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`CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
`022036Orig1s000
`
`OTHER REVIEW(S)
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`
`Department of Health and Human Services
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Surveillance and Epidemiology
`
`
`
`Date:
`
`To:
`
`Thru:
`
`From:
`
`Subject:
`
`Drug Name:
`
`March 8, 2010
`
`Russell Katz, MD, Director
`Division of Neurology Products
`
`Melina Griffis, R.Ph, Team Leader
`Denise Toyer, PharmD, Deputy Director
`Division of Medication Error Prevention and Analysis
`
`Lubna Najam, M.S., PharmD, Safety Evaluator
`Division of Medication Error Prevention and Analysis
`Label and Labeling Review
`
`Silenor (Doxepin Tablets)
`3 mg, and 6 mg
`Application Type/Number: NDA 022036
`Applicant:
`Somaxon Pharmaceuticals, Inc.
`OSE RCM #:
`2008-1836
`
`
`
`

`

`
`
`Contents
`
`INTRODUCTION........................................................................................................................... 3
`1 METHODS AND MATERIALS REVIEWED ...................................................................... 3
`2 CONCLUSION AND RECOMMENDATIONS .................................................................... 3
`2.1
`Comments to the Applicant............................................................................................ 3
`APPENDICES................................................................................................................................. 5
`
`2
`
`

`

`
`
`INTRODUCTION
`The Division of Medication Error Prevention and Analysis (DMEPA) completed a labeling
`review for Silenor (OSE RCM #2008-96) on October 23, 2008 in which we made
`recommendations regarding the proposed container labels and carton labeling. The Applicant
`submitted their revisions dated December 15, 2008 addressing DMEPA’s requested changes
`which were found to be acceptable (OSE RCM #2008-1836) on January 13, 2009. Subsequently,
`the applicant has submitted revised carton labeling, container and blister pack labels in addition to
`new physician sample pack.
`
`1 METHODS AND MATERIAL REVIEWED
`In a submission dated February 25, 2010, the applicant has submitted revised container labels and
`carton labeling to incorporate the required medication guide statement. In addition this
`submission contained new physician sample pack labels, which were not previously reviewed by
`DMEPA. Our review of the container labels and trade blister pack labels and carton labeling was
`limited to the evaluation of the medication guide statement since these labels and labeling were
`previously found to be acceptable (OSE RCM #2008-1836) on January 13, 2009. However the
`physician sample blister pack label and labeling was fully evaluated since they were not
`previously reviewed by DMEPA. Using Failure Mode and Effects Analysis (FMEA),1 we
`evaluated the blister physician sample pack label and labeling. See Appendices A through C for
`pictures of the labels and labeling.
`• Commercial Bottle Labels (3 mg, 6 mg)
`• Trade Pack Blister Card Label and Carton Labeling
`• Physician Sample Blister Card Label and Carton Labeling (4 and 7 count samples)
`
`2 CONCLUSIONS AND RECOMMENDATIONS
`We provide recommendations in Section 2.1 and request they be communicated to the Applicant
`prior to approval.
`Please copy the Division of Medication Error Prevention and Analysis on any communication to
`the Applicant with regard to this review. If you have further questions or need clarifications on
`this review, please contact the OSE Regulatory Project Manager, Laurie Kelley at 301-796-5068.
`
`2.1 COMMENTS TO THE APPLICANT
`A. General Comment (all labels)
`In accordance with 21 CFR 201.10 (g)(2), ensure that the established name is printed in
`letters that are at least half as large as the letters comprising the proprietary name or
`designation with which it is joined, and the established name shall have a prominence
`commensurate with the prominence with which such proprietary name or designation
`appears, taking into account all pertinent factors, including typography, layout, contrast,
`and other printing features.
`
`
`
`
`1 Institute for Healthcare Improvement (IHI). Failure Modes and Effects Analysis. Boston. IHI:2004.
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`B. Bottle Container Label (3 mg and 6 mg)- 30, 100 and 500 tablet containers
`1. The medication guide statement is currently displayed
` and is difficult to
`identify and read. In accordance with 21 CFR 208.24 (2)(d) the medication guide
`statement should appear in a prominent and conspicuous manner on the label. Relocate the
`medication guide statement to the principal display panel on the label. This statement
`should not intervene with other pertinent information, e.g. strength, established name and
`proprietary name and should also not decrease the prominence of this information.
`2. Please ensure that sufficient numbers of Medication Guides are provided with the product
`such that a dispenser can provide one Medication Guide with each new or refilled
`prescription.
`C. Physician Sample Blister Carton Labeling (3 mg and 6 mg) 4 and 7 count samples
`In several instances the proprietary and established names are displayed without the
`strength presentation or vice versa. Revise these labels to ensure that the product strength
`appears in conjunction with the proprietary and established names.
`D. Physician Sample Blister Pack Label (3 mg and 6 mg) 4 and 7 count samples
`Increase the font size of the statement “Each tablet contains the equivalent of 3 mg
`doxepin” present on both the 3 mg and 6 mg blister card label to increase its prominence.
`
`
`
`4
`
`13 pp of Draft Labeling have been withheld in full as b4 (CCI/TS)
`immediately following this page.
`
`(b) (4)
`
`

`

`Application
`Type/Number
`--------------------
`NDA-22036
`
`Submission
`Type/Number
`--------------------
`ORIG-1
`
`Submitter Name
`
`Product Name
`
`--------------------
`SOMAXON
`PHARMACEUTICA
`LS INC
`
`------------------------------------------
`SILENOR (DOXEPIN HCL)
`
`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`LUBNA NAJAM
`03/09/2010
`
`MELINA N GRIFFIS
`03/09/2010
`
`DENISE P TOYER
`03/09/2010
`
`

`

`Department of Health and Human Services
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Surveillance and Epidemiology
`
`November 9, 2009
`Russell Katz, MD, Director
`Division of Neurology Products (DNP)
`Mary Willy, PhD, Deputy Division Director
`Division of Risk Management (DRISK)
`Sharon R. Mills, BSN, RN, CCRP
`Senior Patient Labeling Reviewer, Acting Team Leader
`Division of Risk Management (DRISK)
`
`Melissa Hulett, MSBA, BSN, RN
`Patient Labeling Reviewer
`Division of Risk Management
`DRISK Review of Patient Labeling (Medication Guide)
`SILENOR (doxepin hydrochloride) tablets
`NDA 22-036
`
`Somaxon Pharmaceuticals, Inc.
`2008-1663
`
`
`
`Date:
`To:
`
`Through:
`
`From:
`
`Subject:
`Drug Name(s):
`Application
`Type/Number:
`Applicant/sponsor:
`OSE RCM #:
`
`
`

`

`1
`
`INTRODUCTION
`Somaxon Pharmaceuticals, Inc. originally submitted a 505 (b) (2) New Drug
`Application (NDA), NDA 22-036, for SILENOR (doxepin hydrochloride) tablets, on
`January 31, 2008. The NDA was reviewed by the Division of Neurology Products
`(DNP) and it was determined that the application could not be approved in the
`present form. The Agency issued a Complete Response letter outlining the
`deficiencies in the application on February 25, 2009. The Applicant submitted a
`Complete Response to the Agency’s Complete Response letter for SILENOR
`(doxepin hydrochloride) tablets on June 4, 2009. SILENOR (doxepin hydrochloride)
`tablets are indicated for the treatment of insomnia as demonstrated by improvement
`in sleep maintenance and the
` The active
`ingredient in SILENOR is doxepin hydrochloride, the same active ingredient in
`Sinequan and multiple generic antidepressant drug products. Sinequan and the
`multiple generic products currently carry the single issue antidepressant Medication
`Guide (MG) which addresses suicidality. Since SILENOR (doxepin hydrochloride)
`tablets acts as a sedative-hypnotic when dosed according to the PI, DNP proposes
`a comprehensive MG for the product which includes language related to suicidality,
`as well as complex behaviors and other product specific information.
`This review is written in response to a request by the Division of Neurology
`Products (DNP) for the Division of Risk Management (DRISK) to review the
`Applicant’s proposed MG for SILENOR (doxepin hydrochloride) tablets.
`Please let us know if DNP would like a meeting to discuss this review or any of our
`changes prior to sending to the Applicant. The proposed REMS is being reviewed
`by DRISK and will be provided to DNP under separate cover.
`
` 2
`
` MATERIAL REVIEWED
`(cid:131) Draft SILENOR (doxepin hydrochloride) Prescribing Information (PI) submitted
`June 4, 2009 and revised by the Review Division throughout the current review
`cycle.
`(cid:131) Draft SILENOR (doxepin hydrochloride) Medication Guide (MG) submitted on
`June 4, 2009 and revised by the review division throughout the review cycle.
`
` 3
`
` RESULTS OF REVIEW
`In our review of the MG, we have:
`simplified wording and clarified concepts where possible
`•
`•
`ensured that the MG is consistent with the PI
`•
`removed unnecessary or redundant information
`•
`ensured that the MG meets the Regulations as specified in 21 CFR 208.20
`•
`ensured that the MG meets the criteria as specified in FDA’s Guidance for
`Useful Written Consumer Medication Information (published July 2006)
`
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`1
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`(b) (4)
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`

`

`Our annotated MG is appended to this memo. Any additional revisions to the PI
`should be reflected in the MG.
`
`
`Please let us know if you have any questions.
`
`
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`
`2
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`

`

`Application
`Type/Number
`--------------------
`NDA-22036
`
`Submission
`Type/Number
`--------------------
`ORIG-1
`
`Submitter Name
`
`Product Name
`
`--------------------
`SOMAXON
`PHARMACEUTICA
`LS INC
`
`------------------------------------------
`SILENOR (DOXEPIN HCL)
`
`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`MELISSA I HULETT
`11/09/2009
`
`MARY E WILLY
`11/09/2009
`I concur
`
`

`

`Department of Health and Human Services
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Surveillance and Epidemiology
`
`
`
`Date:
`To:
`
`Thru:
`
`January 13, 2009
`Russell Katz, MD, Director
`Division of Neurology Products
`Kellie Taylor, PharmD, MPH, Team Leader
`Denise Toyer, PharmD, Deputy Director
`Carol Holquist, RPh, Director
`Division of Medication Error Prevention and Analysis
`Jinhee J. Lee, PharmD, Safety Evaluator
`Division of Medication Error Prevention and Analysis
`Label and Labeling Review
`Silenor (Doxepin Tablets)
`1 mg, 3 mg, and 6 mg
`Application Type/Number: NDA 22-036
`Applicant:
`Somaxon Pharmaceuticals, Inc.
`OSE RCM #:
`2008-1836
`
`From:
`
`Subject:
`Drug Name:
`
`

`

`1
`INTRODUCTION
`The Division of Medication Error Prevention and Analysis (DMEPA) completed a labeling
`review for Silenor (OSE RCM #2008-96) on October 23, 2008 in which we made various
`recommendations regarding the proposed container labels and carton labeling. On December 5,
`2008, DMEPA thereafter had an informal teleconference with the Applicant in which our
`label/labeling recommendations were conveyed. Subsequently, the Applicant submitted their
`revisions dated December 15, 2008 addressing DMEPA’s requested changes.
`
`2 MATERIAL REVIEWED
`DMEPA reviewed our initial labeling review for Silenor on October 23, 2008 in OSE RCM
`#2008-963 and we also reviewed the revised labels submitted by the Applicant dated December
`15, 2008. See Appendices A through C for pictures of the labels and labeling.
`• Commercial Container Labels (1 mg, 3 mg, 6 mg)
`• Commercial Blister Carton Labeling
`• Sample Blister Carton Labeling (4 and 7 count samples)
`
`3 DISCUSSION
`The Applicant has changed the container labels and carton labeling according to our
`recommendations and we have no further comments.
`
`4 CONCLUSIONS AND RECOMMENDATIONS
`The Applicant has satisfactorily revised the labels and labeling per our August 2008 request.
`If you have further questions or need clarifications, please contact Daniel Brounstein, OSE
`Project Manager, at 301-796-0674.
`
`
`
`
`
`1
`
`14 pp of Draft Labeling have been Withheld in Full as b4 (CCI/TS)
`immediately following this page.
`
`

`

`---------------------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`---------------------------------------------------------------------------------------------------------------------
` /s/
`---------------------
`Jinhee Lee
`1/13/2009 02:02:55 PM
`DRUG SAFETY OFFICE REVIEWER
`
`Kellie Taylor
`1/21/2009 03:34:18 PM
`DRUG SAFETY OFFICE REVIEWER
`
`Denise Toyer
`1/22/2009 06:43:32 AM
`DRUG SAFETY OFFICE REVIEWER
`
`Carol Holquist
`1/22/2009 09:06:37 AM
`DRUG SAFETY OFFICE REVIEWER
`
`

`

`M E M O R A N D U M
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`CONTROLLED SUBSTANCE STAFF
`
`November 12, 2008
`
`Russell Katz, M.D., Director
`Division of Neurology Products
`
`
`Date:
`
`To:
`
`
`
`
`Through: Michael Klein, Ph.D., Director
`
`
`Controlled Substance Staff (CSS)
`
`From:
`
`
`
`
`Subject:
`
`Katherine Bonson, Ph.D., Pharmacologist
`Controlled Substance Staff (CSS)
`
`
`
`Evaluation of Abuse Potential of Doxepin (Silenor)
`Labeling Recommendations
`NDA 22-036
`Indication: Treatment of Insomnia (1, 3 and 6 mg/day)
`Sponsor: Somaxon Pharmaceuticals, Inc.
`
`
`Materials Reviewed:
`
`CSS has reviewed abuse potential-related sections of the NDA for doxepin, references
`available in the medical and scientific literature, and data in the Drug Abuse Warning
`Network (DAWN) Live! epidemiological database for this consult.
`
`Background:
`
`This consult responds to a request by the Division of Neurology Products for an abuse
`potential assessment of doxepin (NDA 22-036), to help determine appropriate labeling of
`the drug and to assess whether the drug should be recommended for scheduling.
`
`Doxepin is proposed for the treatment of insomnia at an oral daily dose of 1, 3 or 6 mg,
`under the tradename Silenor. The mechanism of action of doxepin is primarily as an
`antagonist at H1 histamine receptors, but it also has activity as an inhibitor of the
`serotonin and norepinephrine transporters, as an antagonist at serotonin 5-HT2A and 5-
`HT2C, and as an antagonist at acetylcholine muscarinic receptors. Doxepin is currently
`marketed in the U.S. as a nonscheduled drug for the treatment of depression (Sinequan,
`75 mg tablets) and for the treatment of pruritis secondary to eczematous dermatoses
`(Zonalon, 5% cream). The Sponsor proposes that doxepin not be scheduled under the
`Controlled Substances Act.
`
`
`

`

`CSS Consult on Doxepin (Silenor)
`NDA 22-036
`
`In November 2005, the Sponsor submitted a 14-page “position paper” to CSS regarding
`the abuse potential of doxepin, accompanied by the drug label for Sinequan. In this
`document, the Sponsor provided arguments supporting their conclusion that doxepin is
`not a drug of abuse. Subsequently, in a pre-NDA meeting in May 2006, the Sponsor was
`informed that, “The information submitted by the Sponsor [in the position paper]
`regarding abuse liability is acceptable. CSS concurs with the Sponsor’s conclusions that
`low-dose doxepin has minimal abuse potential and that Silenor tablets should not be
`scheduled. Further testing regarding abuse liability potential (sic) for this NDA is
`unnecessary.”
`
`Conclusion:
`
`CSS has evaluated the abuse-related data submitted in the NDA and reiterates our
`previous conclusion that doxepin does not have abuse potential and should not be
`recommended for scheduling.
`
`Drug Label Recommendations:
`
`1) The label text proposed by the Sponsor for Section 9.0 should be changed. CSS
`proposes the following text:
`
`
`9.0 Drug Abuse and Dependence
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`9.1 Controlled Substance Class
`
`Doxepin is not a controlled substance.
`
`9.2 Abuse
`
`
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`
`
`Doxepin is not associated with abuse potential in animals or in humans.
`Physicians should carefully evaluate patients for history of drug abuse and
`follow such patients closely, observing them for signs of misuse or abuse
`of doxepin (e.g., incrementation of dose, drug-seeking behavior).
`
`9.3 Dependence
`
`In a brief assessment of adverse events observed during discontinuation of
`doxepin following chronic administration, no symptoms indicative of a
`withdrawal syndrome were observed. Thus, doxepin does not appear to
`produce physical dependence.
`
`2
`
`(b) (4)
`
`

`

`CSS Consult on Doxepin (Silenor)
`NDA 22-036
`
`APPENDIX
`
`Summary of Preclinical and Clinical Information Submitted Related to the
`Abuse Potential Assessment of Doxepin
`
`This section provides summaries of the abuse potential-related information on doxepin
`submitted in NDA 22-036, followed by a discussion of the submitted material.
`
`I. Summary of Information Related to Abuse Potential from Preclinical Studies
`
`The Sponsor did not conduct any abuse-related preclinical studies with doxepin. Thus,
`no primary data were submitted from receptor binding studies or animal behavioral
`studies (including drug discrimination or self-administration) that are useful in the
`assessment of abuse potential. Additionally, no primary data were submitted regarding
`the preclinical evaluation of physical dependence with doxepin.
`
`Instead, the Sponsor conducted a search of papers published in the scientific and medical
`literature reporting on preclinical studies related to doxepin. This search produced a list
`of studies related to receptor binding and functionality, second messenger systems, pain
`response and safety pharmacology. Of these, only the receptor binding studies contain
`relevant information to the assessment of abuse potential. These published studies are
`summarized below (references cited below are provided as complete papers in the NDA).
`
`Doxepin has very high affinity (0.3 nM in human brain tissue; Kanba and Richelson,
`1984) for the H1 histamine receptor, where it acts as an antagonist. It also has relatively
`high affinity for the 5-HT2A receptor (26 nM in rodent cell line; Palvimaki et al., 1996)
`the 5-HT2C receptor (72 nM in porcine brain tissue; Jenck et al., 1994) and the
`acetylcholine muscarinic receptor (23 nM; Cusack et al., 1994) and acts as an antagonist
`at all three receptors. It has only moderate-to-low affinity for the dopamine D2 receptor
`(360 to 2400 nM in human brain tissue; Cusack et al., 1994 and Richelson and Nelson,
`1984), where it may act as a weak agonist or antagonist. Doxepin also acts an inhibitor
`of two monoamine transporters, the serotonin transporter (68 nM in human cell line;
`Tatsumi et al., 1997) and norepinephrine transporter (30 nM in human cell line; Tatsumi
`et al., 1997). However, doxepin shows no affinity for the dopamine transporter (>5700
`nM; Richelson and Pfenning, 1984), GABA transporter (>31,000 nM; Nakashita et al.,
`1997), benzodiazepine receptors (>1000 nM; Heal et al., 1992) or opioid receptors
`(>10,000 nM; Wong et al., 1983).
`
`CSS conducted an independent literature search on preclinical studies with doxepin
`related to abuse potential. The binding studies reported by the Sponsor in the NDA
`correctly represent the studies reported in the medical and scientific literature. No papers
`are listed in PubMed that report on self-administration studies with doxepin. There is one
`paper reporting on a drug discrimination study conducted with doxepin in pigeons (Zhang
`and Barrett, 1991). In this study, doxepin produced generalization to the cue produced by
`the tricyclic antidepressant imipramine, demonstrating that doxepin has similarity to
`another drug with serotonin-norepinephrine reuptake inhibitor (SNRI) properties.
`
`
`
`3
`
`

`

`CSS Consult on Doxepin (Silenor)
`NDA 22-036
`
`However, no drug discrimination studies evaluating the similarity between doxepin and
`known drugs of abuse have been published.
`
`In conclusion, there is very limited information provided in the NDA and identified in the
`scientific and medical literature related to the assessment of doxepin’s abuse potential.
`However, based on the receptor binding studies and a single drug discrimination study,
`there is no suggestion that doxepin has similarity to known drugs of abuse.
`
`II. Summary of Information Related to Abuse Potential from Clinical Studies
`
`The Sponsor did not conduct any abuse-related clinical studies with doxepin. Thus, the
`only available information submitted in relation to the human abuse potential of doxepin
`is the adverse events (AE) profile observed during clinical efficacy studies. Additionally,
`the Sponsor conducted a brief evaluation of withdrawal following discontinuation of
`doxepin after 35 days of administration.
`
`Clinical Efficacy Studies with Doxepin in Patients with Insomnia
`
`During Phase 3 clinical efficacy studies, a total of 437 patients with insomnia received
`doxepin at doses of 1, 3 or 6 mg/day. As expected from a drug being developed for the
`treatment of insomnia, the most frequent CNS-related AE was somnolence (5.5%). All
`other psychiatric and neurological AEs had an incidence of less than 2%. Thus, no AEs
`related to abuse potential, including euphoria, were observed during administration of
`doxepin at doses of 6 mg/day or less.
`
`Assessment of Withdrawal Following Doxepin Discontinuation
`
`The Sponsor conducted a study in which withdrawal signs and symptoms were assessed
`following a 35-day administration of doxepin at 3 and 6 mg/day to patients with
`insomnia. On Days 36 and 37 of the study, patients received placebo instead of doxepin
`and were monitored for rebound insomnia (using ECG recordings and Wake After Sleep
`Onset (WASO) assessments) and for withdrawal (using Tyler’s Symptom Checklist,
`which was formerly known as the Benzodiazepine Withdrawal Symptom Questionnaire).
`Additionally, AEs reported during this two-day period were also monitored.
`
`During the two-day drug discontinuation period, a total of 4 subjects of 73 (5%) who
`received the 6 mg/day dose of doxepin experienced intermittent gastrointestinal distress,
`including nausea and vomiting. The investigator determined that only 2 of these patients
`(2.5%) had the AE that was directly related to doxepin. In the group of patients who
`received the 3 mg/day dose of doxepin, 2 of 75 (3%) experienced an increase in glucose
`levels and 1 of 75 (1%) experienced a headache upon drug discontinuation. In the
`placebo group, 1 patient of 73 (1%) experienced gastrointestinal distress, and 2 of 73
`(3%) experienced headache.
`
`Data from Tyler’s Symptom Checklist show that none of the patients in any of the
`treatment groups experienced benzodiazepine-like withdrawal AEs upon doxepin
`
`
`
`4
`
`

`

`CSS Consult on Doxepin (Silenor)
`NDA 22-036
`
`discontinuation. However, rebound insomnia (defined as a change from baseline of
`greater than 35 minutes) was observed in patients in all three treatment groups on the first
`night after drug discontinuation, with an incidence of 10% in 6 mg doxepin group, 15%
`in 3 mg doxepin group and 9% in placebo group.
`
`Overall, the reports of AEs experienced during the discontinuation phase following
`chronic doxepin administration do not suggest that doxepin produces a withdrawal
`syndrome. Thus, doxepin does not appear to produce physical dependence.
`
`
`III. Summary of Epidemiological Information Related to Abuse Potential
`
`The Sponsor did not submit any information from epidemiological databases. However,
`CSS conducted an independent review of data in the Drug Abuse Warning Network
`(DAWN), a public health surveillance system sponsored by the Substance Abuse and
`Mental Health Services Administration (SAMHSA) that monitors drug-related visits to
`hospital emergency departments (EDs) to track the impact of drug use, misuse and abuse
`in the U.S. When a DAWN analysis was conducted for doxepin, the number of ED
`episodes for case types related to abuse potential was below the cut-off for validity
`because of variability in the reporting system. Thus, the DAWN data do not support the
`contention that doxepin is associated with adverse events related to abuse potential that
`necessitate emergency medical care.
`
`
`
`
`5
`
`

`

`---------------------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`---------------------------------------------------------------------------------------------------------------------
` /s/
`---------------------
`Katherine Bonson
`11/12/2008 04:32:55 PM
`PHARMACOLOGIST
`
`Michael Klein
`11/20/2008 01:03:36 PM
`PHARMACOLOGIST
`
`

`

`
`
`
`
`CARCINOGENICITY ASSESSMENT COMMITTEE (CAC/CAC-EC) REPORT
`AND
`FDA-CDER RODENT CARCINOGENICITY DATABASE FACTSHEET
`P/T REVIEWER:
`
`
`
`Melissa Banks, Ph.D.
`DATE:
`
`
`
`
`October 28, 2008
`NDA:
`
`
`
`
`22-036
`DRUG CODE#:
`
`
`
`doxepin HCl
`CAS#:
`
`
`
`
`1229-29-4
`DIVISION(s):
`
`
`
`Div. of Neurology Products; HFD-120
`SilenorTM
`DRUG NAME(s):
`
`
`
`SPONSOR:
`Somaxon Pharmaceuticals
`
`3721 Valley Centre Drive, Suite 500
`
`San Diego, CA 92130
`
`T: 858-480-0400, F: 858-509-1761
`
`www.somaxon.com
`
`LABORATORY:
`
`
`
`
`
`
`
`1/24/08
`
`Insomnia- Hypnotic
`FDA approved as an antidepressant & anxiolytic as
` Sinequan® and treatment of atopic dermatitis &
` lichen simplex chronicus as Zonalon®
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`CARCINOGENICITY STUDY
`REPORT DATE:
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`THERAPEUTIC CATEGORY:
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`PHARMACOLOGICAL /
`CHEMICAL CLASSIFICATION: dibenzoxepin tricyclic, histamine H1 antagonist
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`MUTAGENIC/GENOTOXIC:
`Not genotoxic
`[Based on results of in vitro bacterial reverse mutation assay, in vitro chromosomal
`aberrations assay (HPBL) and in vivo rat micronucleus assay]
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`Note:
`RAT CARCINOGENICITY STUDY:
` 2-yr Bioassay Pending
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`The protocol for the 2-yr. rat carcinogenicity bioassay was submitted for ExecCAC
`concurrence (SN057, dated 6/19/07); the ExecCAC meeting was held 7/31/07 and the
`meeting minutes (dated 8/1/07) were faxed to the sponsor.
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`1
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`(b) (4)
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`0 (vehicle), 25, 50, 75 & 100 mg/kg/day
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`MOUSE CARCINOGENICITY STUDY:
`Sponsor initiated study without ExecCAC concurrence on doses.
`MOUSE STUDY DURATION:
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`26 weeks (183-183 days) control- and
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` doxepin-treated; 114/116 days for
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` urethane-treated positive control
`STUDY STARTING DATE:
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`4/16/07
`STUDY ENDING DATE:
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`1/4/08
`MOUSE STRAIN:
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`Tg.rasH2 mice
`ROUTE:
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`Oral gavage
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`(urethane pos. control, 1000 mg/kg, 3x IP)
`DOSING COMMENTS:
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`QD for 182 days
`NUMBER OF MICE:
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`25/sex/gp main study
` (TK: 5/sex/gp control, 35/sex/gp doxepin)
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`MOUSE DOSE LEVELS (mg/kg/day):
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`MTD, based on 5- and 28-day study
`BASIS FOR DOSES SELECTED:
`(cid:131)
`In 28-day study, MTD = 50 mg/kg, based on moderately severe clinical signs
`(e.g., comatose, dyspnea]) that resolved by D12-D13
`In 5-day study, “prolonged” clinical signs (@ 100) and mortality (@150)
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`(cid:131)
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`PRIOR FDA DOSE CONCURRENCE: None (see explanation below)
`The 26-week oral carcinogenicity transgenic (Tg.rasH2) mouse protocol was submitted
`as special protocol for concurrence by the ECAC (SN055, dated 4/26/07), but was denied
`because the study was already ongoing.
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`MOUSE CARCINOGENICITY:
`The sponsor (and FDA statistical reviewer) concluded that doxepin hydrochloride was
`not tumorigenic in Tg.rasH2 mice administered the drug daily for 26 weeks, based on: 1)
`a lack of statistical difference between tumor frequencies in doxepin treatment groups
`and vehicle controls and 2) the lack of dose- or exposure-dependence for the doxepin
`group tumors (nasal cavity, lung and spleen). The sponsor considered the development
`of splenic hemangiosarcomas and nasal adenocarcinomas in doxepin groups
`“noteworthy” because these tumors were not observed in the concurrent vehicle controls.
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`Mortality was not statistically increased in the doxepin-treated groups, although there
`appeared to be a slight increase in HDM (3/25), compared to vehicle controls (0/25);
`mortality in the HDM TK group supported an effect. Increased mortality was observed
`in the urethane-treated positive controls. “Comatose” was only reported through day 8,
`but other clinical signs persisted (e.g., labored breathing/dyspnea, lethargy, decreased
`motor activity, rapid/shallow breathing). Group mean body weights were statistically
`significantly and dose-dependently reduced in doxepin treated groups; reductions on day
`183 ranged from 6.2-13.2% in males and 5.1-9.5% in females, compared to controls.
`Complete histopathology was performed on all control and doxepin-treated groups; select
`tissues were assessed from the positive control animals.
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`MOUSE TUMOR FINDINGS: None statistically significant by FDA review
`In the doxepin-treated animals, possibly drug-related neoplastic alterations were observed
`in the nasal cavity, the lung and the spleen.
`In addition to the acute inflammatory lesion observed in vehicle controls and the chronic-
`active inflammation noted in the nasal cavity of doxepin-treated animals, hyperplastic
`and neoplastic lesions (adenocarcinomas) were noted in the nasal cavities of doxepin-
`treated animals of both sexes. See the sponsor’s summary table 25, below, for details.
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`Doxepin-treated animals were observed to have adenomas and carcinomas of the lung.
`Pulmonary tumors are spontaneous tumors known to occur in this strain of mouse. See
`the sponsor’s summary table 23, next page.
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`Splenic hemangiosarcomas were observed in a few animals in most doxepin-treated
`groups (see the sponsor’s summary table 24, following). Splenic hemangiosarcomas are
`a spontaneous tumor in this strain of mice.
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`MOUSE STUDY COMMENTS:
`There were no statistically significant, dose-related increases in tumors in doxepin-treated
`animals. The nasal cavity tumors are of note because they are a new finding for
` and this strain of mice. The splenic hemangiosarcomas are of note because
`the incidence rate in males, though not dose-dependent, exceeded the historical
`background rate. These two tumors could be considered for inclusion in the label.
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`4
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`(b) (4)
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`2.6.6.3 Repeat Dose Toxicology
`Study title: SP-D0110: 28-Day Repeated-Dose Oral Toxicity and Toxicokinetic Study in
`CByB6F1 Hybrid Mice With A Preliminary Range-finding Toxicity Study
`Key study findings:
`(cid:131)
`In 28-day study, MTD = 50 mg/kg (based on moderate clinical signs [e.g.,
`comatose, dyspnea] that resolved); Also “prolonged” clinical signs (@ 100) and
`mortality (@150) in 5-day
`In 28-day study, sponsor NOAEL = “between 25 & 50 mg/kg/day”
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`(cid:131)
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`Study no.:
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`Volume #, and page #:
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`Conducting laboratory and location:
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`Date of study initiation:
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`GLP compliance:
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`QA report: yes ( X ) no ( )
`Drug, lot #, and % purity:
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`Methods
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`Doses:
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`AB37CC.2G3R
`Electronic submission, 325 pgs.
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`October 2, 2006
`Yes, pg. 2
`Pgs. 3-4
`Doxepin HCl, lot 3045911,
`in sterile water for injection, USP
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`5-Day
`0, 10, 25, 50, 100 & 150 mg/kg/day
`28-day
`0, 10, 25 and 50 mg/kg/day
`CByB6F1 hybrid mice, Tg.rasH2
`non-transgenic littermates
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`5
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`Species/strain:
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