HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
` These highlights do not include all the information needed to use
` TRULANCE safely and effectively. See full prescribing information for
`
`
` TRULANCE.
`TRULANCE® (plecanatide) tablets, for oral use
`
`
`
`Initial U.S. Approval: 2017
`
`
`
`
`
`
`WARNING: RISK OF SERIOUS DEHYDRATION IN PEDIATRIC
`
` PATIENTS
`
`
`
` See full prescribing information for complete boxed warning.
`
` TRULANCE is 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 TRULANCE in patients 6 years to less than 18 years of
`
`
`age. (5.1, 8.4)
`
`The safety and effectiveness of TRULANCE have not been
`
`
`
` established in patients less than 18 years of age. (8.4)
`
`
`
`•
`
`
`•
`
`
`•
`
` --------------------------- INDICATIONS AND USAGE -------------------------­
`
`
`
`
`TRULANCE is a guanylate cyclase-C agonist indicated in adults for treatment
`of:
`
`
`•
`
`•
`
`chronic idiopathic constipation (CIC). (1)
`
`
`irritable bowel syndrome with constipation (IBS-C). (1)
`
`
`
`
`
`
`---------------------- DOSAGE AND ADMINISTRATION ---------------------­
`
`The recommended adult dosage of TRULANCE is
`
`
`
`CIC: 3 mg taken orally once daily. (2.1)
`•
`
`
`
`
`
`IBS-C: 3 mg taken orally once daily. (2.1)
`•
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`WARNING: RISK OF SERIOUS DEHYDRATION IN PEDIATRIC
`
`
`
`PATIENTS
`
`
`INDICATIONS AND USAGE
`1
`
`
`2
`DOSAGE AND ADMINISTRATION
`
`
`2.1 Recommended Dosage
`
`
`Preparation and Administration Instructions
`2.2
`
`DOSAGE FORMS AND STRENGTHS
`
`
`CONTRAINDICATIONS
`
`WARNINGS AND PRECAUTIONS
`
`
`5.1 Risk of Serious Dehydration in Pediatric Patients
`
`
`5.2 Diarrhea
`
`ADVERSE REACTIONS
`
`
`6.1 Clinical Trials Experience
`
`USE IN SPECIFIC POPULATIONS
`
`
`8.1
`Pregnancy
`
`8.2
`Lactation
`
`
`
`
`
`3
`
`4
`
`5
`
`
`6
`
`8
`
`Administration Instructions (2.2):
`
`
`
`Take with or without food.
`•
`Swallow tablets whole.
`
`
`
`•
`
`
`For patients who have difficulty 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 ----------------------------­
`
`
`
`
`Patients less than 6 years of age due to the risk of serious dehydration.
`
`
`•
`(4, 5.1, 8.4)
`
`
`
`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 common adverse reaction (≥2%) is diarrhea. (6.1)
`
`To report SUSPECTED ADVERSE REACTIONS, contact Salix
`
`
`Pharmaceuticals at 1-800-321-4576 or FDA at 1-800-FDA-1088 or
`
`
`www.fda.gov/medwatch.
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide.
`
`
`Revised: 10/2020
`
`
`
`
`
`
`11
`
`12
`
`
`
`Pediatric Use
`8.4
`
`
`8.5 Geriatric Use
`
`DESCRIPTION
`
`
`CLINICAL PHARMACOLOGY
`
`
`
`Mechanism of Action
`12.1
`
`
`12.2
`Pharmacodynamics
`
`
`12.3
`Pharmacokinetics
`
`NONCLINICAL TOXICOLOGY
`
`
`13.1
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`CLINICAL STUDIES
`
`14.1 Chronic Idiopathic Constipation (CIC)
`
`14.2 Irritable Bowel Syndrome with Constipation (IBS-C)
`
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`
`
`17
`PATIENT COUNSELING INFORMATION
`
`
`
`13
`
`14
`
`
`
`
`
`*Sections or subsections omitted from the full prescribing information are not listed.
`
`
`
`Reference ID: 4694216
`
`

`

`
`
` FULL PRESCRIBING INFORMATION
`
`
`
`
` WARNING: RISK OF SERIOUS DEHYDRATION IN PEDIATRIC PATIENTS
`
`
`
`
`
`
` • TRULANCE is 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 TRULANCE in patients 6 years to less than 18 years of age [see Warnings and Precautions (5.1),
`
`
`
`Use in Specific Populations (8.4)].
`
`
`• The safety and effectiveness of TRULANCE have not been established in patients less than 18 years of age
`
`[see Use in Specific Populations (8.4)].
`
`
` INDICATIONS AND USAGE
` 1
`
`
` TRULANCE is indicated in adults for the treatment of:
`
`
`
`
`•
`
`•
`
` chronic idiopathic constipation (CIC).
`
` irritable bowel syndrome with constipation (IBS-C)
`
`
`
`
`
` 2
`
` DOSAGE AND ADMINISTRATION
` 2.1
` Recommended Dosage
`
`
` The recommended dosage of TRULANCE for the treatment of CIC and IBS-C is 3 mg taken orally once daily.
`
`
`
`
`
` Preparation and Administration Instructions
`
`
` 2.2
`
`
` • Take TRULANCE with 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 doses at the same
`•
`
`time.
`
`
`• Swallow a tablet whole for each dose.
`
`
`
`• For adult patients with swallowing difficulties, TRULANCE tablets can be crushed and administered orally either in
`
`
`applesauce or with water or administered with water via a 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 a clean container, crush the TRULANCE tablet to a powder and mix with 1 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 a 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.
`
`
`
`
`Reference ID: 4694216
`
`

`

`
`
` Administration with Water via a Nasogastric or Gastric Feeding Tube:
`
`
`
`
`
`
`1. Place the TRULANCE tablet in a 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 a 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 a fresh syringe, flush the nasogastric or gastric feeding tube with at least 10 mL of water.
`
`
`
` DOSAGE FORMS AND STRENGTHS
` 3
`
` TRULANCE Tablets:
`
`
`
`
`
`
` 3 mg: white to off-white, plain, round tablet debossed with “SP” on one side and “3” for 3 mg on the other side.
`
`
`
`
`
`
`
`
`
`
`
` CONTRAINDICATIONS
` 4
`
` TRULANCE is contraindicated in:
`
`
`
`
` • Patients less than 6 years of age due to 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
` TRULANCE is contraindicated in patients less than 6 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 1 month to less than 2 years), plecanatide increased fluid-secretion into the intestines as a consequence of
`
`
`
`
`
`
`
` stimulation of guanylate cyclase-C (GC-C), resulting in mortality in some mice within the first 24 hours, apparently due to
` dehydration. Due to increased intestinal expression of GC-C, patients less than 6 years of age may be more likely than
`
`
`
` patients 6 years of age and older to develop severe diarrhea and its potentially serious consequences.
`
`
`
`
`
` Avoid the use of TRULANCE in patients 6 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 6 years to less than 18 years of age [see Contraindications (4), Warnings and
`
`
`Precautions (5.2), Use in Specific Populations (8.4)].
`
`
`
`
`
` Diarrhea
` 5.2
`
`
` 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.
`
`
`Reference ID: 4694216
`
`

`

`
`
` 6
`
` ADVERSE REACTIONS
` 6.1
` Clinical Trials Experience
`
`
` Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical
`
`
`
` trials of a 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 1 and Study 2) to receive placebo or 3 mg of TRULANCE once daily for 12 weeks.
`
`
`
`
`
`
`Most Common Adverse Reactions
`
`Table 1 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 1
`
`
`and Study 2] in Patients with CIC
`
`
`
`Adverse Reaction
`
`
`
`
` Diarrhea
`
`TRULANCE, 3 mg
`
`
` (N = 863)
`
` %
`
` 5
`
`
`
`Placebo
`
` (N = 870)
`
` %
`
`
` 1
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` a: Reported in at least 2% of TRULANCE-treated patients with CIC 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.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Diarrhea
`
` The majority of reported cases of diarrhea occurred within 4 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 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 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 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
`
`biochemical tests (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 upper limit of normal).
`
`
`Irritable Bowel Syndrome with Constipation (IBS-C)
`
`
`
`Reference ID: 4694216
`
`

`

`The safety data described below reflect data from 1449 adults patients with IBS-C randomized in two double-blind,
`placebo-controlled clinical trials (Study 3 and Study 4) to receive placebo or 3 mg TRULANCE once daily for 12 weeks.
`
`
`
`
`
`Most Common Adverse Reactions
`
`Table 2 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 3 and Study 4] in Patients with IBS-C
`
`
`Adverse Reaction
`
`
`
`
` Diarrheab
`
`TRULANCE, 3 mg
`
`
` (N = 723)
`
` %
`
`
`
` 4.3
`
`Placebo
`
` (N = 726)
`
`
` %
`
`
`
` 1
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 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.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Diarrhea
`
` The majority of reported cases of diarrhea occurred within 4 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 Discontinuation
`
`Discontinuations 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 Reactions
`
`Adverse 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 5 to 15 times the upper
`
`
`limit of normal).
`
`
`
`
` USE IN SPECIFIC POPULATIONS
` 8
`
` Pregnancy
`
` 8.1
`
`
` Risk Summary
`
`
`
`
`Plecanatide 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 a background risk of birth defect, loss, or other adverse outcomes. In the United States general
`
`
`
`Reference ID: 4694216
`
`

`

`
`
` 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 Data
`
`
`
`
`Pregnant 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 a 60-kg body weight. Limited
`
`systemic exposure to plecanatide was achieved in animals during organogenesis (area under the plasma concentration-
`time curve (AUCt) = 449 ng●h/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.
`
`
`
`
` Lactation
` 8.2
`
`
` Risk Summary
`
`
`
`
`
`
`After administration of multiple doses of TRULANCE 3 mg once daily for 2 weeks to nursing mothers, plecanatide and
`
`
`
`
`its active metabolite were not measurable in breast milk collected at 2 hours, 6 hours, and 12 hours post-dosing. In adults,
`
`
`
`concentrations of plecanatide and its active metabolite were mostly unmeasurable in plasma following multiple doses of
`
`
`
`
`
`
`TRULANCE 3 mg once daily for up to 12 weeks [see Clinical Pharmacology (12.3)].
`
`Maternal use of TRULANCE is not expected to result in clinically relevant exposure to plecanatide or its active
`
`
`
`
`
`metabolite in breastfed infants. The developmental and health benefits of breastfeeding should be considered along with
`
`
`the mother's clinical need for TRULANCE and any potential adverse effects on the breastfed infant from TRULANCE or
`
`from the underlying maternal condition.
`
`
` Pediatric Use
` 8.4
`
`
`
`
` TRULANCE is contraindicated in pediatric patients less than 6 years of age. Avoid use of TRULANCE in patients 6
` 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 1
`
`
`month to less than 2 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 6 years of age may be more likely than
`
`
`
`
`patients 6 years of age and older to develop diarrhea and its potentially serious consequences. TRULANCE is
`
`
`contraindicated in patients less than 6 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 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
`
`
`
`Reference ID: 4694216
`
`

`

`
`
` juvenile animal toxicity studies. Animal and human doses should not be compared directly for evaluating relative
`
` exposure.
`
`
`
`
`
` 8.5 Geriatric 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.
`
`
`
`
` 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-α-aspartyl-L-α-glutamyl-L-cysteinyl-L-α-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 3 mg
`
`
`
`
`tablets for oral administration. The inactive ingredients are magnesium stearate and microcrystalline cellulose.
`
`
`
`
`
`
`
` 12 CLINICAL PHARMACOLOGY
`
` 12.1 Mechanism of Action
`
`
`
` Plecanatide is a structural analog of human uroguanylin, and similarly to uroguanylin, plecanatide functions as a
` 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 a 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, a measure of intestinal pain.
`
`
`
`
`
`Reference ID: 4694216
`
`

`

` 12.2 Pharmacodynamics
`
`
` Food Effect
`
`
`
`
`
`
`Subjects who received either a low-fat, low calorie (LF-LC) meal or a high fat, high calorie (HF-HC) meal reported looser
`
`
`
`
`stools than fasted subjects up to 24 hours after a single dose of TRULANCE 9 mg (3 times the recommended dose). In
`
`
`clinical studies, TRULANCE was administered with or without food [see Dosage and Administration (2.2)].
`
` 12.3 Pharmacokinetics
`
`
` Absorption
`
`
`
`
`
`
`
`Plecanatide 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 multiple oral dosing of TRULANCE 3 mg once daily up to 12 weeks. Therefore, standard pharmacokinetic
`
`
`
`
`parameters such as AUC, maximum concentration (Cmax), and half-life (t½) could not be calculated.
`
`
`Food Effect
`
`
`
`In a crossover study, 24 healthy subjects were given a single dose of TRULANCE 9 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 was detected 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
`
`
`Given 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
`
`
`
`a GC-C agonist with negligible systemic exposure. Plecanatide exhibited little to no binding to human serum albumin or
`
`human α-1-acid glycoprotein.
`
`
`Elimination
`
`
`Metabolism
`
`
`Plecanatide 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.
`
`
`Excretion
`
`
`No 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 Studies
`
`
`
`
`Neither 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.
`
`Reference ID: 4694216
`
`

`

` 13 NONCLINICAL TOXICOLOGY
`
`
` 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
` Carcinogenesis
`
`
`
`
`
`
`
`
`The 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.
`
`
`Mutagenesis
`
`Plecanatide 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 Fertility
`
`
`Plecanatide had no effect on fertility or reproductive function in male or female mice at oral doses of up to 600
`
`mg/kg/day.
`
`
` 14 CLINICAL 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 1 and Study 2). In the Intention-to-
`
`
`Treat (ITT) population, a total of 905 patients (Study 1) and 870 patients (Study 2) were randomized 1:1 to either placebo
`
`
`or TRULANCE 3 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 3 months prior to the
`
`
`
`screening visit, with symptom onset for at least 6 months prior to diagnosis. Rome III 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
`
`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:
`
`
`• Straining during at least 25% of defections
`
`
`• Lumpy or hard stool in at least 25% of defecations
`
`
`• Sensation of incomplete evacuations for at least 25% of defecations
`
`
`
`• Sensation of anorectal obstruction/blockage for at least 25% of defecations
`
`
`
`
`Patients who met these criteria were also required to demonstrate the following during the last 2 weeks of the screening
`
`period:
`
`
`• Less than 3 complete spontaneous bowel movements (CSBMs) (a CSBM is an SBM that is associated with a sense of
`
`
`complete evacuation) in each of the two weeks
`
`
`• Bristol Stool Form Scale (BSFS) of 6 or 7 in less than 25% of spontaneous bowel movements (SBMs) (an SBM is a
`
`
`
`
`bowel movement occurring in the absence of laxative use)
`
`• One out of the following three:
`
`
`o BSFS of 1 or 2 in at least 25% of defecations
`
`
`
`o A straining value recorded on at least 25% of days when a BM was reported
`
`
`
`Reference ID: 4694216
`
`

`

`
`
`
`
` o At least 25% of BMs result in a sense of incomplete evacuation
`
` The efficacy of TRULANCE was assessed using a responder analysis and change-from-baseline in CSBM and SBM
`
`
`
`
` endpoints. Efficacy was assessed using information provided by patients on a daily basis in an electronic diary.
`
`
`
` A responder was defined as a patient who had at least 3 CSBMs in a given week and an increase of at least 1 CSBM from
`
`
`baseline in the same week for at least 9 weeks out of the 12 week treatment period and at least 3 of the last 4 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 9 of 12 weeks
`
`and at least 3 of the last 4 weeks (ITT Population)
`
`
`
`
`
` Responderc
`
`
`
`
`
` Responderc
`
`Study 1
`
`
`TRULANCE 3 mg
`
`N = 453
`
`
`
`
` 21%
`
`Study 2
`
`
`TRULANCE 3 mg
`
`N = 430
`
`
`
`
` 21%
`
`Placebo
`
`N = 452
`
`
`
`
` 10%
`
`Placebo
`
`N = 440
`
`
`
`
` 13%
`
`
` Treatment
`Differencea
`
`[95% CIb]
`
`
` 11%
`
` [6.1%, 15.4%]
`
`
`
`
` Treatment
`Differencea
`
`[95% CIb]
`
`
` 8%
`
` [2.6%, 12.4%]
`
`
`
` a: p-value <0.005
`
`
`b: CI = confidence interval
`
`
`c: Primary endpoint defined as a patient who had a least 3 CSBMs in a given week and an increase of at least 1 CSBM from baseline in
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`the same week for at least 9 weeks out of the 12 week treatment period and at least 3 of the last 4 weeks of the study.
`
`
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`
`
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`
`
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`
`
`
`
` In both studies, improvements in the frequency of CSBMs/week were seen as early as week 1 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 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 TRULANCE 6 mg once daily did not demonstrate additional
` treatment benefit and had a greater incidence of adverse reactions than TRULANCE 3 mg once daily. Therefore,
`
`
`
` TRULANCE 6 mg once daily is not recommended [see Dosage and Administration (2.1)].
`
`
`
`
`
` 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 3 and Study 4). In the Intention-to-
`
`
`
`
`Reference ID: 4694216
`
`

`

`
`
`
`
`Treat (ITT) population, a total of 699 patients (Study 3) and 754 patients (Study 4) received treatment with placebo or
`
`
`TRULANCE 3 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),