DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
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`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
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`M E M O R A N D U M
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`DATE:
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`FROM:
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`May 6, 2008
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`Thomas P. Laughren, M.D.
`Director, Division of Psychiatry Products
`HFD-130
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`SUBJECT: Recommendation for approval actions for Abilify supplements for a 15 mg/day
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`starting dose in bipolar disorder and for Abilify supplements for adjunctive
`therapy at a 15 mg/day starting dose in bipolar disorder patients who are “partial
`
`
`non-responders” to either valproate or lithium
`
`
`TO:
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`-File NDAs 21-436/S-019 (Abilify tabs), 21-713/S-014 (oral solution), 21-729/S-
`006 (ODT), and 21-866/S-006 (IM)
`-File NDAs 21-436/S-020 (Abilify tabs), 21-713/S-015 (oral solution), 21-729/S-
`007 (ODT), and 21-866/S-007 (IM)
`-[Note: This overview should be filed with the 7-11-07 original submission of
`these supplements.]
`
`BACKGROUND
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`
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`1.0
`
`Abilify (aripiprazole) is an atypical antipsychotic (5HT2 antagonist and D2 receptor partial
`agonist) that is approved for both schizophrenia and bipolar disorder in adults (mania and mixed
`
`episodes), both acute and maintenance therapy for both, for schizophrenia and bipolar disorder
`(mania and mixed episodes) in pediatric patients, and as adjunctive treatment in patients with
`MDD who have had a partial response to available antidepressant therapy. These supplements
`provide support for:
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`• The efficacy and safety of a 15 mg/day starting dose in the treatment of bipolar disorder
`(mania and mixed episodes). [Note: Current labeling recommends a starting dose of 30
`mg/day.] The support for this new claim includes the results of 2 short-term (3-week) studies
`in this population where the starting dose was 15 mg/day, and where the dose could be
`increased to 30 mg/day as needed.
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`• The efficacy and safety of a 15 mg/day starting dose as adjunctive therapy in bipolar disorder
`patients who were “partial non-responders” to either valproate or lithium. The support for
`this new claim includes the results of a short-term (6-week) study in this population where
`the starting dose was 15 mg/day, and where the dose could be increased to 30 mg/day as
`needed.
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`• We held a preNDA meeting with the sponsor on 2-26-07.
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`1
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`CHEMISTRY
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`PHARMACOLOGY
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`BIOPHARMACEUTICS
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`2.0
`
`The only CMC issues requiring review were very minor labeling changes and environmental
`assessment. The minor labeling issues have been addressed, and the sponsor sought and was
`granted a categorical exclusion.
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`3.0
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`There were no pharm/tox review issues for consideration.
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`4.0
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`The only relevant biopharmaceutics results requiring review came from a drug-drug interaction
`study involving aripiprazole and lamotrigine. These data were submitted in a separate
`supplement but were reviewed and will be acted on as part of the review of these supplements.
`This review revealed no effect of aripiprazole on lamotrigine pharmacokinetics. OCP
`recommended a slight modification to labeling regarding these findings, and we have reached
`agreement with the sponsor on these changes.
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`5.0
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`5.1
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`5.1.1 Efficacy data for a 15 mg/day starting dose in mania
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`Our efficacy review focused on two nearly identically designed 3-week, multicenter, double-
`blind, parallel group, randomized, placebo-controlled, flexible-dose monotherapy studies in adult
`patients with bipolar disorder (mania or mixed episodes) (CN138135 and CN138162). Each
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`study had an active comparator group, lithium for study C-135 and haloperidol for study C-162.
`Thus, patients were assigned to aripiprazole, an active comparator, or placebo. Patients assigned
`to aripiprazole had a starting dose of 15 mg/day, and the dose could be increased to 30 mg/day as
`early as day 4, if needed. The primary endpoint was change from baseline to endpoint in YMRS
`total score, and the key secondary endpoint was change from baseline to endpoint in the CGI-S-
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`BP (bipolar) score. There was a 9-week active controlled phase following the initial 3 weeks of
`treatment during which patients who had been receiving placebo were switched to aripiprazole
`and patients already receiving active drug were simply continued. Data from this phase have not
`been reviewed from the standpoint of efficacy.
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`5.1.1.1 Study CN-138135
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`N=480 patients were randomized to treatment (ITT Sample: 163 to placebo, 155 to lithium, and
`154 to aripiprazole). Overall, there was about a 50% dropout rate by week 3. The mean
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`CLINICAL DATA
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`Efficacy Data
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`2
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`aripiprazole dose during the 3rd week was approximately 23 mg/day. The outcome for
`aripiprazole vs placebo was significant for both YMRS (P<0.001) and CGI-S-BP (P=0.002).
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`5.1.1.2 Study CN-138162
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`N=485 patients were randomized to treatment (ITT Sample: 152 to placebo, 161 to lithium, and
`166 to aripiprazole). Overall, there was about a 25% dropout rate by week 3. The mean
`aripiprazole dose during the 3rd week was approximately 23 mg/day. The outcome for
`aripiprazole vs placebo was significant for both YMRS (P=0.039) and CGI-S-BP (P=0.044).
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`5.1.2 Efficacy data for adjunctive therapy in bipolar disorder patients who were “partial
`non-responders” to either valproate or lithium t a 15 mg/day starting dose
`
`
`Our efficacy review focused on a 6-week, multicenter, double-blind, parallel group, randomized,
`placebo-controlled, flexible-dose, adjunctive therapy study in adult patients with bipolar disorder
`(mania or mixed episodes, with or without psychotic features) (CN138134) who were partially
`non-responsive to either lithium or valproate. Thus, patients were assigned to either adjunctive
`aripiprazole or adjunctive placebo, on a 2:1 ratio. Patients assigned to adjunctive aripiprazole
`had a starting dose of 15 mg/day, and the dose could be increased to 30 mg/day as early as day 7,
`if needed. The primary endpoint was change from baseline to endpoint in YMRS total score,
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`and the key secondary endpoint was change from baseline to endpoint in the CGI-S-BP (bipolar)
`score. N=384 patients were randomized to treatment (ITT Sample: 130 to placebo and 247 to
`aripiprazole). Overall, about 81% of patients completed the study. The outcome for aripiprazole
`vs placebo was significant for both YMRS (P=0.002) and CGI-S-BP (P=0.014).
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`5.1.3 Summary of Efficacy
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`There was unanimous agreement within the review team on the positive outcomes for the
`primary and key secondary endpoints in these studies. I agree.
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`5.2
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`The safety data for the monotherapy supplements were derived from a total of n=917 bipolar
`patients exposed to treatment with aripiprazole monotherapy. This was a database that combined
`aripiprazole exposures from this program and the previous monotherapy studies of aripiprazole
`in bipolar disorder. Overall, the adverse event profile for aripiprazole when used as
`monotherapy in bipolar disorder was similar to that seen when it has been used in other
`disorders.
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`The safety data for the adjunctive therapy supplements were derived primarily from study 134.
`Overall, the adverse event profile for aripiprazole when used as adjunctive treatment in bipolar
`disorder was similar to that seen when it has been used in other disorders. There was a
`suggestion that the combination of aripiprazole and lithium was associated with a somewhat
`higher
`incidence of akathisia
`than was seen with aripiprazole alone or with
`the
`aripiprazole/valproate combination.
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`Safety Data
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`3
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`Clinical Sections of Labeling
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`5.3
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`We made several modifications to the sponsor’s proposed labeling, and have now reached
`agreement on final labeling.
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`6.0 WORLD LITERATURE
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`The sponsor warranted that they conducted an extensive literature review and found no relevant
`papers that would adversely affect conclusions about the safety of aripiprazole for the proposed
`use.
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`7.0
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`Inspections were conducted at 2 sites, i.e., 1 for study 162 from the 15 mg/day starting dose
`program and 1 for study 134 from the adjunctive therapy program. Data from the study 162 site
`were deemed to be acceptable. However, data from 6 patients from the study 134 site were
`deemed to be unreliable. A re-analysis of the data for study 134 was still positive, even without
`the data from this unreliable site.
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`8.0
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`We decided to waive the requirement for pediatric studies with a starting dose of 15 mg/day,
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`because the recommended pediatric starting dose is 2 mg/day, and the target dose is 10 mg/day.
`Regarding pediatric studies for adjunctive therapy, it is our judgment that it is reasonable to
`extrapolate from the adult adjunctive studies to pediatric patients. Thus, we have not requested
`pediatric adjunctive studies. Given our current views on extrapolation from adult studies, we
`have also extrapolated from the adult schizophrenia and bipolar studies (i.e., positive acute
`studies in adults and pediatric patients, and positive maintenance studies in adults) to
`maintenance therapy in pediatric patients with these conditions, resulting in our judgment that
`this product is entitled to maintenance claims for both conditions in the pediatric population.
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`9.0
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`We have included the mutually agreed upon final label with the approval letter.
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`LABELING AND APPROVAL LETTER
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`DSI INSPECTIONS
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`PREA REQUIREMENTS
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`10.0 CONCLUSIONS AND RECOMMENDATIONS
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`I believe that Otsuka has submitted sufficient data to support the conclusion that aripiprazole is
`effective and acceptably safe as monotherapy with a starting dose of 15 mg/day in the treatment
`of patients with bipolar disorder (manic or mixed episodes) and as adjunctive therapy (i.e., added
`on to either lithium or valproate) with a starting dose of 15 mg/day in the treatment of patients
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`4
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`with bipolar disorder (manic or mixed episodes). We have now reached agreement with the
`sponsor on final labeling, and we will issue the attached approval letter along with agreed upon
`final labeling.
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`cc:
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`Orig NDAs 21-436/S-019 (Abilify tabs), 21-713/S-014 (oral solution), 21-729/S-006 (ODT), and
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`21-866/S-006 (IM)
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`Orig NDAs 21-436/S-020 (Abilify tabs), 21-713/S-015 (oral solution), 21-729/S-007 (ODT), and
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`21-866/S-007 (IM)
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`HFD-130/TLaughren/MMathis/GZornberg/KBrugge/DBates
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`DOC: Aripiprazole_15 mg Start Dose_ Adjunctive Therapy_Bipolar_Laughren_AP_Memo.doc
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`5
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`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
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`/s/
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`---------------------
`Thomas Laughren
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`5/6/2008 09:00:03 AM
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`MEDICAL OFFICER
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`