
`
`assessment of the REMS. We acknowledge, however, that subsequent to our
`
`initial requirement for a REMS for lacosamide, we determined that all members
`
`of the anti-epileptic drug (AED) class, including lacosamide, should have
`
`individual Medication Guides that include all risk information that is
`
`
`
`
`
`2
`
`

`

`necessary for patients’ safe and effective use of each drug, including but not
`limited to the increased risk of suicidal thoughts and behavior. Thus, the REMS
`assessment due by April 2010 may consist of a statement that the Medication
`Guide would be adequate to achieve its purpose.”
`
`
`
`
`
`
`The title of the April 13, 2010 Vimpat submission is Proposed REMS Modification-
`Amendment REMS Assessment; however, there is no mention of the REMS Assessment
`in the submission.
`
` Discussion and Conclusion
`
` 4
`
`
`DRISK performed a comparison of the April 19, 2010 submitted proposed REMS
`modification and the March 31, 2010 proposed Medication Guide to the approved
`Vimpat REMS and Medication Guide and found them to be identical with the exception
`of the inclusion of oral solution text in the REMS and oral solution text and ingredients in
`the MG; no safety information was added or revised.
`
`5. Recommendation
`
`Approve the Vimpat REMS for all formulations as submitted April 19, 2010.
`
`
`
`
`
`
`
`
`3
`
`

`

`Application
`Type/Number
`--------------------
`NDA-22255
`
`NDA-22253
`
`NDA-22254
`
`Submission
`Type/Number
`--------------------
`ORIG-1
`
`SUPPL-6
`
`SUPPL-3
`
`Submitter Name
`
`Product Name
`
`--------------------
`SCHWARZ
`BIOSCIENCES INC
`SCHWARZ
`BIOSCIENCES INC
`SCHWARZ
`BIOSCIENCES INC
`
`------------------------------------------
`VIMPAT
`
`VIMPAT
`
`VIMPAT
`
`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`MARY J DEMPSEY
`04/20/2010
`
`MARY E WILLY
`04/20/2010
`For Claudia Karowski
`
`

`

`________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________
`
`
`
`
`Risk Evaluation and Mitigation Strategy (REMS) Memorandum
`
`U.S. FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`Office of Drug Evaluation I
`Division of Neurology Products
`
`____ ____________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________
`NDA/BLA #s:
`22-255
`Products:
`Vimpat (lacosamide) Oral Solution
`APPLICANT:
`Schwarz Pharma
`FROM:
`Russell Katz, M.D., Director
`DATE:
`01/11/2010
`
`
`
`
`
`Section 505-1 of the Federal Food, Drug, and Cosmetic Act (FDCA) authorizes FDA to
`require the submission of a Risk Evaluation and Mitigation Strategy (REMS) if FDA
`determines that such a strategy is necessary to ensure that the benefits of the drug
`outweigh the risks (section 505-1(a)). Section 505-1(a)(1) provides the following factors:
`
`
`________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________
`________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________
`
`(A) The estimated size of the population likely to use the drug involved;
`(B) The seriousness of the disease or condition that is to be treated with the drug;
`(C) The expected benefit of the drug with respect to such disease or condition;
`(D) The expected or actual duration of treatment with the drug;
`(E) The seriousness of any known or potential adverse events that may be related to
`the drug and the background incidence of such events in the population likely to
`use the drug;
`(F) Whether the drug is a new molecular entity (NME).
`
`After consultations between the Office of New Drugs and the Office of Surveillance and
`Epidemiology, we have determined that a REMS is necessary for Vimpat (lacosamide) Oral
`Solution to ensure that the benefits of the drug outweigh the increased risk of suicidal
`thoughts and behavior associated with the class of antiepileptic drugs (AEDs), of which
`Vimpat (lacosamide) Oral Solution is a member. In reaching this determination, we
`considered the following:
`
`
`A. It is not possible to precisely estimate the size of the population likely to use Vimpat
`(lacosamide) oral solution. The estimated number of patients in the United States
`with partial-onset seizures is approximately 0.9 to 1.8 million. This estimate is based
`on a US population of about 300 million. The prevalence of epilepsy has been
`estimated to be 5-10 persons per 1000,1 with about 60% of these patients having
`partial seizures.2
`B. Patients with epilepsy have approximately two to three times the risk of death from
`any cause compared with persons without epilepsy.1 Seizures may cause significant
`trauma, drowning, and accidental injury. Many of the deaths in persons with epilepsy
`are directly related to seizures, accidents and injuries arising from seizures, and the
`
`1 Harrison’s Principles of Internal Medicine, 17th Ed. (2008).
`2 Hauser WA, Annegers JF, Rocca WA. Descriptive epidemiology of epilepsy: contributions of
`
`population-based studies from Rochester, Minnesota. Mayo Clin Proc. 1996;71(6):576–586.
`
`

`

`underlying condition resulting in seizures.
`C. The efficacy of Vimpat (lacosamide) for the treatment of partial onset seizures was
`demonstrated in two phase 3 placebo-controlled trials and one supportive phase 2
`placebo-controlled trial.
`D. If approved, Vimpat (lacosamide) oral solution will be administered on a chronic
`basis to patients with epilepsy, generally for period of at least 2 years. Such treatment
`may extend to a lifetime.
`E. A known serious risk of AEDs as a therapeutic class is an increased risk of suicidal
`thoughts and behavior (which are risk factors for completed suicide). The increased
`risk of suicidal thoughts and behavior were demonstrated in a meta-analysis of
`randomized, placebo-controlled clinical trial data for 11 AEDs.3
`In this meta-analysis, the odds ratio for suicidal behavior or ideation for all AEDs
`studied was 1.80 (95% CI: 1.24, 2.66); 0.37% of all drug-treated patients and 0.24%
`of placebo-treated patients had an event of suicidal behavior or ideation. This
`finding was generally consistent among drugs in the data analyzed. It was shared by
`drugs with varying mechanisms of action and was observed for all indications
`studied; this observation suggests that the risk applies to all antiepileptic drugs
`regardless of indication of use.
`The background incidence of suicide in patients with epilepsy is estimated as being
`higher than the incidence of suicide in the general population. Estimates of the
`incidence of suicide in patients with epilepsy vary widely, but studies have
`consistently indicated a higher incidence of suicide (and suicide attempts) in patients
`with epilepsy.
`In addition to suicidal ideation, Vimpat (lacosamide) has been associated with various
`other serious adverse effects that include a hypersensitivity syndrome that may affect
`multiple organ systems (Drug Reaction with Eosinophilia and Systemic Symptoms
`[DRESS]), cardiac conduction abnormalities (heart block), syncope, dizziness and
`ataxia.
`F. Vimpat (lacosamide) Oral Solution is not a new molecular entity. It is already approved in
`tablet form.
`
`
`In accordance with section 505-1 of FDCA and under 21 CFR 208, FDA has determined
`that a Medication Guide is required for Vimpat (lacosamide) Oral Solution. FDA has
`determined that Vimpat (lacosamide) Oral Solution poses a serious and significant public
`health concern requiring the distribution of a Medication Guide. The Medication Guide
`is necessary for patients’ safe and effective use of Vimpat (lacosamide) Oral Solution. FDA
`has determined that Vimpat (lacosamide) Oral Solution is a product for which patient
`labeling could help prevent serious adverse events. FDA has also determined that Vimpat
`(lacosamide) Oral Solution has serious risks (relative to benefits) of which patients should
`be made aware because information concerning the risks could affect patients’ decisions
`to use, or continue to use Vimpat (lacosamide) Oral Solution.
`
`The elements of the REMS will be a Medication Guide and a timetable for submission of
`assessments of the REMS.
`
`
`
`
`2
`
`

`

`Application
`Type/Number
`--------------------
`SAFETY-547
`NDA-22255
`
`Submission
`Type/Number
`--------------------
`ORIG-1
`ORIG-1
`
`Submitter Name
`
`Product Name
`
`--------------------
`NO FIRM
`SCHWARZ
`BIOSCIENCES INC
`
`------------------------------------------
`antiepileptic drugs
`VIMPAT
`
`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`SUSAN B DAUGHERTY
`01/11/2010
`
`RUSSELL G KATZ
`01/11/2010
`
`