ADVERSE REACTIONS SECTION.


6ADVERSE REACTIONS. Most common adverse 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/medwatch.. 6.1Clinical Trials Experience. Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.Demographic characteristics were comparable between the TRULANCE and placebo groups in all studies [see Clinical Studies (14)].. Chronic Idiopathic Constipation (CIC)The safety data described below reflect data from 1733 adult patients with CIC randomized in two double-blind, placebo-controlled clinical trials (Study and Study 2) to receive placebo or mg of TRULANCE once daily for 12 weeks.. Most Common Adverse ReactionsTable provides the incidence of adverse reactions reported in at least 2% of CIC patients in the TRULANCE-treated group and at an incidence that was greater than in the placebo group.Table 1: Most Common Adverse Reactionsa in Two Placebo-Controlled Trials of TRULANCE [Study and Study 2] in Patients with CICAdverse ReactionTRULANCE, mg(N 863)%Placebo(N 870)%a: Reported in at least 2% of TRULANCE-treated patients with CIC and at an incidence greater than placebo.Diarrhea51. DiarrheaThe majority of reported cases of diarrhea occurred within weeks of treatment initiation. Severe diarrhea was reported in 0.6% of TRULANCE-treated patients compared to 0.3% of placebo-treated patients. Severe diarrhea was reported to occur within the first days of treatment [see Warnings and Precautions (5.2)].. Adverse Reactions Leading to DiscontinuationDiscontinuations due to adverse reactions occurred in 4% of TRULANCE-treated patients and 2% of placebo-treated patients. The most common adverse reaction leading to discontinuation was diarrhea: 2% of TRULANCE-treated patients and 0.5% of placebo-treated patients withdrew due to diarrhea. Less Common Adverse ReactionsAdverse 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 biochemical tests (2 patients with alanine aminotransferase (ALT) greater than to 15 times the upper limit of normal and patients with aspartate aminotransferase (AST) greater than times the upper limit of normal).. Irritable Bowel Syndrome with Constipation (IBS-C)The safety data described below reflect data from 1449 adult patients with IBS-C randomized in two double-blind, placebo-controlled clinical trials (Study and Study 4) to receive placebo or mg TRULANCE once daily for 12 weeks.. Most Common Adverse ReactionsTable provides the incidence of adverse reactions reported in at least 2% of IBS-C patients treated with TRULANCE and at an incidence that was greater than in the placebo group.Table 2: Most Common Adverse Reactionsa in Two Placebo-Controlled Trials of TRULANCE [Study and Study 4] in Patients with IBS-CAdverse ReactionTRULANCE, mg(N 723)%Placebo(N 726)%a: Reported in at least 2% of TRULANCE-treated patients with IBS-C and at an incidence greater than placebo.b: Verbatim reports of diarrhea were recorded as adverse reactions; reports of loose stools and increase in stool frequency were recorded as adverse reactions if they were also reported to be bothersome to the patient.Diarrheab 4.31. DiarrheaThe majority of reported cases of diarrhea occurred within weeks of treatment initiation. Severe diarrhea was reported in 1% of TRULANCE-treated patients compared to 0.1% of placebo-treated patients [see Warnings and Precautions (5.2)]. Severe diarrhea was reported to occur within the first day of treatment.. Adverse Reactions Leading to DiscontinuationDiscontinuations due to adverse reactions occurred in 2.5% of TRULANCE-treated patients and 0.4% of placebo-treated patients. The most common adverse reaction leading to discontinuation was diarrhea: 1.2% of TRULANCE-treated patients and 0% of placebo-treated patients withdrew due to diarrhea. Less Common Adverse ReactionsAdverse reactions reported in 1% or more but less than 2% of TRULANCE-treated patients and at an incidence greater than placebo were: nausea, nasopharyngitis, upper respiratory tract infection, urinary tract infection, and dizziness. Two patients reported increased liver biochemical tests (alanine aminotransferase (ALT) greater than to 15 times the upper limit of normal).

BOXED WARNING SECTION.


WARNING: RISK OF SERIOUS DEHYDRATION IN PEDIATRIC PATIENTS. oTRULANCE is contraindicated in patients less than years of age; in nonclinical studies in young juvenile mice administration of single oral dose of plecanatide caused deaths due to dehydration [see Contraindications (4), Use in Specific Populations (8.4)].oAvoid use of TRULANCE in patients years to less than 18 years of age [see Warnings and Precautions (5.1), Use in Specific Populations (8.4)].oThe safety and effectiveness of TRULANCE have not been established in patients less than 18 years of age [see Use in Specific Populations (8.4)].. oTRULANCE is contraindicated in patients less than years of age; in nonclinical studies in young juvenile mice administration of single oral dose of plecanatide caused deaths due to dehydration [see Contraindications (4), Use in Specific Populations (8.4)].. oAvoid use of TRULANCE in patients years to less than 18 years of age [see Warnings and Precautions (5.1), Use in Specific Populations (8.4)].. oThe safety and effectiveness of TRULANCE have not been established in patients less than 18 years of age [see Use in Specific Populations (8.4)].. WARNING: RISK OF SERIOUS DEHYDRATION IN PEDIATRIC PATIENTSSee full prescribing information for complete boxed warning.oTRULANCE is contraindicated in patients less than years of age; in young juvenile mice, plecanatide caused death due to dehydration. (4, 8.4)oAvoid use of TRULANCE in patients years to less than 18 years of age. (5.1, 8.4)oThe safety and effectiveness of TRULANCE have not been established in patients less than 18 years of age. (8.4). oTRULANCE is contraindicated in patients less than years of age; in young juvenile mice, plecanatide caused death due to dehydration. (4, 8.4). oAvoid use of TRULANCE in patients years to less than 18 years of age. (5.1, 8.4). oThe safety and effectiveness of TRULANCE have not been established in patients less than 18 years of age. (8.4).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.


13.1Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisThe carcinogenic potential of plecanatide was assessed in 2-year carcinogenicity studies in mice and rats. Plecanatide was not tumorigenic in mice at oral doses up to 90 mg/kg/day or in rats at oral doses up to 100 mg/kg/day. Limited systemic exposure to plecanatide was achieved at the tested dose levels in animals, whereas no detectable exposure occurred in humans. Therefore, animal and human doses should not be compared directly for evaluating relative exposure.. MutagenesisPlecanatide was not genotoxic in the in vitro bacterial reverse mutation (Ames) assay, in vitro mouse lymphoma mutation assay, or the in vivo mouse bone marrow micronucleus assay.. Impairment of FertilityPlecanatide had no effect on fertility or reproductive function in male or female mice at oral doses of up to 600 mg/kg/day.

CLINICAL PHARMACOLOGY SECTION.


12CLINICAL PHARMACOLOGY. 12.1Mechanism of Action. Plecanatide is structural analog of human uroguanylin, and similarly to uroguanylin, plecanatide functions as guanylate cyclase-C (GC-C) agonist. Both plecanatide and its active metabolite bind to GC-C and act 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 extracellular cGMP has been associated with decrease in the activity of pain-sensing nerves in animal models of visceral pain. 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 shown to increase fluid secretion into the gastrointestinal (GI) tract, accelerate intestinal transit, and cause changes in stool consistency.In an animal model of visceral pain, plecanatide reduced abdominal muscle contractions, measure of intestinal pain.. 12.2Pharmacodynamics. Food EffectSubjects who received either low-fat, low calorie (LF-LC) meal or high fat, high calorie (HF-HC) meal reported looser stools than fasted subjects up to 24 hours after single dose of TRULANCE mg (3 times the recommended dose). In clinical studies, TRULANCE was administered with or without food [see Dosage and Administration (2.2)].. 12.3Pharmacokinetics. AbsorptionPlecanatide was minimally absorbed with negligible systemic availability following oral administration. Concentrations of plecanatide and its active metabolite in plasma were below the limit of quantitation in the majority of analyzed plasma samples after an oral TRULANCE dose of mg. Therefore, standard pharmacokinetic parameters such as AUC, maximum concentration (Cmax), and half-life (t 1/2 could not be calculated.. Food EffectIn crossover study, 24 healthy subjects were given single dose of TRULANCE mg (3 times the recommended dose) in different states: fasted; following low-fat, low-calorie meal (LF-LC; approximately 350 calories: 17% from fat, 66% from carbohydrate, and 17% from protein); and following high-fat, high-calorie meal (HF-HC; approximately 1000 calories: 60% from fat, 25% from carbohydrate, and 15% from protein). Plecanatide was detected in subject (fasted state) at 0.5 and 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.. DistributionGiven that plecanatide concentrations following clinically relevant oral doses were not measurable, plecanatide is expected to be minimally distributed in tissues. Oral plecanatide was localized to the GI tract where it exerted its effects as GC-C agonist with negligible systemic exposure. Plecanatide exhibited little to no binding to human serum albumin or human -1-acid glycoprotein.. Elimination. MetabolismPlecanatide was metabolized in the GI tract to an active metabolite by loss of the terminal leucine moiety. Both plecanatide and the metabolite were proteolytically degraded within the intestinal lumen to smaller peptides and naturally occurring amino acids.. ExcretionNo excretion studies have been conducted in humans. Plecanatide and its active metabolite were not measurable in plasma following administration of the recommended clinical doses.. Drug Interaction StudiesNeither plecanatide nor its active metabolite inhibited the cytochrome P450 (CYP) enzymes 2C9 and 3A4, and they did not induce CYP3A4 in vitro.Plecanatide and its active metabolite were neither substrates nor inhibitors of the transporters P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) in vitro.

CLINICAL STUDIES SECTION.


14CLINICAL STUDIES. 14.1 Chronic Idiopathic Constipation (CIC). The efficacy of TRULANCE for the management of symptoms of CIC was established in two 12-week, double-blind, placebo-controlled, randomized, multicenter clinical studies in adult patients (Study and Study 2). In the Intention-to-Treat (ITT) population, total of 905 patients (Study 1) and 870 patients (Study 2) were randomized 1:1 to either placebo or TRULANCE mg, once daily. 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 Rome III criteria for at least months prior to the screening visit, with symptom onset for at least months prior to diagnosis. Rome III criteria were modified to require that patients report less than defecations per week, rarely have loose stool without the use of laxatives, not use manual maneuvers to facilitate defecations, and not meet criteria for IBS-C. In addition, patients were required to report at least two of the following symptoms:oStraining during at least 25% of defecationsoLumpy or hard stool in at least 25% of defecationsoSensation of incomplete evacuations for at least 25% of defecationsoSensation of anorectal obstruction/blockage for at least 25% of defecationsPatients who met these criteria were also required to demonstrate the following during the last weeks of the screening period:oLess than complete spontaneous bowel movements (CSBMs) (a CSBM is an SBM that is associated with sense of complete evacuation) in each of the two weeksoBristol Stool Form Scale (BSFS) of or in less than 25% of spontaneous bowel movements (SBMs) (an SBM is bowel movement occurring in the absence of laxative use)oOne out of the following three: oBSFS of or in at least 25% of defecationsoA straining value recorded on at least 25% of days when BM was reportedoAt least 25% of BMs result in sense of incomplete evacuationThe efficacy of TRULANCE was assessed using responder analysis and change-from-baseline in CSBM and SBM endpoints. Efficacy was assessed using information provided by patients on daily basis in an electronic diary. responder was defined as patient who had at least CSBMs in given week and an increase of at least CSBM from baseline in the same week for at least weeks out of the 12 week treatment period and at least of the last weeks of the study. The responder rates are shown in Table 3.Table 3: Efficacy Responder Rates in the Two Placebo-controlled Studies of CIC: at least of 12 weeks and at least of the last weeks (ITT Population)a: p-value <0.005b: CI confidence intervalc: Primary endpoint defined as patient who had least CSBMs in given week and an increase of at least CSBM from baseline in the same week for at least weeks out of the 12 week treatment period and at least of the last weeks of the study.Study 1TRULANCE mgN 453PlaceboN 452Treatment Differencea [95% CIb]Responderc 21%10%11%[6.1%, 15.4%]Study 2TRULANCE mgN 430PlaceboN 440Treatment Differencea [95% CIb]Responderc 21%13%8%[2.6%, 12.4%]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 TRULANCE group and the placebo group in the mean change of CSBMs/week frequency from baseline to week 12 was approximately 1.1 CSBMs/week.Over the 12 week treatment period, improvements were observed in stool frequency (number of CSBMs/week and SBMs/week) and/or stool consistency (as measured by the BSFS), and/or in the amount of straining with bowel movements (amount of time pushing or physical effort to pass stool) in the TRULANCE group as compared to placebo.Following completion of the study drug treatment period, patients continued to record data in the daily diary for 2 week Post-Treatment Period. During this time, TRULANCE-treated patients generally returned to baseline for these study endpoints.In Studies and 2, third randomized treatment arm of TRULANCE mg once daily did not demonstrate additional treatment benefit and had greater incidence of adverse reactions than TRULANCE mg once daily. Therefore, TRULANCE mg once daily is not recommended [see Dosage and Administration (2.1)]. oStraining during at least 25% of defecations. oLumpy or hard stool in at least 25% of defecations. oSensation of incomplete evacuations for at least 25% of defecations. oSensation of anorectal obstruction/blockage for at least 25% of defecations. oLess than complete spontaneous bowel movements (CSBMs) (a CSBM is an SBM that is associated with sense of complete evacuation) in each of the two weeks. oBristol Stool Form Scale (BSFS) of or in less than 25% of spontaneous bowel movements (SBMs) (an SBM is bowel movement occurring in the absence of laxative use). oOne out of the following three: oBSFS of or in at least 25% of defecationsoA straining value recorded on at least 25% of days when BM was reportedoAt least 25% of BMs result in sense of incomplete evacuation. oBSFS of or in at least 25% of defecations. oA straining value recorded on at least 25% of days when BM was reported. oAt least 25% of BMs result in sense of incomplete evacuation. 14.2 Irritable Bowel Syndrome with Constipation (IBS-C). The efficacy of TRULANCE for the management of symptoms of IBS-C was established in two 12-week, double-blind, placebo-controlled, randomized, multicenter clinical studies in adult patients (Study and Study 4). In the Intention-to-Treat (ITT) population, total of 699 patients (Study 3) and 754 patients (Study 4) received treatment with placebo or TRULANCE mg once daily. In clinical studies, study medication was administered without respect to food intake. Demographics for these studies included an overall mean age of 44 years (range 18 to 83 years), 74% female, 73% white, and 22% black.To be eligible, patients were required to meet the Rome III criteria for IBS for at least months prior to the screening visit, with symptom onset for at least months prior to diagnosis. Diagnosis required recurrent abdominal pain or discomfort at least days/month in the last months associated with or more of 1) improvement with defecation, 2) onset associated with change in frequency of stool, and 3) onset associated with change in form (appearance) of stool. Patients also met the IBS-C differentiation criteria for constipation, characterized by stool pattern such that at least 25% of defecations are hard or lumpy stools and no more than 25% of defecations are loose or watery stool.Patients who met these criteria were excluded if they demonstrated the following during the last weeks of the screening period:oWorst abdominal pain intensity (WAPI) score of on an 11-point scale for more than days during each weekoAn average WAPI of less than for either weekoMore than complete spontaneous bowel movements (CSBMs) or more than six spontaneous bowel movements (SBMs) per week in either weekoBristol Stool Form Scale (BSFS) of for any SBM recordedoMore than day in either week with BSFS of for any SBM recordedoNo use of rescue laxative (bisacodyl) within 72 hours before randomizationThe efficacy of TRULANCE was assessed using responder analysis based on abdominal pain intensity and stool frequency responder (CSBM) endpoint. Efficacy was assessed using information provided by patients on daily basis through an electronic phone diary system.A responder was defined as patient who met both the abdominal pain intensity and stool frequency responder criteria in the same week for at least of the 12 treatment weeks. The abdominal pain intensity and stool frequency responder criteria assessed each week were defined as:oAbdominal pain intensity responder: patient who experienced decrease in the weekly average of worst abdominal pain in the past 24 hours score (measured daily) of at least 30% compared with baseline weekly average.oStool frequency responder: patient who experienced an increase of at least CSBM per week from baseline.The responder rates are shown in Table 4.Table 4: Efficacy Responder Rates in the Two Placebo-controlled Studies of IBS-C: Overall Responder for at least of the 12 Treatment Weeks (ITT Population)a: CI confidence interval b: responder for these trials was defined as patient who met both the abdominal pain and CSBM weekly responder criteria for at least of the 12 weeks.c: An abdominal pain responder was defined as patient who met the criteria of at least 30% reduction from baseline in weekly average of the worst daily abdominal pain, for at least of the 12 weeks. d: CSBM responder was defined as patient who achieved an increase in at least CSBM per week, from baseline, for at least of 12 weeks. Study 3PlaceboN 350TRULANCE mgN 349Treatment Difference[95% CIa]Responderb 18%30%12%[6%, 18%] Components of Responder Endpoint Abdominal Pain Responderc 32%41% CSBM Responderd 35%48%Study 4PlaceboN 379TRULANCE mgN 375Treatment Difference[95% CIa]Responderb 14%21%7%[2%, 13%] Components of Responder Endpoint Abdominal Pain Responderc 23%33% CSBM Responderd 28%34%In both studies, the proportion of responders who were also weekly responders for at least of the treatment weeks in month 3, the last month of treatment was greater in the TRULANCE groups compared to placebo.Over the 12 week treatment period, improvements were observed in both stool consistency (as measured by the BSFS) and in the amount of straining with bowel movements (amount of time pushing or physical effort to pass stool) in the mg TRULANCE group as compared to placebo.Following completion of the study drug treatment period, patients continued to record data in the daily diary for 2-week Post-Treatment Period. During this time, TRULANCE-treated patients generally returned to baseline for these study endpoints.In Studies and 4, third randomized treatment arm of TRULANCE mg once daily did not demonstrate additional treatment benefit over the mg dose. Therefore, TRULANCE mg once daily is not recommended [see Dosage and Administration (2.1)]. oWorst abdominal pain intensity (WAPI) score of on an 11-point scale for more than days during each week. oAn average WAPI of less than for either week. oMore than complete spontaneous bowel movements (CSBMs) or more than six spontaneous bowel movements (SBMs) per week in either week. oBristol Stool Form Scale (BSFS) of for any SBM recorded. oMore than day in either week with BSFS of for any SBM recorded. oNo use of rescue laxative (bisacodyl) within 72 hours before randomization. oAbdominal pain intensity responder: patient who experienced decrease in the weekly average of worst abdominal pain in the past 24 hours score (measured daily) of at least 30% compared with baseline weekly average.. oStool frequency responder: patient who experienced an increase of at least CSBM per week from baseline.

CONTRAINDICATIONS SECTION.


4CONTRAINDICATIONS. TRULANCE is contraindicated in:oPatients less than years of age due to the risk of serious dehydration [see Warnings and Precautions (5.1), Use in Specific Populations (8.4)].oPatients with known or suspected mechanical gastrointestinal obstruction.. oPatients less than years of age due to the risk of serious dehydration [see Warnings and Precautions (5.1), Use in Specific Populations (8.4)].. oPatients with known or suspected mechanical gastrointestinal obstruction.. oPatients less than years of age due to the risk of serious dehydration. (4, 5.1, 8.4)oPatients with known or suspected mechanical gastrointestinal obstruction. (4). oPatients less than years of age due to the risk of serious dehydration. (4, 5.1, 8.4). oPatients with known or suspected mechanical gastrointestinal obstruction. (4).

DESCRIPTION SECTION.


11DESCRIPTION. TRULANCE (plecanatide) is guanylate cyclase-C (GC-C) agonist. Plecanatide is 16 amino acid peptide with the following chemical name: L-Leucine, L-asparaginyl-L--aspartyl-L--glutamyl-L-cysteinyl-L--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 C65H104N18O26S4 and the molecular weight is 1682 Daltons. The amino acid sequence for plecanatide is shown below:The solid lines linking cysteines illustrate disulfide bridges.Plecanatide is an amorphous, white to off-white powder. It is soluble in water. TRULANCE tablets are supplied as mg tablets for oral administration. The inactive ingredients are magnesium stearate and microcrystalline cellulose.. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.


2DOSAGE AND ADMINISTRATION. The recommended adult dosage of TRULANCE isoCIC: mg taken orally once daily. (2.1)oIBS-C: mg taken orally once daily. (2.1)Administration Instructions (2.2):oTake with or without food.oSwallow tablets whole.oFor patients who have difficulty swallowing tablets whole or those with nasogastric or gastric feeding tube, see full prescribing information with instructions for crushing the tablet and administering with applesauce or water.. oCIC: mg taken orally once daily. (2.1). oIBS-C: mg taken orally once daily. (2.1). oTake with or without food.. oSwallow tablets whole.. oFor patients who have difficulty swallowing tablets whole or those with nasogastric or gastric feeding tube, see full prescribing information with instructions for crushing the tablet and administering with applesauce or water.. 2.1Recommended Dosage. The recommended dosage of TRULANCE for the treatment of CIC and IBS-C is mg taken orally once daily.. 2.2Preparation and Administration Instructions. oTake TRULANCE with or without food [see Clinical Pharmacology (12.3)].oIf dose is missed, skip the missed dose and take the next dose at the regular time. Do not take two doses at the same time.oSwallow tablet whole for each dose.oFor adult patients with swallowing difficulties, TRULANCE tablets can be crushed and administered orally either in applesauce or with water or administered with water via nasogastric or gastric feeding tube. Mixing TRULANCE crushed tablets in other soft foods or in other liquids has not been tested.. oTake TRULANCE with or without food [see Clinical Pharmacology (12.3)].. oIf dose is missed, skip the missed dose and take the next dose at the regular time. Do not take two doses at the same time.. oSwallow tablet whole for each dose.. oFor adult patients with swallowing difficulties, TRULANCE tablets can be crushed and administered orally either in applesauce or with water or administered with water via nasogastric or gastric feeding tube. Mixing TRULANCE crushed tablets in other soft foods or in other liquids has not been tested.. Oral Administration in Applesauce:1.In clean container, crush the TRULANCE tablet to powder and mix with teaspoonful of room temperature applesauce. 2.Consume the entire tablet-applesauce mixture immediately. Do not store the mixture for later use.. 1.In clean container, crush the TRULANCE tablet to powder and mix with teaspoonful of room temperature applesauce. 2.Consume the entire tablet-applesauce mixture immediately. Do not store the mixture for later use.. Oral Administration in Water:1.Place the TRULANCE tablet in clean cup.2.Pour approximately 30 mL of room temperature water into the cup.3.Mix by gently swirling the tablet and water mixture for at least 10 seconds. The TRULANCE tablet will fall apart in the water.4.Swallow the entire contents of the tablet water mixture immediately.5.If any portion of the tablet is left in the cup, add another 30 mL of water to the cup, swirl for at least 10 seconds, and swallow immediately.6.Do not store the tablet-water mixture for later use.. 1.Place the TRULANCE tablet in clean cup.. 2.Pour approximately 30 mL of room temperature water into the cup.. 3.Mix by gently swirling the tablet and water mixture for at least 10 seconds. The TRULANCE tablet will fall apart in the water.. 4.Swallow the entire contents of the tablet water mixture immediately.. 5.If any portion of the tablet is left in the cup, add another 30 mL of water to the cup, swirl for at least 10 seconds, and swallow immediately.. 6.Do not store the tablet-water mixture for later use.. Administration with Water via Nasogastric or Gastric Feeding Tube:1.Place the TRULANCE tablet in clean cup with 30 mL of room temperature water.2.Mix by gently swirling the tablet and water mixture for at least 15 seconds. The TRULANCE tablet will fall apart in the water.3.Flush the nasogastric or gastric feeding tube with 30 mL of water using catheter tip syringe.4.Draw up the mixture using the syringe and immediately administer via the nasogastric or gastric feeding tube. Do not reserve for future use.5.If any portion of the tablet is left in the cup, add another 30 mL of water to the cup, swirl for at least 15 seconds, and using the same syringe, administer via the nasogastric or gastric feeding tube. 6.Using the same or fresh syringe, flush the nasogastric or gastric feeding tube with at least 10 mL of water.. 1.Place the TRULANCE tablet in clean cup with 30 mL of room temperature water.. 2.Mix by gently swirling the tablet and water mixture for at least 15 seconds. The TRULANCE tablet will fall apart in the water.. 3.Flush the nasogastric or gastric feeding tube with 30 mL of water using catheter tip syringe.. 4.Draw up the mixture using the syringe and immediately administer via the nasogastric or gastric feeding tube. Do not reserve for future use.. 5.If any portion of the tablet is left in the cup, add another 30 mL of water to the cup, swirl for at least 15 seconds, and using the same syringe, administer via the nasogastric or gastric feeding tube. 6.Using the same or fresh syringe, flush the nasogastric or gastric feeding tube with at least 10 mL of water.

DOSAGE FORMS & STRENGTHS SECTION.


3DOSAGE FORMS AND STRENGTHS. Tablets: mg (3). TRULANCE Tablets:3 mg: white to off-white, plain, round tablet debossed with SP on one side and 3 for mg on the other side.

GERIATRIC USE SECTION.


8.5Geriatric Use. Chronic Idiopathic Constipation (CIC)Of 2601 subjects in placebo-controlled clinical trials of TRULANCE, 273 (10%) were 65 years of age and over, and 47 (2%) were 75 years and over. Clinical studies of TRULANCE did 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.. Irritable Bowel Syndrome with Constipation (IBS-C)Of 1621 subjects in the placebo-controlled clinical studies of TRULANCE, 134 (8.3%) were 65 years of age and over, and 25 (1.5%) were 75 years and over. Clinical studies of TRULANCE did 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.

HOW SUPPLIED SECTION.


16HOW SUPPLIED/STORAGE AND HANDLING. TRULANCE tablets are packaged in an aluminum foil unit dose blister pack of 30 in child-resistant pack or in white, opaque, high-density polyethylene round bottle with screw-top polypropylene child-resistant cap and heat-activated induction seal. Each bottle container-closure system also contains desiccant and polyester coil.TRULANCE mg tablets are white to off-white, plain and round, debossed with SP on one side and 3 for mg on the other side and supplied as:NDC NumberSize70194-203-30Bottle of 3070194-003-30Aluminum foil unit dose blister pack of 30 in child-resistant pack. Store at room temperature, 20 to 25C (68 to 77F); excursions permitted to 15 to 30C (59 to 86F) [see USP Controlled Room Temperature].Keep TRULANCE in dry place. Protect from moisture. For bottles, keep TRULANCE in the original bottle. Do not remove desiccant from the bottle. Do not subdivide or repackage.

INDICATIONS & USAGE SECTION.


1INDICATIONS AND USAGE. TRULANCE is indicated in adults for the treatment of:ochronic idiopathic constipation (CIC).oirritable bowel syndrome with constipation (IBS-C). ochronic idiopathic constipation (CIC).. oirritable bowel syndrome with constipation (IBS-C). TRULANCE is guanylate cyclase-C agonist indicated in adults for treatment of:ochronic idiopathic constipation (CIC). (1)oirritable bowel syndrome with constipation (IBS-C). (1). ochronic idiopathic constipation (CIC). (1). oirritable bowel syndrome with constipation (IBS-C). (1).

INFORMATION FOR PATIENTS SECTION.


17PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Medication Guide).Advise Patients:. DiarrheaTo stop TRULANCE and contact their healthcare provider if they experience severe diarrhea [see Warnings and Precautions (5.2)].. Accidental IngestionAccidental ingestion of TRULANCE in children, especially in children less than years of age, may result in severe diarrhea and dehydration. Instruct patients to take steps to store TRULANCE securely and out of reach of children and to dispose of unused TRULANCE [see Contraindications (4), Warnings and Precautions (5.2)].. Administration and Handling InstructionsoTo take TRULANCE once daily with or without food [see Dosage and Administration (2.2)].oIf dose is missed, skip the missed dose and take the next dose at the regular time. Do not take two doses at the same time.oTo swallow TRULANCE tablets whole.oIf adult patients have swallowing difficulties, TRULANCE tablets can be crushed and administered orally in either applesauce or with water, or administered with water via nasogastric or gastric feeding tube, as described in the Medication Guide.oTo keep TRULANCE in dry place. Protect from moisture. For bottles, keep TRULANCE in the original 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)].. oTo take TRULANCE once daily with or without food [see Dosage and Administration (2.2)].. oIf dose is missed, skip the missed dose and take the next dose at the regular time. Do not take two doses at the same time.. oTo swallow TRULANCE tablets whole.. oIf adult patients have swallowing difficulties, TRULANCE tablets can be crushed and administered orally in either applesauce or with water, or administered with water via nasogastric or gastric feeding tube, as described in the Medication Guide.. oTo keep TRULANCE in dry place. Protect from moisture. For bottles, keep TRULANCE in the original 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)].

LACTATION SECTION.


8.2Lactation. Risk SummaryThere 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 and its 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 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 and health benefits of breastfeeding should be considered along with the mothers clinical need for TRULANCE and any potential adverse effects on the breastfed infant from TRULANCE or from the underlying maternal condition.

MECHANISM OF ACTION SECTION.


12.1Mechanism of Action. Plecanatide is structural analog of human uroguanylin, and similarly to uroguanylin, plecanatide functions as guanylate cyclase-C (GC-C) agonist. Both plecanatide and its active metabolite bind to GC-C and act 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 extracellular cGMP has been associated with decrease in the activity of pain-sensing nerves in animal models of visceral pain. 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 shown to increase fluid secretion into the gastrointestinal (GI) tract, accelerate intestinal transit, and cause changes in stool consistency.In an animal model of visceral pain, plecanatide reduced abdominal muscle contractions, measure of intestinal pain.

NONCLINICAL TOXICOLOGY SECTION.


13NONCLINICAL TOXICOLOGY. 13.1Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisThe carcinogenic potential of plecanatide was assessed in 2-year carcinogenicity studies in mice and rats. Plecanatide was not tumorigenic in mice at oral doses up to 90 mg/kg/day or in rats at oral doses up to 100 mg/kg/day. Limited systemic exposure to plecanatide was achieved at the tested dose levels in animals, whereas no detectable exposure occurred in humans. Therefore, animal and human doses should not be compared directly for evaluating relative exposure.. MutagenesisPlecanatide was not genotoxic in the in vitro bacterial reverse mutation (Ames) assay, in vitro mouse lymphoma mutation assay, or the in vivo mouse bone marrow micronucleus assay.. Impairment of FertilityPlecanatide had no effect on fertility or reproductive function in male or female mice at oral doses of up to 600 mg/kg/day.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


PRINCIPAL DISPLAY PANEL 3 mg Tablet Blister Pack Carton. NDC 70194-003-30Trulance(R) (plecanatide) tablets3 mgATTENTION PHARMACIST:Dispense the accompanyingMedication Guide to each patient.Rx Only 30 TabletsKEEP OUT OF REACH OF CHILDREN.Dosage and Administration:One tablet once daily.See full Prescribing Information.Each tablet contains mg plecanatideStore at room temperature, 20-25C(68-77F); excursions permitted to15-30C (59-86F) [USP ControlledRoom Temperature].. PRINCIPAL DISPLAY PANEL 3 mg Tablet Blister Pack Carton.

PEDIATRIC USE SECTION.


8.4Pediatric Use. TRULANCE is contraindicated in pediatric patients less than years of age. Avoid use of TRULANCE in patients years to less than 18 years of age [see Contraindications (4), Warnings and Precautions (5.1)]. The safety and effectiveness of TRULANCE in patients 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 month to less than years) following oral administration of plecanatide, as described below in Juvenile Animal Toxicity Data. Because of increased intestinal expression of GC-C, patients less than years of age may be more likely than patients years of age and older to develop diarrhea and its potentially serious consequences. TRULANCE is contraindicated in patients less than years of age. Given the deaths in young juvenile mice and the lack of clinical safety and efficacy data in pediatric patients, avoid the use of TRULANCE in patients years to less than 18 years of age.. Juvenile Animal Toxicity DataSingle oral doses of plecanatide at 0.5 mg/kg and 10 mg/kg caused mortality in young juvenile mice on postnatal days and 14, respectively (human age equivalent of approximately month to less than 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 years), consistent with increased fluid in the intestinal lumen. Although the recommended human dose is approximately 0.05 mg/kg/day, based on 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.

PHARMACODYNULLMICS SECTION.


12.2Pharmacodynamics. Food EffectSubjects who received either low-fat, low calorie (LF-LC) meal or high fat, high calorie (HF-HC) meal reported looser stools than fasted subjects up to 24 hours after single dose of TRULANCE mg (3 times the recommended dose). In clinical studies, TRULANCE was administered with or without food [see Dosage and Administration (2.2)].

PHARMACOKINETICS SECTION.


12.3Pharmacokinetics. AbsorptionPlecanatide was minimally absorbed with negligible systemic availability following oral administration. Concentrations of plecanatide and its active metabolite in plasma were below the limit of quantitation in the majority of analyzed plasma samples after an oral TRULANCE dose of mg. Therefore, standard pharmacokinetic parameters such as AUC, maximum concentration (Cmax), and half-life (t 1/2 could not be calculated.. Food EffectIn crossover study, 24 healthy subjects were given single dose of TRULANCE mg (3 times the recommended dose) in different states: fasted; following low-fat, low-calorie meal (LF-LC; approximately 350 calories: 17% from fat, 66% from carbohydrate, and 17% from protein); and following high-fat, high-calorie meal (HF-HC; approximately 1000 calories: 60% from fat, 25% from carbohydrate, and 15% from protein). Plecanatide was detected in subject (fasted state) at 0.5 and 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.. DistributionGiven that plecanatide concentrations following clinically relevant oral doses were not measurable, plecanatide is expected to be minimally distributed in tissues. Oral plecanatide was localized to the GI tract where it exerted its effects as GC-C agonist with negligible systemic exposure. Plecanatide exhibited little to no binding to human serum albumin or human -1-acid glycoprotein.. Elimination. MetabolismPlecanatide was metabolized in the GI tract to an active metabolite by loss of the terminal leucine moiety. Both plecanatide and the metabolite were proteolytically degraded within the intestinal lumen to smaller peptides and naturally occurring amino acids.. ExcretionNo excretion studies have been conducted in humans. Plecanatide and its active metabolite were not measurable in plasma following administration of the recommended clinical doses.. Drug Interaction StudiesNeither plecanatide nor its active metabolite inhibited the cytochrome P450 (CYP) enzymes 2C9 and 3A4, and they did not induce CYP3A4 in vitro.Plecanatide and its active metabolite were neither substrates nor inhibitors of the transporters P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) in vitro.

PREGNULLNCY SECTION.


8.1Pregnancy. Risk SummaryPlecanatide and its active metabolite are negligibly absorbed systemically following oral administration [see Clinical Pharmacology (12.3)] and maternal use is not expected to result in fetal exposure to the drug. The available data on TRULANCE use in pregnant women are not sufficient 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 background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the United States general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.. Data. Animal DataPregnant mice and rabbits were administered plecanatide during the period of organogenesis. There was no evidence of harm to embryo-fetal development at oral doses up to 800 mg/kg/day in mice and 250 mg/kg/day in 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, or fertility in the offspring through maturation.The maximum recommended human dose is approximately 0.05 mg/kg/day, based on 60-kg body weight. Limited systemic exposure to plecanatide was achieved in animals during organogenesis (area under the plasma concentration-time curve (AUCt) 449 ngh/mL in rabbits given 250 mg/kg/day). Plecanatide and its 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.

RECENT MAJOR CHANGES SECTION.


Indications and Usage (1)01/2018Dosage and Administration, Recommended Dosage (2.1)01/2018Warnings and Precautions, Diarrhea (5.2)01/2018.

SPL MEDGUIDE SECTION.


Medication GuideTRULANCE(R) (TROO lans)(plecanatide) tabletsThis Medication Guide has been approved by the U.S. Food and Drug Administration.Revised: 02/2018 What is the most important information should know about TRULANCEoDo not give TRULANCE to children who are less than years of age. It may harm them.oYou should not give TRULANCE to children years to less than 18 years of age. It may harm them. See What are the possible side effects of TRULANCE for more information about side effects.What is TRULANCETRULANCE is prescription medicine used in adults to treat:oa type of constipation called chronic idiopathic constipation (CIC). Idiopathic means the cause of the constipation is unknown.oirritable bowel syndrome with constipation (IBS-C).It is not known if TRULANCE is safe and effective in children less than 18 years of age.Who should not take TRULANCEoDo not give TRULANCE to children who are less than years of age.oDo not take TRULANCE if doctor has told you that you have bowel blockage (intestinal obstruction).Before taking TRULANCE, tell your doctor about all of your medical conditions, including if you:oare pregnant or plan to become pregnant. It is not known if TRULANCE will harm your unborn baby.oare breastfeeding or plan to breastfeed. It is not known if TRULANCE passes into 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 take TRULANCEoTake TRULANCE exactly as your doctor tells you to take it.oTake TRULANCE by mouth, time each day with or without food.oIf you miss dose, skip the missed dose. Take the next dose at your regular time. Do not take doses at the same time.oTRULANCE tablets should be swallowed whole. oAdults 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 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 other liquids. Taking TRULANCE in applesauce: oCrush the TRULANCE tablet in clean container until it is powder and mix with teaspoon of room temperature applesauce.oSwallow all of the TRULANCE and applesauce mixture right away. Do not keep the TRULANCE and applesauce mixture for future use.Taking TRULANCE in water:oPlace the TRULANCE tablet in clean cup and pour ounce (30 mL) of room temperature water into the cup.oGently swirl the TRULANCE tablet and water for at least 10 seconds. The TRULANCE tablet will fall apart in the water.oSwallow all of the TRULANCE tablet and water mixture right away. Do not keep the mixture for future use.oIf you see any part of the tablet left in the cup, add another ounce (30 mL) of water to the cup, swirl for at least 10 seconds, and swallow right away.Taking TRULANCE through nasogastric or gastric feeding tube:Gather the supplies you will need to take your TRULANCE dose. Your doctor should tell you what size catheter tip syringe you will need for your dose. Ask your doctor if you have any questions about how to give TRULANCE the right way.oPlace the TRULANCE tablet in clean cup with ounce (30 mL) of room temperature water.oGently swirl the TRULANCE tablet and water for at least 15 seconds. The TRULANCE tablet will fall apart in the water.oFlush the nasogastric or gastric feeding tube with ounce (30 mL) of water.oDraw up the TRULANCE tablet and water mixture into catheter tip syringe and give right away through the nasogastric or gastric feeding tube. Do not keep the mixture for future use. oIf you see any part of the tablet left in the cup, add another ounce (30 mL) of water to the cup, swirl for at least 15 seconds and use the same catheter tip syringe to give the mixture through the nasogastric or gastric feeding tube. oUsing the same or another catheter tip syringe, flush the nasogastric or gastric feeding tube with at least 10 mL of water. What are the possible side effects of TRULANCE TRULANCE can cause serious side effects, including:oSee What is the most important information should know about TRULANCEoDiarrhea is the most common side effect of TRULANCE, and it can sometimes be severe.oDiarrhea often begins within the first weeks of TRULANCE treatment. Stop taking TRULANCE and call your doctor if you develop severe diarrhea.These are not all the possible side effects of TRULANCE. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store TRULANCEoStore TRULANCE at room temperature between 68F to 77F (20C to 25C).oKeep TRULANCE in secure place and in the bottle or blister pack that it comes in.oThe TRULANCE bottle contains desiccant packet to help keep your medicine dry (protect it from moisture). Do not remove the desiccant packet from the bottle.oThe TRULANCE bottle contains polyester coil to help protect the tablets during shipping. Remove the polyester coil from the bottle and throw it away after opening the bottle.oKeep the container of TRULANCE tightly closed and in dry place.oSafely throw away TRULANCE that is out of date or no longer needed.Keep TRULANCE and all medicines out of the reach of children. General information about the safe and effective use of TRULANCE.Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use TRULANCE for condition for which it was not prescribed. Do not give TRULANCE to other people, even if they have the same symptoms that you have. It may harm them. You can ask your doctor or pharmacist for information about TRULANCE that is written for health professionals.What are the ingredients in TRULANCEActive ingredient: plecanatide Inactive ingredients: magnesium stearate and microcrystalline celluloseTRULANCE(R) is registered trademark of Synergy Pharmaceuticals Inc.Manufactured for: Synergy Pharmaceuticals Inc. 420 Lexington Avenue, Suite 2012 New York, New York 10170 (C)2016 Synergy Pharmaceuticals Inc. All rights reserved.For more information, go to www.synergypharma.com or call 1-888-869-8869.. oDo not give TRULANCE to children who are less than years of age. It may harm them.. oYou should not give TRULANCE to children years to less than 18 years of age. It may harm them.. See What are the possible side effects of TRULANCE for more information about side effects.. oa type of constipation called chronic idiopathic constipation (CIC). Idiopathic means the cause of the constipation is unknown.. oirritable bowel syndrome with constipation (IBS-C).. oDo not give TRULANCE to children who are less than years of age.. oDo not take TRULANCE if doctor has told you that you have bowel blockage (intestinal obstruction).. oare pregnant or plan to become pregnant. It is not known if TRULANCE will harm your unborn baby.. oare breastfeeding or plan to breastfeed. It is not known if TRULANCE passes into your breast milk. Talk with your doctor about the best way to feed your baby if you take TRULANCE.. oTake TRULANCE exactly as your doctor tells you to take it.. oTake TRULANCE by mouth, time each day with or without food.. oIf you miss dose, skip the missed dose. Take the next dose at your regular time. Do not take doses at the same time.. oTRULANCE tablets should be swallowed whole. oAdults 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 nasogastric or gastric feeding tube.. oAdults 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 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 other liquids. Taking TRULANCE in applesauce: oCrush the TRULANCE tablet in clean container until it is powder and mix with teaspoon of room temperature applesauce.. oSwallow all of the TRULANCE and applesauce mixture right away. Do not keep the TRULANCE and applesauce mixture for future use.. oPlace the TRULANCE tablet in clean cup and pour ounce (30 mL) of room temperature water into the cup.. oGently swirl the TRULANCE tablet and water for at least 10 seconds. The TRULANCE tablet will fall apart in the water.. oSwallow all of the TRULANCE tablet and water mixture right away. Do not keep the mixture for future use.. oIf you see any part of the tablet left in the cup, add another ounce (30 mL) of water to the cup, swirl for at least 10 seconds, and swallow right away.. oPlace the TRULANCE tablet in clean cup with ounce (30 mL) of room temperature water.. oGently swirl the TRULANCE tablet and water for at least 15 seconds. The TRULANCE tablet will fall apart in the water.. oFlush the nasogastric or gastric feeding tube with ounce (30 mL) of water.. oDraw up the TRULANCE tablet and water mixture into catheter tip syringe and give right away through the nasogastric or gastric feeding tube. Do not keep the mixture for future use. oIf you see any part of the tablet left in the cup, add another ounce (30 mL) of water to the cup, swirl for at least 15 seconds and use the same catheter tip syringe to give the mixture through the nasogastric or gastric feeding tube. oUsing the same or another catheter tip syringe, flush the nasogastric or gastric feeding tube with at least 10 mL of water.. What are the possible side effects of TRULANCE TRULANCE can cause serious side effects, including:. oSee What is the most important information should know about TRULANCE. oDiarrhea is the most common side effect of TRULANCE, and it can sometimes be severe.oDiarrhea often begins within the first weeks of TRULANCE treatment.. oDiarrhea often begins within the first weeks of TRULANCE treatment.. Stop taking TRULANCE and call your doctor if you develop severe diarrhea.These are not all the possible side effects of TRULANCE. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.. oStore TRULANCE at room temperature between 68F to 77F (20C to 25C).. oKeep TRULANCE in secure place and in the bottle or blister pack that it comes in.. oThe TRULANCE bottle contains desiccant packet to help keep your medicine dry (protect it from moisture). Do not remove the desiccant packet from the bottle.. oThe TRULANCE bottle contains polyester coil to help protect the tablets during shipping. Remove the polyester coil from the bottle and throw it away after opening the bottle.. oKeep the container of TRULANCE tightly closed and in dry place.. oSafely throw away TRULANCE that is out of date or no longer needed.. General information about the safe and effective use of TRULANCE.Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use TRULANCE for condition for which it was not prescribed. Do not give TRULANCE to other people, even if they have the same symptoms that you have. It may harm them. You can ask your doctor or pharmacist for information about TRULANCE that is written for health professionals.

SPL UNCLASSIFIED SECTION.


2.1Recommended Dosage. The recommended dosage of TRULANCE for the treatment of CIC and IBS-C is mg taken orally once daily.

STORAGE AND HANDLING SECTION.


Store at room temperature, 20 to 25C (68 to 77F); excursions permitted to 15 to 30C (59 to 86F) [see USP Controlled Room Temperature].Keep TRULANCE in dry place. Protect from moisture. For bottles, keep TRULANCE in the original bottle. Do not remove desiccant from the bottle. Do not subdivide or repackage.

USE IN SPECIFIC POPULATIONS SECTION.


8USE IN SPECIFIC POPULATIONS. 8.1Pregnancy. Risk SummaryPlecanatide and its active metabolite are negligibly absorbed systemically following oral administration [see Clinical Pharmacology (12.3)] and maternal use is not expected to result in fetal exposure to the drug. The available data on TRULANCE use in pregnant women are not sufficient 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 background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the United States general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.. Data. Animal DataPregnant mice and rabbits were administered plecanatide during the period of organogenesis. There was no evidence of harm to embryo-fetal development at oral doses up to 800 mg/kg/day in mice and 250 mg/kg/day in 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, or fertility in the offspring through maturation.The maximum recommended human dose is approximately 0.05 mg/kg/day, based on 60-kg body weight. Limited systemic exposure to plecanatide was achieved in animals during organogenesis (area under the plasma concentration-time curve (AUCt) 449 ngh/mL in rabbits given 250 mg/kg/day). Plecanatide and its 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. 8.2Lactation. Risk SummaryThere 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 and its 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 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 and health benefits of breastfeeding should be considered along with the mothers clinical need for TRULANCE and any potential adverse effects on the breastfed infant from TRULANCE or from the underlying maternal condition.. 8.4Pediatric Use. TRULANCE is contraindicated in pediatric patients less than years of age. Avoid use of TRULANCE in patients years to less than 18 years of age [see Contraindications (4), Warnings and Precautions (5.1)]. The safety and effectiveness of TRULANCE in patients 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 month to less than years) following oral administration of plecanatide, as described below in Juvenile Animal Toxicity Data. Because of increased intestinal expression of GC-C, patients less than years of age may be more likely than patients years of age and older to develop diarrhea and its potentially serious consequences. TRULANCE is contraindicated in patients less than years of age. Given the deaths in young juvenile mice and the lack of clinical safety and efficacy data in pediatric patients, avoid the use of TRULANCE in patients years to less than 18 years of age.. Juvenile Animal Toxicity DataSingle oral doses of plecanatide at 0.5 mg/kg and 10 mg/kg caused mortality in young juvenile mice on postnatal days and 14, respectively (human age equivalent of approximately month to less than 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 years), consistent with increased fluid in the intestinal lumen. Although the recommended human dose is approximately 0.05 mg/kg/day, based on 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.. 8.5Geriatric Use. Chronic Idiopathic Constipation (CIC)Of 2601 subjects in placebo-controlled clinical trials of TRULANCE, 273 (10%) were 65 years of age and over, and 47 (2%) were 75 years and over. Clinical studies of TRULANCE did 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.. Irritable Bowel Syndrome with Constipation (IBS-C)Of 1621 subjects in the placebo-controlled clinical studies of TRULANCE, 134 (8.3%) were 65 years of age and over, and 25 (1.5%) were 75 years and over. Clinical studies of TRULANCE did 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.

WARNINGS AND PRECAUTIONS SECTION.


5WARNINGS AND PRECAUTIONS. Diarrhea: Patients may experience severe diarrhea. If severe diarrhea occurs, suspend dosing and rehydrate the patient. (5.2). 5.1Risk of Serious Dehydration in Pediatric Patients. TRULANCE is contraindicated in patients less than years of age. The safety and effectiveness of TRULANCE in patients less than 18 years of age have not been established. In young juvenile mice (human age equivalent of approximately month to less than years), plecanatide increased fluid-secretion into the intestines as 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 years of age may be more likely than patients years of age and older to develop severe diarrhea and its potentially serious consequences.Avoid the use of TRULANCE in patients years to less than 18 years of age. Although there were no deaths in older juvenile mice, given the deaths in younger mice and the lack of clinical safety and efficacy data in pediatric patients, avoid the use of TRULANCE in patients years to less than 18 years of age [see Contraindications (4), Warnings and Precautions (5.2), Use in Specific Populations (8.4)].. 5.2Diarrhea. Diarrhea was the most common adverse reaction in four placebo-controlled clinical trials, two in patients with CIC and two in patients with IBS-C. Severe diarrhea was reported in 0.6% of patients in two trials in patients with CIC and in 0.6% of patients in the two trials in patients with IBS-C [see Adverse Reactions (6.1)]. If severe diarrhea occurs, suspend dosing and rehydrate the patient.