CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`'
`
`21-729
`
`PHARMACOLOGY REVIEW
`
`

`

`PHARMACOLOGY/TOXICOLOGY MEMORANDUM
`
`NDA number: 21729
`
`Sequence number/date/type of submission: 000/ December 22, 2003 (NDA electronic
`submission)
`Information to sponsor: No
`
`Sponsor and/or agent:
`Otsuka America Pharmaceutical, Inc.
`. 2440 Research Boulevard, Rockville, MD 20850
`Phone (30]) 497-0900
`Fax (301) 990—0036
`Manufacturer for drug substance:
`Otsuka Pharmaceutical Co., Ltd
`2-9 Kanda Tsukasa—cho, Chiyoda-ku Tokyo, 101-8535, Japan
`
`Reviewer name: Sonia Tabacova, Ph.D.
`Division name: Neuropharmacological Drug Products, HFD #: 120
`Review completion date: September 27, 2004
`
`Drug:
`
`Trade name: ABILIFY
`
`Generic name (list alphabetically): Aripiprazole
`Code name: CFC—14597, EMS-337039
`'
`Chemical name: 7-[4-[4-(2, 3-dic/7lor0phenyl)—1-piperazinyl]but0xy]-3,4—dihydr0-2(]H)-
`quinolinone
`I
`7
`CAS registry number: 129—22-12-9
`
`Relevant INDs/ND'As/DMFS: IND 62 181; NDA No. 21 436
`
`Drug class: Psychotropic (partial D2 and SHTIA agonist, 5HT2 antagonist)
`Indication: Treatment of schizophrenia
`
`Clinical formulation: Oral Disintegrating Tablet 4 ,- 10 mg, 15 mg, 20 mg and 30 mg)
`
`Summary of Nonclinical Findings: No new pharmacology/toxicology studies were submitted with
`this application. One (previously submitted) preclinical study [a PK study in monkeys, entitled
`“Phannacokinetics of Various Formulations of EMS-337039 (aripiprazole) in Male Cynomolgus
`Monkeys” (Study MAP024; Protocol # 178/337039/004 and 178/337039/004A)] was reviCWed
`under NDA 21 713 (S. Tabacova, Pharmacology/Toxicology Review of 9/21/2004).
`
`Nonclinical Safety Issues Relevant to Clinical Use: Compatibility data are not provided for one of
`the excipients (aspartame) in order to demonstrate that no potentially toxic adducts are formed by
`interaction with the other ingredients of the formulation.
`Note: Aspartame and crospovidone are major excipients in this formulation.
`Aspartame is considered a direct food additive by FDA, and has been commonly used since its introduction
`1981 as a low—calorie sweetener under the brand names of NutraSweet or Equal. FDA has determined that
`aspartame is safe for use in foods, and supporting information from recent National Toxicology Program
`(NTP) toxicological studies is published at the NTP site.
`Crospovidone is a synthetic insoluble but rapidly swellable homopolymer of N—vinyl-Z—pyrrholidone which
`is used as absorbent in the formulation of delivery systems; according to ISP data, it is chemically inert, not
`
`

`

`absorbed through the gastrointestinal tract, and of extremely low — if any — toxicity (e.g., LD50 (rat) >100
`000 mg/kg). As shown in the CDER Inactive Ingredient Search database for Approved Drug Products,
`crospovidone has been used as an inactive ingredient in many approved drug products [up to a maximal
`daily oral amount of over 30 times the amount of crospovidone (21 mg) in the max. daily dose of
`Aripiprazole ODT (30 mg)].
`Therefore, neither aspartame, nor crospovidone are of toxicological concern, provided compatibility data
`showing that no potentially toxic adducts are formed by interaction of aspartame with the other components
`(compatibility data for crospovidone are provided by the sponsor).
`
`Recommendations
`
`A. Recommendation on Approvability: Approvable
`
`B. Recommendation for Nonclinical Studies: None
`
`Recommendations on Labeling: None
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Sonia Tabacova
`
`10/12/04 04 12 07 PM
`PHARMACOLOGIST
`
`This is the revised memo'(lO/12/O4)
`
`Lois Freed
`
`10/13/04 07:07:40 AM
`PHARMACOLOGIST
`
`