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`DEPARTMENT OF HEALTH & HUMAN SERVICES
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`Public Health Service
`Food and Drug Administration
`Rockville, MD 20857
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`NDA 18-936/S-071/S-073
`NDA 20-101/S-032
`NDA 20-974/S-005
`NDA 21-235/S-003
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`Eli Lilly and Company
`Attention: Gregory T. Brophy, Ph.D.
`Director, U.S. Regulatory Affairs
`Lilly Corporate Center
`Indianapolis, IN 46285-2643
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`Dear Dr. Brophy:
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`Please refer to your supplemental new drug applications dated September 2, 2004, and December 14,
`2004, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act for Prozac and
`Sarafem (fluoxetine hydrochloride) pulvules (NDA 18-936), Prozac solution (NDA 20-101), Prozac
`tablets (NDA 20-974), and Prozac Delayed-Release Capsules (NDA 21-235).
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`We acknowledge receipt of your submission dated May 31, 2005.
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`Your submission of May 31, 2005 constituted a complete response to our May 12, 2005 action letter.
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`Reference is also made to an e-mail from CAPT Paul A. David of this Agency to Dr. Barbara Arning,
`of Eli Lilly, dated August 31, 2005, requesting that you agree to revise the labeling.
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`We additionally refer to Dr. Arning’s e-mail dated November 3, 2005, accepting the agreed upon
`labeling (as noted below).
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`These supplements, submitted as “Changes Being Effected” applications, provide for revisions to the
`labeling
`to
`incorporate
`the results of your
`juvenile animal
`toxicology studies under
`the
`CARCINOGENESIS, MUTAGENESIS,
`IMPAIRMENT
`of FERTILITY, ANIMAL
`TOXICOLOGY, and Pediatric Use sections as well as minor editorial changes.
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`We completed our review of these application, as amended. These applications are approved, effective
`on the date of this letter, for use as recommended in the agreed-upon labeling text.
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`NDAs 18-936/S-071/S-073, 20-101/S-032, 20-974/S-005, & 21-235/S-003
`Page 2
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`We note your agreement to add the following language at the end of the PRECAUTIONS-Pediatric
`Use section as follows:
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`PRECAUTIONS-Pediatric Use
`Significant toxicity, including myotoxicity, long-term neurobehavioral and reproductive toxicity,
`and impaired bone development, has been observed following exposure of juvenile animals to
`fluoxetine. Some of these effects occurred at clinically relevant exposures.
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`In a study in which fluoxetine (3, 10, or 30 mg/kg) was orally administered to young rats from
`weaning (Postnatal Day 21) through adulthood (Day 90), male and female sexual development
`was delayed at all doses, and growth (body weight gain, femur length) was decreased during the
`dosing period in animals receiving the highest dose. At the end of the treatment period, serum
`levels of creatine kinase (marker of muscle damage) were increased at the intermediate and high
`doses, and abnormal muscle and reproductive organ histopathology (skeletal muscle degeneration
`and necrosis, testicular degeneration and necrosis, epididymal vacuolation and hypospermia) was
`observed at the high dose. When animals were evaluated after a recovery period (up to 11 weeks
`after cessation of dosing), neurobehavioral abnormalities (decreased reactivity at all doses and
`learning deficit at the high dose) and reproductive functional impairment (decreased mating at all
`doses and impaired fertility at the high dose) were seen; in addition, testicular and epididymal
`microscopic lesions and decreased sperm concentrations were found in the high dose group,
`indicating that the reproductive organ effects seen at the end of treatment were irreversible. The
`reversibility of fluoxetine-induced muscle damage was not assessed. Adverse effects similar to
`those observed in rats treated with fluoxetine during the juvenile period have not been reported
`after administration of fluoxetine to adult animals. Plasma exposures (AUC) to fluoxetine in
`juvenile rats receiving the low, intermediate, and high dose in this study were approximately 0.1 -
`0.2, 1 - 2, and 5 - 10 times, respectively, the average exposure in pediatric patients receiving the
`maximum recommended dose (MRD) of 20 mg/day. Rat exposures to the major metabolite,
`norfluoxetine, were approximately 0.3 - 0.8, 1 - 8, and 3 - 20 times, respectively, pediatric
`exposure at the MRD.
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`A specific effect of fluoxetine on bone development has been reported in mice treated with
`fluoxetine during the juvenile period. When mice were treated with fluoxetine (5 or 20 mg/kg,
`intraperitoneal) for 4 weeks starting at 4 weeks of age, bone formation was reduced resulting in
`decreased bone mineral content and density. These doses did not affect overall growth (body
`weight gain or femoral length). The doses administered to juvenile mice in this study are
`approximately 0.5 and 2 times the MRD for pediatric patients on a body surface area (mg/m2)
`basis.
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`In another mouse study, administration of fluoxetine (10 mg/kg intraperitoneal) during early
`postnatal development (Postnatal Days 4 to 21) produced abnormal emotional behaviors
`(decreased exploratory behavior in elevated plus-maze, increased shock avoidance latency) in
`adulthood (12 weeks of age). The dose used in this study is approximately equal to the pediatric
`MRD on a mg/m2 basis. Because of the early dosing period in this study, the significance of these
`findings to the approved pediatric use in humans is uncertain.
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`Additionally, and as communicated in our May 12, 2005 letter, we concur with your proposed
`revisions to the CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT of FERTILITY section.
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`NDAs 18-936/S-071/S-073, 20-101/S-032, 20-974/S-005, & 21-235/S-003
`Page 3
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`The final printed labeling (FPL) must be identical to the labeling above.
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`Please submit an electronic version of the FPL according to the guidance for industry titled Providing
`Regulatory Submissions in Electronic Format - NDA. Alternatively, you may submit 20 paper copies
`of the FPL as soon as it is available but no more than 30 days after it is printed. Individually mount 15
`of the copies on heavy-weight paper or similar material. For administrative purposes, designate these
`submissions "FPL for approved supplements 18-936/S-071/S-073, 20-101/S-032, 20-974/S-005, & 21-
`235/S-003”. Approval of these submissions by FDA is not required before the labeling is used.
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`If you issue a letter communicating important information about this drug product (i.e., a “Dear Health
`Care Professional” letter), we request that you submit a copy of the letter to this NDA and a copy to
`the following address:
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`We remind you that you must comply with reporting requirements for an approved NDA (21 CFR
`314.80 and 314.81).
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`If you have any questions, call Paul David, R.Ph., Chief Project Management Staff, at (301) 796-1058.
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`MEDWATCH, HFD-410
`FDA
`5600 Fishers Lane
`Rockville, MD 20857
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`Sincerely,
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`{See appended electronic signature page}
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`Thomas Laughren, M.D.
`Director
`Division of Psychiatry Products
`Office of Drug Evaluation I
`Center for Drug Evaluation and Research
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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
`12/1/2005 03:34:44 PM
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