CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`208745Orig1s000
`
`
`CROSS DISCIPLINE TEAM LEADER REVIEW
`
`

`

`Cross Discipline Team Leader Review
`NDA 208745: Trulance (plecanatide) tablets for the treatment of CIC in adults
`
`Cross-Discipline Team Leader Review
`
`
`Date
`January 12, 2017
`From
`Joette M. Me er, PharmD.
`Sub'ect
`Cross-Disci 0 line Team Leader Review
`
`NDA/BLA #
`
`Su n vlement#
`
`NDA 208745
`
`S er 3 Pharmaceuticals, Inc.
`A licant
`
`Date of Submission
`January 29, 2016
`PDUFA Goal Date
`Jan .
`29, 2017
`
`Trulance® (plecanatide)
`Proprietary Name / Non—
`
`Proprietary Name
`Dosa_e form 5 / Stren_th s
`
`3 m * tablets
`
`
`
`Applicant Proposed
`Indication(s)/Population(s)
`Recommendation on
`Re ulato Action
`
`Recommended
`Indication(s)/Population(s) (if
`a. ulicable
`
`Treatment of chronic idiopathic constipation (CIC) in
`adults
`Approval
`
`Treatment of chronic idiopathic constipation (CIC) in
`adults
`
`* the NDA contained data to support "(0 a 3 mg
`
`)(4) tablet strength: during the review cycle the sponsor (5) (4)
`
`Benefit-Risk Assessment
`
`All disciplines recommend approval of plecanatide 3 mg once daily for the treatment of chronic
`idiopathic constipation (CIC) in adults. I agree with this recommendation. The following is a
`summary of the recommendations/conclusions excerpted from each of the respective reviews,
`followed by a smnmary of labeling and postmarketing requirements/postmarketing
`commitments.
`
`The benefit risk framework OBRF), found as an attachment, summarizes the clinical reviewer’s
`BRF and also reflects the cross-discipline team leader’s (CDTL) additional considerations and
`those of other review disciplines. The overall conclusions do not differ from those of the
`primary clinical reviewer.
`
`
`Recommendations/Conclusions by Discipline (reviewer names and date of
`Review
`final review in DARRTS)
`Disciplines
`
`
`OPQ
`
`Application Technical Lead (ATL) (Hitesh Shroff), 10/6/16:
`
`Not ready for approval: The Office of Process and Facilities (OPF) has not
`made a final overall “Approval” recommendation for the facilities involved in
`
`this a lication as of this review. The label/labelin issues have not been
`
`Reference ID: 4041 064
`
`

`

`Cross Discipline Team Leader Review
`NDA 208745; Trulance (plecanatide) tablets for the treatment of CIC in adults
`
`completely resolved as of this review.
`The ATL review includes the following other reviews:
`
`Drug Substance (Martin Haber), 9/30/16:
`Overall, for the drug substance, the chemistry, manufacturing and controls
`information provided in this application is satisfactory and the recommendation
`is Approval.
`
`Drug Product (Zhengfang Ge), 9/30/16:
`This application has provided adequate information on the drug product 3 mg
` tablets] to assure the identity, strength, purity, and quality with proper
`raw material controls, satisfactory specification, adequate packaging, and
`enough stability data to grant the proposed 24 months expiration dating period.
`Based on assay, plecanatide tablets are stable after been crushed and placed in
`the dosing agents (applesauce and water) for 30 minutes. No significant
`degradation is expected. Since the alternative dosing materials will be
`consumed immediately after the preparation, the applicant’s justification is
`acceptable. Therefore, this NDA is recommended for approval from the drug
`product perspective.
`
`Process/Microbiology (Bo Jiang):
`The application is recommended for approval from manufacturing process
`aspect.
`
`Environmental Analysis (Raanan Bloom), 10/3/16:
`The claim for the categorical exclusion for the Environmental Assessment is
`granted.
`
`Facilities (Juandria Williams), 10/4/16:
`The overall recommendation is pending until the
`pre-approval inspection and associated package is complete and has been
`evaluated.
`
`
`
`Biopharmaceutics (Kalpana Paudel), 9/29/16:
`The dissolution method and acceptance criterion, bridging of the capsule to
`tablet formulation were reviewed and found acceptable. The biowaiver request
`was not needed. Results of an in-use stability study support four alternative
`administration methods to disperse a tablet in applesauce, dissolve a tablet in
`water for oral ingestion and to dissolve a tablet in water with administration
`through nasogastric and gastric feeding tubes.
`
`Addenda:
`Labeling (Moo-Jhong Ree), October 18, 2016:
`The outstanding labeling deficiencies were noted to be adequately addressed by
`the sponsor.
`
`Reference ID: 4041064
`
`(b) (4)
`
`(b)
`(4)
`
`(b) (4)
`
`

`

`Cross Discipline Team Leader Review
`NDA 208745; Trulance (plecanatide) tablets for the treatment of CIC in adults
`
`Facilities (Juandria Williams), 11/22/16:
`. occurred 10/24/16. The
`The inspection of
`investigator found no significant observations and subsequently classified the
`inspection NAI; no 483 was issued to the firm.
`
`There appear to be no significant or outstanding risks to the manufacturing
`process or final product based on the individual and composite evaluation of the
`listed facilities’ inspectional history, relevant experience, and capabilities. The
`facilities are determined acceptable to support approval of NDA 208745.
`
`CDTL Comment: An addendum from the ATL is pending at the time of this
`review.
`Haoheng Yan/Fred Mills, 10/11/16:
`
`OBP
`
`Plecanatide is a guanylate cyclase-C (GC-C) agonist and is structurally related
`to the endogenous proteins uroguanylin, differing in one amino acid, and
`guanylin. Due to the structural similarity, there is a theoretical immunogenicity
`concern for depletion of the endogenous proteins if patients develop cross-
`reacting anti-plecanatide antibodies.
`
`Linaclotide, approved in 2012, is also a GC-C agonist and a structural analog of
`endogenous guanylin. Linaclotide was approved with no immunogenicity assay
`or clinical data (PMRs were issued for the assay and the clinical data). With this
`precedent, the plecanatide NDA was filed with only an antidrug antibody
`(ADA) screening assay and no clinical immunogenicity data. It was agreed the
`clinical data would be submitted during the review cycle.
`
`During the review, the applicant informed FDA that they faced ongoing
`technical issues with the immunogenicity assay. Multiple assay deficiencies
`were communicated between FDA and the applicant during the review cycle.
`
` Overall, the ADA assay
`needs more development work before it can be appropriately validated for
`detection of ADA response.
`
`CDTL Comment:
`Six PMRs related to assay development will be issued. See Postmarketing
`Requirements section.
`Eddie Ng/David Joseph, 10/18/16:
`
`There are no novel excipients and the excipients used appear safe. The
`impurities are considered qualified at the proposed limits in the drug product.
`Plecanatide was not found to be genotoxic and had no effect on fertility or
`reproductive function in male or female mice.
`
`Pharmacology
`Toxicology
`
`Reference ID: 4041064
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Cross Discipline Team Leader Review
`NDA 208745; Trulance (plecanatide) tablets for the treatment of CIC in adults
`
`
`In young juvenile mice (1- to 2-week-old mice), plecanatide increased fluid
`secretion into the intestines as a consequence of stimulation of GC-C resulting
`in mortality in some mice within the first 24 hours, apparently due to
`dehydration.
`
`The Executive CAC Committee concluded the 2—year mouse and rat
`carcinogenicity studies were adequate and there were no treatment-related
`neoplasms.
`
`From a nonclinical standpoint, there are no approvability issues. The findings
`in juvenile mice and clinical relevance to pediatric patients are described in
`labeling.
`
`David Joseph (Secondary Review), 10/2/ 16:
`There are no nonclinical issues which preclude the approval of Trulance. I
`concur with the recommendations related to approvability, stated in the
`Pharmacology/Toxicology review by Dr. Yuk-Chow Ng.
`
`This review concludes that this application contains sufficient evidence to
`support the approval of plecanatide 3 mg for the treatment of chronic idiopathic
`constipation (CIC).
`
`The application included two adequate and well—controlled, phase 3 clinical
`studies which demonstrated that the primary endpoint of the proportion of
`patients who were overall complete spontaneous bowel movement (CSBM)
`responders was significantly greater than placebo for both the plecanatide 3 mg
`and 6 mg treatment groups (p < 0.001). Improvements in CSBM responder rates
`were seen as early as Week 1 with improvement maintained through Week 12.
`
`Additionally, three main secondary endpoint results of weekly CSBMs and
`spontaneous bowel movements (SBMs) frequency and stool consistency were
`clinically meaningful and statistically significant.
`
`Overall, the safety profile of plecanatide treatment appears to be acceptable.
`Patients in the 3 mg plecanatide group had less reports of adverse events,
`particularly gastrointestinal (GD-related, than patients in the 6 mg group.
`Although the 6 mg plecanatide group experiences efficacy benefit, it did not
`show a clear efficacy advantage over the 3 mg plecanatide group. However, the
`6 mg plecanatide dosage may be less well tolerated due to G1 adverse reacgip’ns.
`
`(m4)
`. Hence,
`
`(m4) the 3 mg dose is recommended for approval.
`
`
`
`Abigail Jacobs (Tertiary Review), 10/13/16:
`
`I concur that there are no pharm—tox related approval issues.
`Lesley Hanes / Laurie Muldowney, 10/12/16:
`
`Clinical
`
`
`
`Reference ID: 4041 064
`
`

`

`Cross Discipline Team Leader Review
`NDA 208745; Trulance (plecanatide) tablets for the treatment of CIC in adults
`
`Plecanatide has structural homology to endogenous guanylin/uroguanylin; there
`is a theoretical concern for the development of guanylin/uroguanylin deficiency.
`Adverse events suggestive of fluid/volume overload were explored (e.g.,
`congestive heart failure, dyspnea, pulmonary congestion, edema, weight
`increase, blood pressure increase, hypernatremia, pancreatitis and pancreatic
`enzyme deficiency). There are no clear signals or obvious differences in the
`frequency of the potential UPD syndrome adverse events between plecanatide
`and placebo.
`
`Ischemic colitis was identified as a potential risk with other CIC treatments and
`was assessed during the review. There were no reports of ischemic colitis
`during plecanatide clinical development.
`Dilara Jappar/Sue Chih Lee, 10/6/16:
`
`The Office of Clinical Pharmacology has found the submission acceptable from
`a clinical pharmacology standpoint provided a mutual agreement on labeling
`language is reached between the FDA and the sponsor.
`
`Clinical
`Pharmacology
`
`A thorough QT study was not conducted. FDA determined a study was not
`warranted based on limited systemic exposure to plecanatide and the active
`metabolite (IND 74883, 9/7/14).
`Shahla Farr / Yeh-Fong Chen, 11/2/16:
`
`Biostatistics
`
`After thorough evaluation and clarifications with the sponsor, the statistical
`review team concluded that results of the submitted two studies are statistically
`significance and can be used to support plecanatide’s efficacy for the indication
`of Chronic Idiopathic Constipation (CIC) in adults.
`Sarrit Kovacs/Elektra Papadopoulos, 12/5/16
`
`The review concludes that the evidence submitted by the applicant is sufficient
`to demonstrate that the CSBM stool frequency, SBM stool frequency, and stool
`consistency pre-specified secondary endpoints are suitable for inclusion in
`labeling claims in the context of use. However, the three daily symptom scores
`(abdominal pain, abdominal discomfort, and abdominal bloating) were not pre-
`specified in the endpoint testing hierarchy and were not Type I error controlled.
`This reviewer discussed this with the Clinical review team and these endpoints
`are not part of the CIC disease definition, therefore, the abdominal symptom
`instruments were not reviewed for their adequacy to support labeling claims.
`
`With regard to the straining PRO instrument, the qualitative patient data
`generally supported the relevance and meaningfulness of the straining concept
`and severity. The COA Staff defer to DGIEP regarding the review of the
`clinical data to support the pre-specified secondary endpoint labeling claims
`(i.e., review of the cumulative distribution function [CDF] plots showing
`separation between treatment arms at the meaningful responder thresholds).
`
`Reference ID: 4041064
`
`

`

`Cross Discipline Team Leader Review
`NDA 208745; Trulance (plecanatide) tablets for the treatment of CIC in adults
`
`OSI
`
`The reviewer believes that the four pre-specified secondary endpoints are
`suitable for inclusion in the label, based on the modest but consistent separation
`between treatment arms at the meaningful responder thresholds across both
`studies.
`
`CDTL Comment:
`In reviewing data related to the straining endpoint, the clinical team determined
`that small but meaningful, clinical differences between the 3 mg plecanatide
`and placebo groups were evident in the distinct CDF plot curves, which showed
`the reduction in straining scores averaged over 12 weeks, as anchored by the
`cross-validated, Patient Global Assessment constipation severity score.
`Therefore, the clinical team recommends including “improvement … in the
`amount of straining” in labeling and further defining straining as the “amount
`of time pushing or physical effort to pass stool”.
`Susan Leibenhaut/Susan Thompson, 9/16/16:
`
`Six clinical investigator (CI) sites, a contract research organization (CRO) and
`the sponsor were inspected for this application. Two CI sites have the final
`classification of voluntary action indicated (VAI), and the violations cited are
`not considered to have an impact on data integrity. The four other clinical site
`inspections have classifications of no action indicated (NAI). Both the sponsor
`and CRO sites have the classifications of NAI.
`
`During the process of selecting clinical sites for inspection, it was noted that
`two CI sites that participated in Protocol SP304203-03 were classified as
`Official Action Indicated (OAI) for previous inspections conducted as a result
`of complaints.1,2 It was communicated to the review division that the data from
`these sites be considered unreliable and be removed from the label.
`
`Because all inspected sites, the sponsor, and the CRO did not have issues with
`data integrity and reliability, it is considered that the studies appear to have been
`conducted adequately, and the data generated by the studies, except for the two
`sites noted above, appear acceptable in support of the respective indication.
`OSE/DMEPA Matt Barlow//Mishale Mistry, Proprietary name, 9/8/16:
`
`The proposed proprietary name, Trulance, was found to be conditionally
`acceptable (letter to the sponsor, 5/12/16). Our re-assessment did not identify
`any names that represent a potential source of drug name confusion. Therefore,
`we maintain that the proposed proprietary name is acceptable from a
`promotional and safety perspective.
`
`Sherly Abraham/Mishale Mistry, Label and Labeling Review, 12/2/16:
`1http://www.accessdata.fda.gov/scripts/SDA/sdDetailNavigation.cfm?sd=clinicalinvestigatorsdisqualificationprocee
`dings&id=1E2A9A1BD59D686CE053554DA8C0B073&rownum=126
`2 http://www.fda.gov/iceci/enforcementactions/warningletters/2016/ucm493102.htm
`
`Reference ID: 4041064
`
`

`

`Cross Discipline Team Leader Review
`NDA 208745; Trulance (plecanatide) tablets for the treatment of CIC in adults
`
`On June 8, 2016, the Applicant proposed alternative administration instructions
`for adult patients with swallowing difficulties. The tablets can be crushed and
`administered orally either in applesauce or with water, or administered with
`water via a nasogastric or gastric feeding tube. We identified areas in the
`Prescribing Information that can be improved to clarify the alternate dosing
`information for adult patients with swallowing difficulties. Additionally, we
`identified areas in the container labels and carton labeling that can be improved.
`
`CDTL Comment:
`The carton/container labeling submitted by the sponsor on 1/3/17 was found to
`be acceptable by DMEPA.
`Jacqueline Sheppard/Jamie Wilkins, 11/10/16:
`
`OSE/DRISK
`
`DMPP
`
`DPMH
`
`The sponsor did not submit a proposed REMS or risk management plan with
`this application.
`
`Based on the available data, a REMS is not necessary for plecanatide to ensure
`the benefits outweigh the risks. Plecanatide was effective in increasing the
`frequency of CSBMs and CBMs in patients with CIC. Additionally, the side
`effect profile is similar to other GC-C agonists including the risk of severe
`diarrhea. Therefore, based on available data, the safety and risk mitigation
`approach of plecanatide is similar to other drugs in the class; the risks will be
`communicated via labeling including the use of a Medication Guide and boxed
`warning.
`Karen Dowdy / Marcia Britt Williams, 9/19/16
`
`CDTL Comment:
`DMPP provided edits to the Medication Guide on 9/19/16 and 12/9/16.
`Carolyn Yancey/Mona Khurana (Pediatrics), 10/20/16:
`Pediatrics: Trulance (plecanatide) triggers PREA as a new active ingredient,
`new indication, new dosage form, new dosing regimen, and new route of
`administration. In the NDA, the applicant submitted the initial Pediatric Study
`Plan (iPSP), agreed upon 2/6/15. Based upon a recommendation from the
`Pediatric Review Committee (PeRC) on 9/26/16, the sponsor was asked to
`revise the pediatric plan to align with linaclotide, the other drug in this
`pharmacologic class. The agreed-upon iPSP includes a partial waiver of
`pediatric patients less than 2 years of age. The FDA will require that
`plecanatide not be studied in pediatric patients less than 6 years of age until the
`postmarketing requirement (PMR) to characterize GC-C mRNA expression in
`duodenal and colonic mucosal biopsies in pediatric patients 0 to 6 years
`undergoing diagnostic gastrointestinal endoscopies as part of their medical care
`is submitted and reviewed under NDA 202811 Linzess (linaclotide).
`
`The applicant will also be required to characterize GCC mRNA expression in
`duodenal and colonic mucosal biopsies in pediatric patients undergoing
`diagnostic gastrointestinal endoscopies as part of their medical care. As this
`
`Reference ID: 4041064
`
`

`

`Cross Discipline Team Leader Review
`NDA 208745; Trulance (plecanatide) tablets for the treatment of CIC in adults
`
`study is not treatment dependent, both sponsors should consider collaboration to
`collect the necessary data.
`
`Christos Mastroyannis/Tamara Johnson (Maternal Health), 11/10/16:
`
`Maternal Health: The review provides recommended revisions and structuring
`of existing information related to the Pregnancy, Lactation, and Females and
`Males of Reproductive Potential sections in labeling in order to provide
`clinically relevant information for prescribing decisions and to comply with
`current PLLR regulatory requirements.
`
`The applicant should conduct a milk-only lactation study in patients, using a
`validated assay, in order to appropriately inform the lactation section of
`labeling.
`
`CDTL Comment:
`For additional details on the required pediatric and lactation studies, see
`Postmarketing Requirements section below.
`Adewale Adeleye/Kathleen Klemm, 9/21/16:
`OPDP provided comments on the proposed PI and OPDP/DMPP provided
`comments on the proposed Medication Guide. OPDP had no comments on the
`proposed carton/container labeling.
`
`OPDP
`
`Labeling
`Prescribing Information
`Below is a summary of the substantive issues discussed during the review. Comments from the
`review team and consultants (e.g., DMEPA, Maternal Health, Pediatrics, and OPDP) have been
`incorporated. At the time of this review, the PI is considered to be substantially complete and a
`version was provided to the sponsor on December 9, 2016. A response was received from the
`sponsor on December 22, 2016 and comments from the team were sent to the sponsor on January
`9, 2017. A teleconference with the sponsor was held January 10, 2017 where verbal agreement
`was reached on the Prescribing Information (PI) and Medication Guide (MG).
`
`The review team has ensured the PI and MG are aligned with current labeling regulations (21
`CFR 201.57), PLR labeling guidances, the Selected Requirements for Prescribing Information
`(SRPI), and best labeling practices.
`The following is a summary of the substantive revisions made to the PI by section.
`In general, the information in the PI follows that of Linzess (linaclotide).
`
`HIGHLIGHTS
`
`Reference ID: 4041064
`
`

`

`Cross Discipline Team Leader Review
`NDA 208745: Trulance (plecanatide) tablets for the treatment of CIC in adults
`
`In general, revisions to this section were made in alignment with the revisions in the Full
`Prescribing Information and will not be described here, see below.
`
`The Established Pharmacologic Class (EPC) is “guanylate cyclase—C (GC—C) agonist.”
`Plecanatide is an analog of the endogenous human uroguanylin peptide, and both are GC-C
`agonists. The mechanism of action of plecanatide is the same as Linzess (linaclotide), an analog
`of guanylin.
`
`FULL PRESCRIBING INFORMATION
`
`Boxed Warning
`
`The subject of the warning is the nonclinical findings of death in yormg juvenile mile. The title
`of the warnings is: RISK OF SERIOUS DEHYDRATION IN PEDIATRIC PATIENTS
`
`Plecanatide has not been studied clinically in pediatric patients. There is a theoretical concern
`for severe dehydration in pediatric patients, particularly in pediatric patients less than 2 years of
`age, based on the nonclinical findings of death due to severe dehydration in young juvenile mice.
`Deaths were observed in young juvenile mice 1 to 2 weeks old (human age equivalent of
`approximately 1 month to less than 2 years). Although there were no deaths in older juvenile
`mice at least 3 weeks old, given the deaths in younger mice and the lack of clinical safety and
`efficacy data in pediatric patients, plecanatide is contraindicated in patients less than 6 years of
`age and should be avoided in patients 6 years to less than 18 years of age. Due to similar
`nonclinical study findings during the development of linaclotide, linaclotide is also
`contraindicated for patients less than 6 years of age and recommended to be avoided in patients
`6 years to less than 18 years of age.
`
`DPMH recommends that the upper pediatric age be “less than 18 years of age”, to reflect the
`ages studied in the clinical trials, rather than
`(5)“) (definition of pediatric
`patient, according to the regulations) throughout labeling.
`
`1
`
`INDICATIONS AND USAGE
`
`The indication specifies that plecanatide is indicated in adults for the treatment of chronic
`idiopathic constipation (CIC).
`
`2
`
`DOSAGE AND ADMINISTRATION
`
`The recommended dosage of plecanatide is 3 mg taken orally once daily.
`
`m4)
`
`Reference ID: 4041 064
`
`

`

`Cross Discipline Team Leader Review
`NDA 208745; Trulance (plecanatide) tablets for the treatment of CIC in adults
`
`Plecanatide can be taken with or without food. In a pharmacokinetic/pharmacodynamic study,
`subjects who received either a low-fat, low calorie (LF-LC) meal or a high fat, high calorie (HF-
`HC) meal reported looser stools than fasted subjects up to 24 hours after a single dose of
`plecanatide 9 mg (3 times the recommended dose). Although these results were statistically
`significant, the sponsor did not consider this difference between fed and fasted subjects to be
`clinically significant. In addition, the dose tested was 3 times higher than the recommended
`dose. In clinical studies, plecanatide was administered with or without food.
`During the review, the sponsor submitted information to allow for the tablets to be crushed and
`administered orally either in applesauce or with water or administered with water via a
`nasogastric or gastric feeding tube. This information was found to be adequate by the OPQ
`biopharmaceutics and drug product reviewers. Therefore, this section allows for crushing and
`mixing the tablets for adult patients with swallowing difficulties. Only applesauce or water will
`be allowed, as other soft foods/liquids were not studied. This information has also been
`incorporated into the Medication Guide.
`
`DOSAGE FORMS AND STRENGTHS
`3
`Plecanatide is available as a 3 mg tablet.
`
`CONTRAINDICATIONS
`4
`Plecanatide is contraindicated in patients less than 6 years of age due to the risk of serious
`dehydration, as described above. It is also contraindicated in patients with known or suspected
`mechanical gastrointestinal obstruction, due to the mechanism of action of the drug in the GI
`tract and risk of serious outcomes.
`
`WARNINGS AND PRECAUTIONS
`5
`Risk of Serious Dehydration in Pediatric Patients
`5.1
`This subsection provides more details related to the risk of serious dehydration in pediatric
`patients. In young juvenile mice (1- to 2-week-old mice; human age equivalent of approximately
`1 month to less than 2 years of age), plecanatide increased fluid-secretion into the intestines as a
`consequence of stimulation of guanylate cyclase-C (GC-C), resulting in mortality in some mice
`within the first 24 hours, apparently due to dehydration. Due to increased intestinal expression
`of GC-C, patients less than 6 years of age may be more likely than patients 6 years of age and
`older to develop severe diarrhea and its potentially serious consequences.
`This subsection reiterates:
` Plecanatide is contraindicated in patients less than 6 years of age.
` The safety and effectiveness of plecanatide in patients less than 18 years of age have not
`been established.
` Avoid the use of plecanatide in patients 6 years to less than 18 years of age, given the
`deaths in younger mice and the lack of clinical safety and efficacy data in pediatric
`patients.
`
`Reference ID: 4041064
`
`

`

`Cross Discipline Team Leader Review
`NDA 208745: Trulance (plecanatide) tablets for the treatment of CIC in adults
`
`5.2
`
`Diarrhea
`
`In the adult clinical trials, diarrhea was the most common adverse reaction with severe diarrhea
`
`reported in 0.6% of plecanatide-treated patients compared to 0.3% of placebo—treated patients.
`
`Risk mitigation for the development of severe diarrhea is to suspend plecanatide dosing and
`rehydrate the patient.
`
`6
`
`ADVERSE REACTIONS
`
`During the process of selecting clinical sites for inspection, it was noted that two sites that
`participated in Protocol SP304203-03 were classified as Official Action Indicated (OAI) for
`previous inspections conducted as a result of complaints},4
`
`Data (both safety and efficacy) from these sites was considered unreliable and was removed from
`the label.
`
`The safety data described reflect the safety database from the two double—blind, placebo—
`controlled 12- week clinical studies. Demographic characteristics were comparable between the
`
`treatment groups.
`
`The most common adverse reactions (defined as adverse events occurring at a higher rate in
`the plecanatide group compared to placebo) in the two trials was diarrhea: 5% in the
`plecanatide 3 mg group and 1% in the placebo group. The majority of reported cases of
`diarrhea occurred within 4 weeks of treatment initiation. Diarrhea was also the most common
`
`adverse reaction leading to discontinuation (2% of plecanatide-treated patients and 0.5% of
`placebo-treated patients).
`
`Less common adverse reactions included abdominal distension, flatulence, abdominal
`tenderness, and increased liver biochemical in 5 patients treated with plecanatide 3 mg: 2
`patients with ALT greater than 5 to 15 times the upper limit of normal and 3 patients with AST
`greater than 5 times the upper limit of normal. These laboratory abnormalities were not
`associated with clinical symptoms and did not meet the criteria for Hy’s law.
`
`7
`
`DRUG INTERACTIONS
`
`There are no clinically relevant drug interactions, so this section has been omitted.
`
`a”)
`
`(I!) (4)
`
`3hflp://www.accessdata.fda.gov/scripts/SDA/sdDetailNavigation.cfm?sd=clinicalinvestigatorsdisgualificationprocee
`dings&id=lE2A9A1BD59D686CE053554DA8COB073&rownum=l26
`
`
`‘ http://www.fda.gov/iceci/enforcementactions/warningletters/Z01 6/ucm493 102 .htm
`
`Reference ID: 4041 064
`
`

`

`Cross Discipline Team Leader Review
`NDA 208745; Trulance (plecanatide) tablets for the treatment of CIC in adults
`
`USE IN SPECIFIC POPULATIONS
`8
`Pregnancy
`8.1
`Plecanatide was not mutagenic or clastogenic in genetic toxicology assays when evaluated at the
`highest concentrations of doses tested.
`There is no evidence that administration of plecanatide to mice and rabbits during organogenesis
`causes adverse developmental effects.
`No studies of plecanatide have been conducted in pregnant women. Because the drug has not yet
`been approved, no pharmacovigilance database has been established.
`Plecanatide and its active metabolite are not measurable in animal and human plasma following
`administration of the recommended clinical dosages; therefore, maternal use of plecanatide is not
`expected to result in fetal exposure.
`Overall, the limited cases reported of plecanatide use in pregnant women during clinical
`developed have sparse information and are insufficient to inform a drug associated risk for major
`birth defects and miscarriage.
`8.2
`Lactation
`It is not known if plecanatide is present in animal milk. No animal lactation studies have been
`conducted.
`No clinical lactation studies have been conducted. It is not known whether plecanatide is present
`in breast milk or on the effects on the breastfeeding infant or on lactation.
`Given the low systemic availability of plecanatide, fetal exposure and infant exposure through
`human milk is expected to be limited. Therefore, lactation should not be discouraged with
`maternal use of plecanatide. However, this section will also reiterate that exposure to
`plecanatide in breastfed infants has the potential for
` adverse
`effects.
`
`Pediatric Use
`8.4
`Because the proposed indication will not include pediatric patients, this subsection will state that
`safety and effectiveness have not been established in pediatric patients. Additionally, given the
`results from the juvenile animal toxicity studies that raise potential safety concerns in young
`pediatric patients, the nonclinical safety findings will be summarized:
`Juvenile Animal Toxicity Data
`Single oral doses of plecanatide at 0.5 mg/kg and 10 mg/kg caused mortality in young juvenile mice on
`postnatal days 7 and 14, respectively (human age equivalent of approximately 1 month to less than 2 years).
`
`Reference ID: 4041064
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Cross Discipline Team Leader Review
`NDA 208745; Trulance (plecanatide) tablets for the treatment of CIC in adults
`
`Treatment-related increases in the weight of intestinal contents were observed in juvenile mice following
`single doses of plecanatide on postnatal day 14 (human age equivalent of approximately less than 2 years),
`consistent with increased fluid in the intestinal lumen. Although the recommended human dose is
`approximately 0.05 mg/kg/day, based on a 60-kg body weight, plecanatide and its active metabolite are not
`measurable in adult human plasma whereas systemic absorption was demonstrated in the juvenile animal
`toxicity studies. Animal and human doses should not be compared directly for evaluating relative
`exposure.
` Geriatric Use
`8.5
`There were insufficient numbers of patients aged 65 and older in the clinical trials to make an
`assessment of any efficacy differences between younger and older patients.
`
`11 DESCRIPTION
`
`The sponsor wanted to include a statement
` which is not appropriate for this section. See
`
`discussion in Section 12.2 below.
`
`
`
`CLINICAL PHARMACOLOGY
`12
`12.1 Mechanism of Action
`Plecanatide is structurally similar to human endogenous uroguanylin, differs by only one amino
`acid, and also guanylin. The sponsor states there is no evidence that guanylin is important to the
`physiology of human intestinal water and electrolyte balance and it is not necessary to note the
`similarity between plecanatide and guanylin. They also believe that it is important for
`prescribers to know that plecanatide, by virtue of its GC-C receptor binding affinity, is also
`under the same degree of pH control as uroguanylin. Therefore, plecanatide is not only
`structurally, but also functionally, related to uroguanylin and the following sentence was
`included:
`Plecanatide is structurally related to human uroguanylin, and similar to guanylin, plecanatide functions as a
`guanylate cyclase-C (GC-C) agonist.
`The mechanism by which activation of GC-C results in increased fluid secretion and accelerated
`transit in the GI tract is described, as are the results of a validated animal model of intestinal
`pain:
`
`In an animal model of visceral pain, plecanatide reduced abdominal muscle contraction, a measure of
`intestinal pain. The mechanism has not been studied.
`12.2 Pharmacodynamics
`A description of the