`Salix Pharmaceuticals Inc.
`
`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
`ofage.(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 ofTRULANCE is
`
`• CIC : 3 mg taken orally once daily. (2 .1)
`•
`IBS-C : 3 mg taken orally once daily. (2 .1)
`
`Administration Instructions (2.21.
`
`• Take with or without food .
`• Swallowtabletswhole .
`• 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 STRENGTIIS · --- - - --- - - - --- - - --- - - --- - - - --- - - --- - - ·
`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
`
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`FULL PRESCRIBING INFORMATION: CONTENTS*
`WARNING: RISK OF SERIOUS DEHYDRATION IN PEDIATRIC PATIENTS
`1 INDICATIONS AND USAGE
`2 DOSAGE AND ADMINISTRATION
`2.1 Recommended Dosage
`2.2 Preparation and Administration Instructions
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Risk of Serious Dehydration in Pediatric Patients
`5.2 Diarrhea
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.2 Lactation
`8.4 Pediatric Use
`8.5 Geriatric Use
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`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
`* Sections or subsections omitted from the full prescribing information are not listed.
`
`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)].
`
`1 INDICATIONS AND USAGE
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`TR ULAN CE 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 TR ULAN CE for the treatment of CIC and IBS-C is 3 mg taken orally once
`daily.
`
`2.2 Preparation and Administration Instructions
`
`• 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, TR ULAN CE 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 Am>lesauce:
`
`1. In a clean container, crush the TR ULAN CE 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.
`
`Administration with Water via a Naso gastric 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.
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`6. Using the same or a fresh syringe, flush the nasogastric or gastric feeding tube with at least 10
`mL of water.
`
`3 DOSAGE FORMS AND STRENGTHS
`TRULANCE Tablets:
`3 mg: white to off-white, plain, round tablet de bossed with "SP" on one side and "3" for 3 mg on the
`other side.
`
`4 CONTRAINDICATIONS
`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
`TR ULAN CE is contraindicated in patients less than 6 years of age. The safety and effectiveness of
`TR ULAN CE 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(cid:173)
`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.
`A void the use of TR ULAN CE 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)].
`
`5.2 Diarrhea
`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.
`
`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 TR ULAN CE 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
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`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
`TR ULAN CE-treated group and at an incidence that was greater than in the placebo group.
`
`Table 1: Most Common Adverse Reactions a in Two Placebo-Controlled Trials of TRULANCE
`[Study 1 and Study 2] in Patients with CIC
`
`Placebo
`TRULANCE, 3 mg
`(N = 870)
`(N = 863)
`!Adverse Reaction
`%
`%
`5
`1
`!Diarrhea
`a: Reported in at least 2% of TRULANCE-treated patients with CIC and at an incidence greater than
`lacebo.
`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 TR ULAN CE-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)
`
`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 Reactions a in Two Placebo-Controlled Trials of TR ULAN CE
`[Study 3 and Study 4] in Patients with IBS-C
`
`Adverse Reaction
`
`TRULANCE, 3 mg
`(N = 723)
`%
`
`Placebo
`(N = 726)
`%
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`14.3
`IDiarrheab
`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).
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`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(cid:173)
`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 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 (AUC1) = 449 ng.h/mL in rabbits given 250
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`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.
`
`8.2 Lactation
`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 TR ULAN CE 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.
`
`8.4 Pediatric Use
`TR ULAN CE is contraindicated in pediatric patients less than 6 years of age. A void use of
`TR ULAN CE 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 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 than65 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
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`sufficient numbers of patients aged 65 and over to determine whether they respond differently from
`patients 18 years to less than65 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-a-aspartyl-L-a-glutamyl-L(cid:173)
`cysteinyl-L-a-glutamyl-L-leucyl-L-cysteinyl-L-valyl-L-asparaginyl-L-valyl-L-alanyl-L-cysteinyl-L(cid:173)
`threonylglycyl-L-cysteinyl-, cyclic (4--+ 12),(7--+ 15)-bis(disulfide).
`
`The molecular formula of plecanatide is C6sH104N 13026S4 and the molecular weight is 1682 Daltons .
`The amino acid sequence for plecanatide is shown below:
`
`s- s
`I
`H-Asn 1-Asp2-Glu3-Cys4-Glu5-Leu6-Cys 7-Val8-Asn9-Val lO_AJa11 -Cys 12-Thr l3-Gly' 4-Cys l5-Leu 16-OI
`- S--------='
`
`I
`
`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 guano sine mono phosphate
`(cGMP). Elevation of extracellular cGMP has been associated with a decrease in the activity of pain(cid:173)
`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.
`
`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 TR ULAN CE 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.
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`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 (ti_h) 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% fromprotein); 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 a-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(cid:173)
`glycoprotein (P-gp) or breast cancer resistance protein (BCRP) in vitro .
`
`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 micro nucleus assay.
`
`Irrmairment of Fertility
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`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:
`
`• BSFS of 1 or 2 in at least 25% of defecations
`• A straining value recorded on at least 25% of days when a BM was reported
`• 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)
`
`Study 1
`
`TRULANCE 3 mg Placebo
`
`Treatment
`Differencea
`
`Bausch Health Ireland Exhibit 2064, Page 10 of 18
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`
`
`Responderc
`
`N =453
`21%
`
`N =452
`10%
`
`Study 2
`
`Responderc
`
`TRULANCE 3 mg Placebo
`N=440
`N =430
`21%
`13%
`
`[95% Clb]
`11%
`[6 .1 %, 15.4%]
`
`Treatment
`Differencea
`[95% Clb]
`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.
`
`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 TR ULAN CE 6 mg once daily did not demonstrate
`additional treatment benefit and had a greater incidence of adverse reactions than TR ULAN CE 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-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), 74% female, 73% white, and 22%
`black
`
`To be eligible, patients were required to meet the Rome III criteria for IBS for at least 3 months prior to
`the screening visit, with symptom onset for at least 6 months prior to diagnosis . Diagnosis required
`recurrent abdominal pain or discomfort at least 3 days/month in the last 3 months associated with 2 or
`more of 1) improvement with defecation, 2) onset associated with a change in frequency of stool, and 3)
`onset associated with a change in form (appearance) of stool. Patients also met the IBS-C differentiation
`criteria for const