HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`e
`
`Swallow tablets whole.
`
`These highlights do not include all the information needed to use
`TRULANCEsafely andeffectively. See full prescribing
`information for TRULANCE.
`
`TRULANCE(plecanatide) tablets, for oral use
`Initial U.S. Approval: 2017
`
`WARNING: RISK OF SERIOUS DEHYDRATIONIN
`PEDIATRIC PATIENTS
`Seefullprescribing information for complete boxed warning.
`
`
`
`e
`
`TRULANCEis contraindicated in patients less than 6
`years of age; in young juvenile mice, plecanatide caused
`death due to dehydration.(4, 8.4)
`Avoid use of TRULANCEinpatients 6 yearsto less than
`18 yearsof age. (5.1, 8.4)
`Thesafety andeffectiveness of TRULANCEhavenot
`been established in patients less than 18 years of age.
`(8.4)
`
`INDICATIONS AND USAGE
`TRULANCE1s a guanylate cyclase-C agonist indicated in adults for
`treatment of chronic idiopathic constipation (CIC). (1)
`
`DOSAGE AND ADMINISTRATION——————
`The recommendedadult dosage of TRULANCEis 3 mgtakenorally
`oncedaily. (2.1)
`
`Administration Instructions (2.2):
`e Take with or without food.
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`WARNING: RISK OF SERIOUS DEHYDRATIONIN
`
`PEDIATRIC PATIENTS
`
`mW
`
`i
`INDICATIONS AND USAGE
`2 DOSAGE AND ADMINISTRATION
`2.1 Recommended Dosage
`2.2 Preparation and Administration Instructions
`DOSAGE FORMS AND STRENGTHS
`CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Risk of Serious Dehydration in Pediatric Patients
`5.2 Diarrhea
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`8 USE IN SPECIFIC POPULATIONS
`
`e For patients who havedifficulty swallowing tablets whole or
`those with a nasogastric or gastric feeding tube, see full
`prescribing information with instructions for crushing the
`tablet and administering with applesauce or water.
`
`DOSAGE FORMS AND STRENGTHS————
`Tablets: 3 mg (3)
`
`—————————CONTRAINDICATIONS—————
`
`e Patients less than 6 years of age dueto the risk of serious
`dehydration. (4, 5.1, 8.4)
`e Patients with known or suspected mechanical gastrointestinal
`obstruction. (4)
`
`WARNINGS AND PRECAUTIONS————_
`Diarrhea: Patients may experience severe diarrhea. If severe
`diarrhea occurs, suspend dosing and rehydrate the patient. (5.2)
`
`ADVERSE REACTIONS
`Most commonadverse reaction (=2%)is diarrhea. (6.1)
`
`To report SUSPECTED ADVERSE REACTIONS,contact
`Synergy Pharmaceuticals at 1-888-869-8869 or FDA at 1-800-
`FDA-1088 or www.fda.gov/nedwatch.
`
`See 17 for PATIENT COUNSELING INFORMATIONand
`Medication Guide.
`
`Revised: 01/2017
`
`8.1 Pregnancy
`8.2 Lactation
`8.4 Pediatric Use
`8.5 Geriatric Use
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of
`Fertility
`14 CLINICAL STUDIES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the full prescribing
`information are notlisted.
`
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`FULL PRESCRIBING INFORMATION
`
`yearsof age /see Use in Specific Populations (8.4)].
`
`WARNING: RISK OF SERIOUS DEHYDRATIONIN PEDIATRIC PATIENTS
`
`e TRULANCEis contraindicated in patients less than 6 years of age; in nonclinical studies in young
`juvenile mice administration of a single oral dose of plecanatide caused deaths due to dehydration
`[see Contraindications (4), Use in Specific Populations (8.4)].
`Avoid use of TRULANCEin patients 6 yearsto less than 18 years of age /see Warnings and
`Precautions (5.1), Use in Specific Populations (8.4)].
`The safety and effectiveness of TRULANCEhavenot beenestablished in patients less than 18
`
`1
`
`INDICATIONS AND USAGE
`
`TRULANCEisindicated in adults for the treatment of chronic idiopathic constipation (CIC).
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Recommended Dosage
`
`The recommended dosage of TRULANCEis 3 mgtakenorally oncedaily.
`
`2.2 Preparation and Administration Instructions
`
`Take TRULANCEwith or without food /see Clinical Pharmacology (12.3)].
`If a dose is missed, skip the missed dose and take the next dose at the regular time. Do not take two
`dosesat the same time.
`
`Swallow a tablet whole for each dose.
`For adult patients with swallowing difficulties, TRULANCEtablets can be crushed and administered
`orally either in applesauce or with water or administered with water via a nasogastric or gastric
`feeding tube. Mixing TRULANCEcrushedtablets in other soft foods or in other liquids has not
`beentested.
`
`Oral Administration in Applesauce:
`In a clean container, crush the TRULANCEtablet to a powder and mix with 1 teaspoonful of room
`1.
`temperature applesauce.
`Consumethe entire tablet-applesauce mixture immediately. Do not store the mixture for later use.
`
`2.
`
`2.
`
`3.
`
`Oral Administration in Water:
`Place the TRULANCEtablet in a clean cup.
`1.
`Pour approximately 30 mL of room temperature waterinto the cup.
`Mixby gently swirling the tablet and water mixture for at least 10 seconds. The TRULANCEtablet
`will fall apart in the water.
`Swallow the entire contents of the tablet water mixture immediately.
`If any portion ofthe tabletis left in the cup, add another 30 mL of water to the cup, swirl for at least
`10 seconds, and swallow immediately.
`Do notstore the tablet-water mixture forlater use.
`
`4.
`
`5.
`
`6.
`
`2.
`
`Administration with Water via a Nasogastric or Gastric Feeding Tube:
`Place the TRULANCEtablet in a clean cup with 30 mL of room temperature water.
`1.
`Mixby gently swirling the tablet and water mixture for at least 15 seconds. The TRULANCEtablet
`will fall apart in the water.
`Flush the nasogastric or gastric feeding tube with 30 mL of water using an appropriate syringe.
`
`3.
`
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`5.
`
`4. Draw up the mixture using the syringe and immediately administer via the nasogastric or gastric
`feeding tube. Do not reserve for future use.
`Ifany portion ofthe tablet is left in the cup, add another 30 mL of water to the cup, swirl for at least
`15 seconds, and using the samesyringe, administer via the nasogastric or gastric feeding tube.
`6. Using the sameor a fresh syringe, flush the nasogastric or gastric feeding tube with at least 10 mL of
`water.
`
`3 DOSAGE FORMS AND STRENGTHS
`
`TRULANCETablets:
`
`3 mg: white to off-white, plain, round tablet debossed with “SP” on one side and “3” for 3 mg on the otherside.
`
`4 CONTRAINDICATIONS
`
`TRULANCEis contraindicatedin:
`
`e
`
`e
`
`Patients less than 6 years of age dueto the risk of serious dehydration /see Warnings and Precautions
`(5.1), Use in Specific Populations (8.4)].
`Patients with known or suspected mechanical gastrointestinal obstruction.
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Risk of Serious Dehydration in Pediatric Patients
`
`TRULANCEiscontraindicated in patients less than 6 years of age. The safety and effectiveness of
`TRULANCEin patients less than 18 years of age have not been established. In young juvenile mice (human
`age equivalent of approximately 1 month to less than 2 years), plecanatide increased fluid-secretion into the
`intestines as a consequenceofstimulation of guanylate cyclase-C (GC-C), resulting in mortality in some mice
`within the first 24 hours, apparently due to dehydration. Dueto increasedintestinal expression of GC-C,
`patients less than 6 years of age may be morelikely than patients 6 years of age and older to develop severe
`diarrhea andits potentially serious consequences.
`
`Avoid the use of TRULANCEinpatients 6 years to less than 18 years of age. Although there were no deaths in
`older juvenile mice, given the deaths in younger mice andthe lack of clinical safety and efficacy data in
`pediatric patients, avoid the use of TRULANCEinpatients 6 years to less than 18 years of age /see
`Contraindications (4), Warnings and Precautions (5.2), Use in Specific Populations (8.4)].
`
`5.2 Diarrhea
`
`Diarrhea was the most common adversereaction in the two placebo-controlled clinical trials. Severe diarrhea
`wasreported in 0.6% of patients /see Adverse Reactions (6.1)]. If severe diarrhea occurs, suspend dosing and
`rehydrate the patient.
`
`6 ADVERSE REACTIONS
`
`6.1 Clinical Trials Experience
`
`Because clinical studies are conducted under widely varying conditions, adverse reaction rates observedin the
`clinical trials of a drug cannot be directly compared with rates in the clinicaltrials of another drug and maynot
`reflect the rates observed in practice.
`
`The safety data described below reflect data from 1733 adult patients with CIC randomized in two double-blind,
`placebo-controlled clinical trials (Study 1 and Study 2) to receive placebo or 3 mg of TRULANCEoncedaily
`for 12 weeks. Demographic characteristics were comparable between the TRULANCEandplacebo groups
`[see Clinical Studies (14)].
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`Most Common Adverse Reactions
`
`Table | provides the incidence of adverse reactions reported in at least 2% of CIC patients in the
`TRULANCE-treated group andat an incidence that was greater than in the placebo group.
`Table 1: Most Common Adverse Reactions in Two Placebo-Controlled Trials of TRULANCE
`[Study 1 and Study2] in Patients with CIC
`
`% 0
`
`Adverse Reaction
`
`TRULANCE,3 mg
`(N = 863)
`%
`
`Placebo
`(N = 870)
`%
`
`" reported in at least 2% of TRULANCE-treatedpatients andat an incidence greater than placebo
`
`Diarrhea
`
`The majority of reported cases of diarrhea occurred within 4 weeksof treatmentinitiation. Severe diarrhea was
`reported in 0.6% of TRULANCE-treated patients compared to 0.3% of placebo-treated patients. Severe
`diarrhea wasreported to occur within the first 3 days of treatment /see Warnings and Precautions (5.2)].
`
`Adverse Reactions Leading to Discontinuation
`
`Discontinuations due to adverse reactions occurred in 4% of TRULANCE-treated patients and 2% of
`placebo-treated patients. The most commonadversereaction leading to discontinuation wasdiarrhea: 2% of
`TRULANCE-treated patients and 0.5% of placebo-treated patients withdrew dueto diarrhea.
`
`Less Common Adverse Reactions
`
`Adverse reactions reported in less than 2% of TRULANCE-treated patients and at an incidence greater than
`placebo were: sinusitis, upper respiratory tract infection, abdominal distension, flatulence, abdominal
`tenderness, and increased liver biochemicaltests (2 patients with alanine aminotransferase (ALT) greater than 5
`to 15 times the upper limit of normal and 3 patients with aspartate aminotransferase (AST) greater than 5 times
`the upperlimit of normal).
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`
`Risk Summary
`
`Plecanatide andits active metabolite are negligibly absorbed systemically following oral administration /see
`Clinical Pharmacology (12.3)] and maternaluse is not expected to result in fetal exposure to the drug. The
`available data on TRULANCEuse in pregnant womenare notsufficient to inform any drug-associated risks for
`major birth defects and miscarriage. In animal developmental studies, no effects on embryo-fetal development
`were observed with oral administration of plecanatide in mice and rabbits during organogenesis at doses much
`higher than the recommended human dosage.
`
`The estimated backgroundrisk of major birth defects and miscarriage for the indicated population is unknown.
`All pregnancies have a backgroundrisk of birth defect, loss, or other adverse outcomes. In the United States
`general population, the estimated background risk of major birth defects and miscarriagein clinically
`recognized pregnancies 1s 2% to 4% and 15% to 20%, respectively.
`
`Data
`
`Animal Data
`
`Pregnant mice and rabbits were administered plecanatide during the period of organogenesis. There was no
`evidence of harm to embryo-fetal developmentat oral doses up to 800 mg/kg/day in mice and 250 mg/kg/day in
`
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`rabbits. Oral administration of up to 600 mg/kg/day in mice during organogenesis through lactation produced
`no developmental abnormalities or effects on growth, learning and memory,orfertility in the offspring through
`maturation.
`
`The maximum recommended human doseis approximately 0.05 mg/kg/day, based on a 60-kg body weight.
`Limited systemic exposure to plecanatide was achieved in animals during organogenesis (area under the plasma
`concentration-time curve [AUC;] = 449 ngeh/mLin rabbits given 250 mg/kg/day). Plecanatide andits active
`metabolite are not measurable in human plasma following administration of the recommended clinical dosage.
`Therefore, animal and human doses should not be compared directly for evaluating relative exposure.
`
`8.2 Lactation
`
`Risk Summary
`
`There is no information regarding the presence of plecanatide in human milk,or its effects on milk production
`or the breastfed infant. No lactation studies in animals have been conducted. Plecanatide andits active
`metabolite are negligibly absorbed systemically following oral administration /see Clinical Pharmacology
`(12.3)].
`
`It is unknown whether the negligible systemic absorption of plecanatide by adults will result in a clinically
`relevant exposure to breastfed infants. Exposure to plecanatide in breastfed infants has the potential for serious
`adverse effects /see Use in Special Populations (8.4)]. The developmental andhealth benefits of breastfeeding
`should be considered along with the mother’s clinical need for TRULANCEandanypotential adverse effects
`on the breastfed infant from TRULANCEorfrom the underlying maternal condition.
`
`8.4 Pediatric Use
`
`TRULANCEiscontraindicated in pediatric patients less than 6 years of age. Avoid use of TRULANCEin
`patients 6 years to less than 18 years of age /see Contraindications (4), Warnings and Precautions (5.1)]. The
`safety and effectiveness of TRULANCEinpatients less than 18 years of age have not been established.
`
`In nonclinical studies, deaths occurred within 24 hours in young juvenile mice (human age equivalent of
`approximately 1 month to less than 2 years) following oral administration of plecanatide, as described below in
`Juvenile Animal Toxicity Data. Because ofincreasedintestinal expression of GC-C,patients less than 6 years
`of age may be morelikely than patients 6 years of age and older to develop diarrhea andits potentially serious
`consequences. TRULANCEis contraindicated in patients less than 6 years of age. Given the deaths in young
`juvenile mice andthe lack of clinical safety and efficacy data in pediatric patients, avoid the use of
`TRULANCEinpatients 6 years to less than 18 years of age.
`
`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).
`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.
`
`8.5 Geriatric Use
`
`Clinical studies of TRULANCEdid not include sufficient numbers of patients aged 65 and over to determine
`whether they respond differently from patients 18 years to less than 65 years of age. Of 2601 subjects in
`clinical trials of TRULANCE,273 (10%) were 65 years of age and over, and 47 (2%) were 75 years and over.
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`In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased
`hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
`
`11 DESCRIPTION
`
`TRULANCE(plecanatide) is a guanylate cyclase-C (GC-C) agonist. Plecanatide is a 16 amino acid peptide
`with the following chemical name: L-Leucine, L-asparaginyl-L-a-aspartyl-L-a-glutamyl-L-cysteinyl-L-a-
`glutamyl-L-leucyl-L-cysteinyl-L-valyl-L-asparaginyl-L-valyl-L-alanyl-L-cysteinyl-L-threonylglycyl-L-
`cysteinyl-, cyclic (4—12),(7—15)-bis(disulfide).
`
`The molecular formula of plecanatide is CgsHjo4N1gO026S4 and the molecular weight is 1682 Daltons. The amino
`acid sequence for plecanatide is shown below:
`oSSS
`H-Asn!-Asp?-Glu3-Cys*-Glu°-Leu®-Cys’-Val8-Asn9-Val!°-Ala!!-Cys!?-Thr!3-Gly!4-Cys!>-Leu!®-OH
`<<
`
`Thesolid lines linking cysteinesillustrate disulfide bridges.
`
`Plecanatide is an amorphous, white to off-white powder. It is soluble in water. TRULANCEtablets are
`supplied as a 3 mgtablet for oral administration. The inactive ingredients are magnesium stearate and
`microcrystalline cellulose.
`
`12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`
`Plecanatide is structurally related to human uroguanylin, and similar to uroguanylin, plecanatide functions as a
`guanylate cyclase-C (GC-C) agonist. Both plecanatide andits active metabolite bind to GC-C andact locally
`on the luminal surface of the intestinal epithelium. Activation of GC-C results in an increase in both
`intracellular and extracellular concentrations of cyclic guanosine monophosphate (cGMP). Elevation of
`intracellular cGMP stimulates secretion of chloride and bicarbonate into the intestinal lumen, mainly through
`activation of the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel, resulting in
`increased intestinal fluid and accelerated transit. In animal models, plecanatide has been shownto increase
`fluid secretion into the gastrointestinal (GI) tract, accelerate intestinal transit, and cause changesin stool
`consistency.
`
`In an animal modelof visceral pain, plecanatide reduced abdominal muscle contractions, a measure ofintestinal
`pain. The mechanism hasnotbeenstudied.
`
`12.2 Pharmacodynamics
`
`Food Effect
`
`Subjects who received either a low-fat, low calorie (LF-LC) mealor a high fat, high calorie (HF-HC) meal
`reported looser stools than fasted subjects up to 24 hoursafter a single dose of TRULANCE9 mg(3 timesthe
`recommendeddose). In clinical studies, TRULANCEwasadministered with or without food /see Dosage and
`Administration (2.2)].
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`12.3 Pharmacokinetics
`
`Absorption
`
`Plecanatide is minimally absorbed with negligible systemic availability following oral administration.
`Concentrations of plecanatide and its active metabolite in plasma are below the limit of quantitation after an
`oral TRULANCEdose of 3 mg. Therefore, standard pharmacokinetic parameters such as AUC, maximum
`concentration (Cyax), and half-life (ty,) cannot be calculated.
`
`Food Effect
`
`In a crossover study, 24 healthy subjects were given a single dose of TRULANCE9 mg(3 times the
`recommended dose) in 3 different states: fasted; following a low-fat, low-calorie meal (LF-LC; approximately
`350 calories: 17% from fat, 66% from carbohydrate, and 17% from protein); and following a high-fat,
`high-calorie meal (HF-HC; approximately 1000 calories: 60% from fat, 25% from carbohydrate, and 15% from
`protein). Plecanatide wasdetected in 1 subject (fasted state) at 0.5 and 1 hour post dose. Plecanatide
`concentrations were below the limit of quantitation for all other time points and for all other subjects. The
`active metabolite was not detected in any subject.
`
`Distribution
`
`Giventhat plecanatide concentrations following clinically relevant oral doses are not measurable, plecanatideis
`expected to be minimally distributed in tissues. Oral plecanatide is localized to the GI tract whereit exertsits
`effects as a GC-C agonist with negligible systemic exposure. Plecanatide exhibitslittle to no binding to human
`serum albumin or human a-1-acid glycoprotein.
`
`Elimination
`
`Metabolism
`
`Plecanatide is metabolized in the GItract to an active metabolite by loss of the terminal leucine moiety. Both
`plecanatide and the metabolite are proteolytically degraded within the intestinal lumen to smaller peptides and
`naturally occurring amino acids.
`
`Excretion
`
`No excretion studies have been conducted in humans. Plecanatide andits active metabolite are not measurable
`in plasmafollowing administration of the recommendedclinical doses.
`
`DrugInteraction Studies
`
`Neither plecanatide norits active metabolite inhibited the cytochrome P450 (CYP) enzymes 2C9 and 3A4, and
`they did not induce CYP3A4in vitro.
`
`Plecanatide andits active metabolite are neither substrates nor inhibitors of the transporters P-glycoprotein
`(P-gp) or breast cancer resistance protein (BCRP)in vitro.
`
`13 NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenesis, Impairmentof Fertility
`
`Carcinogenesis
`
`The carcinogenic potential of plecanatide was assessed in 2-year carcinogenicity studies in mice andrats.
`Plecanatide was not tumorigenic in miceat oral doses up to 90 mg/kg/dayorin rats at oral doses up to
`100 mg/kg/day. Limited systemic exposure to plecanatide was achievedat the tested dose levels in animals,
`whereasno detectable exposure occurred in humans. Therefore, animal and human dosesshould not be
`compared directly for evaluating relative exposure.
`
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`Mutagenesis
`
`Plecanatide was not genotoxicin the in vitro bacterial reverse mutation (Ames)assay, in vitro mouse lymphoma
`mutation assay, or the in vivo mouse bone marrow micronucleusassay.
`
`Impairmentof Fertility
`
`Plecanatide had no effect on fertility or reproductive function in male or female miceat oral doses of up to
`600 mg/kg/day.
`
`14 CLINICAL STUDIES
`
`The efficacy of TRULANCEfor the management of symptoms of CIC wasestablished in two 12-week,
`double-blind, placebo-controlled, randomized, multicenter clinical studies in adult patients (Study 1 and
`Study 2). In the Intention-to-Treat (ITT) population, a total of 905 patients (Study 1) and 870 patients (Study 2)
`were randomized1:1 to either placebo or TRULANCE3 mg,oncedaily. In clinical studies, study medication
`was administered without respect to food intake. Demographics for these studies included an overall mean age
`of 45 years (range 18 to 80 years), 80% female, 72% white, and 24% black.
`
`To be eligible for the studies, patients were required to meet modified RomeIII criteria for at least 3 months
`prior to the screening visit, with symptom onsetfor at least 6 months prior to diagnosis. RomeIII criteria were
`modified to require that patients report less than 3 defecations per week, rarely have a loose stool without the
`use of laxatives, not use manual maneuversto facilitate defecations, and not meetcriteria for IBS-C. In
`addition, patients were required to report at least two of the following symptoms:
`
`e
`e
`e
`e
`
`Straining during at least 25% of defecations
`Lumpyorhardstoolin at least 25% of defecations
`Sensation of incomplete evacuationsfor at least 25% of defecations
`Sensation of anorectal obstruction/blockage for at least 25% of defecations
`
`Patients who metthese criteria were also required to demonstrate the following during the last 2 weeksof the
`screening period:
`
`e Less than 3 complete spontaneous bowel movements (CSBMs) (a CSBM is an SBMthatis associated
`with a sense of complete evacuation) in each of the two weeks
`e Bristol Stool Form Scale (BSFS) of 6 or 7 in less than 25% of spontaneous bowel movements (SBMs)
`(an SBM is a bowel movementoccurring in the absence of laxative use)
`e One out of the following three:
`o BSFS of 1 or 2 in at least 25% of defecations
`oA straining value recorded onat least 25% of days when a BM wasreported
`o At least 25% of BMsresult in a sense of incomplete evacuation
`
`The efficacy of TRULANCEwasassessed using a responder analysis and change-from-baseline in CSBM and
`SBM endpoints. Efficacy was assessed using information provided bypatients on a daily basis in an electronic
`diary.
`
`A responder wasdefined as a patient who had a least 3 CSBMsin a given week andan increaseofat least 1
`CSBMfrom baseline in the same week for at least 9 weeks out of the 12 week treatment period andat least 3 of
`the last 4 weeks of the study. The responderrates are shown in Table 2.
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`Table 2: Efficacy Responder Rates in the Two Placebo Controlled Studies of CIC: at least 9 of 12 weeks
`and atleast 3 of the last 4 weeks (ITT Population)
`
`Study 1
`
`TRULANCE3 mg
`N= 453
`°
`
`Study 2
`
`TRULANCE3 mg
`N= 430
`°
`
`Placebo
`N=452
`°
`
`Placebo
`N=440
`°
`
`Treatment
`Difference®
`[95% CI]
`11%
`
`Treatment
`Difference®
`[95% CI]
`8%
`
`Responder
`
`Responder
`
`
`
`CI = confidence interval
`* primary endpoint defined as a patient who had a least 3 CSBMsinagiven week and an increaseofat least 1 CSBM from baselinein
`the same weekfor at least 9 weeks out of the 12 week treatment period andat least 3 of the last 4 weeks ofthe study
`* p-value <0.005
`
`In both studies, improvements in the frequency of CSBMs/week were seen as early as week | with
`improvement maintained through week 12. The difference between the TRULANCEgroup and the placebo
`group in the mean change of CSBMs/week frequency from baseline to week 12 was approximately
`1.1 CSBMs/week.
`
`Overthe 12 week treatment period, improvements were observedin stool frequency (number of CSBMs/week
`and SBMs/week) and/or stool consistency (as measured by the BSFS), and/or in the amountof straining with
`bowel movements (amountof time pushing or physical effort to pass stool) in the TRULANCEgroup as
`comparedto placebo.
`
`Following completion of the study drug treatment period, patients continued to record data in the daily diary for
`a 2 week Post-Treatment Period. During this time, TRULANCE-treated patients generally returned to baseline
`for these study endpoints.
`
`In Studies 1 and 2, a third randomized treatment arm of TRULANCE6 mg once daily did not demonstrate
`additional treatment benefit and had a greater incidence of adverse reactions than TRULANCE3 mgoncedaily.
`Therefore, TRULANCE6 mg oncedaily is not recommended /see Dosage and Administration (2.1)].
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`TRULANCEtablets are packaged in an aluminum foil unit dose blister pack of 30 in a child-resistant pack or in
`a white, opaque, high-density polyethylene round bottle with a screw-top polypropylene child-resistant cap and
`heat-activated induction seal. Each bottle container-closure system also contains a desiccant and a polyester
`coil.
`
`TRULANCE3 mgtablets are white to off-white, plain and round, debossed with “SP” on oneside and “3”for
`3 mg on the other side and supplied as:
`
`Aluminum foil unit dose blister pack of 30 in a child-resistant pack
`
`NDC Number
`
`Size
`
`70194-203-30
`
`Bottle of 30
`
`70194-003-30
`
`Reference ID: 4044252
`
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`Store at room temperature, 20 to 25°C (68 to 77°F); excursions permitted to 15 to 30°C (59 to 86°F) [see USP
`Controlled Room Temperature].
`
`Keep TRULANCEinadry place. Protect from moisture. For bottles, keep TRULANCEintheoriginalbottle.
`Do not removedesiccant from the bottle. Do not subdivide or repackage.
`
`17 PATIENT COUNSELING INFORMATION
`
`Advise the patient to read the FDA-approved patient labeling (Medication Guide).
`
`Advise Patients:
`
`Diarrhea
`
`To stop TRULANCEandcontact their healthcare provider if they experience severe diarrhea /see Warnings
`and Precautions (5.2)].
`
`Accidental Ingestion
`
`Accidental ingestion of TRULANCEin children, especially in children less than 6 years of age, may result in
`severe diarrhea and dehydration. Instruct patients to take steps to store TRULANCEsecurely and out of reach
`of children and to dispose of unused TRULANCE/see Contraindications (4), Warnings and Precautions (5.2)].
`
`Administration and Handling Instructions
`
`e To take TRULANCEoncedaily with or without food /see Dosage and Administration (2.2)].
`e
`Ifa dose is missed, skip the missed dose andtake the next doseat the regular time. Do not take two dosesat
`the sametime.
`
`e To swallow TRULANCEtablets whole.
`e
`Ifadult patients have swallowing difficulties, TRULANCEtablets can be crushed and administered orally in
`either applesauce or with water, or administered with water via a nasogastric or gastric feeding tube, as
`described in the Medication Guide.
`e To keep TRULANCEinadry place. Protect from moisture. For bottles, keep TRULANCEintheoriginal
`bottle. Do not remove desiccant from the bottle. Do not subdivide or repackage. Remove and discard
`polyester coil after opening. Keep bottles closed tightly /see How Supplied/Storage and Handling (16)/.
`
`TRULANCE™is a trademark of Synergy Pharmaceuticals Inc.
`
`Manufactured for:
`Synergy Pharmaceuticals Inc.
`420 Lexington Avenue, Suite 2012
`New York, New York 10170
`
`Reference ID: 4044252
`
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`Medication Guide
`TRULANCE™(troo’ lans)
`(plecanatide) tablets
`
`Whatis the most important information | should know about TRULANCE?
`e Do not give TRULANCE to children whoare less than 6 years of age.
`It may harm them.
`e You should not give TRULANCE to children 6 yearsto less than 18 years of age.
`It may harm
`them.
`
`See “Whatare the possible side effects of TRULANCE?”for more information aboutside effects.
`
`What is TRULANCE?
`
`TRULANCE is a prescription medicine used in adults to treat a type of constipation called chronic
`idiopathic constipation (CIC).
`Idiopathic means the cause of the constipation is unknown.
`It is not known if TRULANCE is safe and effective in children less than 18 years of age.
`
`Whoshould not take TRULANCE?
`
`Swallow all of the TRULANCE tablet and water mixture right away. Do not keep the mixture for
`
`e Do not give TRULANCE tochildren whoare less than 6 years of age.
`e Do not take TRULANCE if a doctor has told you that you have a bowel blockage (intestinal obstruction).
`
`Before taking TRULANCE,tell your doctor aboutall of your medical conditions, includingif you:
`e are pregnantor plan to become pregnant.
`It is not known if TRULANCE will harm your unborn baby.
`e are breastfeeding or plan to breastfeed.
`It is not known if TRULANCE passesinto your breast milk.
`Talk with your doctor about the best way to feed your baby if you take TRULANCE.
`Tell your doctor about all the medicines you take, including prescription and over-the-counter
`medicines, vitamins, and herbal supplements.
`
`How should I take TRULANCE?
`
`e Take TRULANCE exactly as your doctortells you to takeit.
`e Take TRULANCE by mouth, 1 time each daywith or without food.
`e If you miss a dose, skip the missed dose. Take the next dose at your regular time. Do not take 2
`doses at the same time.
`e TRULANCE tablets should be swallowed whole.
`
`o Adults who cannot swallow TRULANCE tablets whole may crush the TRULANCE tablet and mix with
`applesauce or dissolve TRULANCE in water before swallowing. TRULANCE tablets may also be
`taken with water by adults through a nasogastric or gastric feeding tube.
`It is not known if TRULANCE is safe and effective when crushed and mixed with other foods or dissolved
`in otherliquids.
`Taking TRULANCE in applesauce:
`
`e
`
`e Crush the TRULANCE tablet in a clean containeruntil it is a powder and mix with 1 teaspoon of
`room temperature applesauce.
`Swallow all of the TRULANCE and applesauce mixture right away. Do not keep the TRULANCE
`and applesauce mixture for future use.
`Taking TRULANCE in water:
`Place the TRULANCE tablet in a clean cup and pour 1 ounce (30 mL) of room temperature water
`into the cup.
`Gently swirl the TRULANCE tablet and waterfor at least 10 seconds. The TRULANCE tabletwill
`fall apart in the water.
`
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`future use.
`
`e
`
`If you see any part of the tabletleft in the cup, add another 1 ounce (30 mL) of waterto the cup,
`swirl for at least 10 seconds, and swallow right away.
`Taking TRULANCE through a nasogastric or gastric feeding tube:
`Gatherthe supplies you will need to take your TRULANCE dose. Your doctor should tell you what size
`cathetertipped syringe you will need for your dose. Ask your doctorif you have any questions about how
`to give TRULANCE theright way.
`Place the TRULANCE tablet in a clean cup with 1 ounce (30 mL) of room temperature water.
`Gently swirl the TRULANCE tablet and waterfor at least 15 seconds. The TRULANCE tabletwill
`fall apart in the water.
`Flush the nasogastric or gastric feeding tube with 1 ounce (30 mL) of water.
`Draw up the TRULANCE tablet and water mixture into a catheter tipped syringe and give right
`awaythrough the nasogastric or gastric feeding tube. Do not keep the mixture for future use.
`If you see anypart of the tablet left in the cup, add another 1 ounce (30 mL) of water to the cup,
`sw