`
`
`
`
`
`
`
`
` • 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
`
`
`Synergy Pharmaceuticals at 1-888-869-8869 or FDA at 1-800­
`FDA-1088 or www.fda.gov/medwatch.
`
`
`
`
`
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and
`
`Medication Guide.
`
`
`
`
`
`
`Revised: 01/2017
`
`
`
`
` 8.1 Pregnancy
`
`
` 8.2 Lactation
`
`
` 8.4 Pediatric Use
`
`
` 8.5 Geriatric Use
`
` 11 DESCRIPTION
`
`
` 12 CLINICAL PHARMACOLOGY
`
` 12.1 Mechanism of Action
`
`
`
` 12.2 Pharmacodynamics
`
`
` 12.3 Pharmacokinetics
`
`
` 13 NONCLINICAL TOXICOLOGY
`
`
` 13.1 Carcinogenesis, Mutagenesis, Impairment of
`
`
`
` Fertility
`
` 14 CLINICAL STUDIES
`
` 16 HOW SUPPLIED/STORAGE AND HANDLING
`
` 17 PATIENT COUNSELING INFORMATION
`
`
`
` *Sections or subsections omitted from the full prescribing
`
`
` information are not listed.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 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)
`
` DOSAGE AND ADMINISTRATION
`
`
`
`
`
`
`
`
`The recommended adult dosage of TRULANCE is 3 mg taken orally
`
`
`once daily. (2.1)
`
`
`Administration Instructions (2.2):
`
`
`• Take with or without food.
`
`
`
`
` FULL PRESCRIBING INFORMATION: CONTENTS*
`
`WARNING: RISK OF SERIOUS DEHYDRATION IN
`
`PEDIATRIC PATIENTS
`
`
`INDICATIONS AND USAGE
`1
`
`
`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
`
`
`
`
`Reference ID: 4044252
`
`
`
` 1
`
`

`

`
` 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).
`
` 2 DOSAGE AND ADMINISTRATION
`
`
`
` 2.1 Recommended Dosage
`
` The recommended dosage of TRULANCE 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, 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.
`
`
`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 an appropriate syringe.
`
`
`2
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4044252
`
`

`

`
`
`
`
`
`
`
`
`
` 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.
` 3 DOSAGE FORMS AND STRENGTHS
`
`
`
` 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.
`
` 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
`
`
`
`
` 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)].
`
`
`
`
`
` 5.2 Diarrhea
`
`
` Diarrhea was the most common adverse reaction in the two placebo-controlled clinical trials. Severe diarrhea
`
`
` was reported in 0.6% of patients [see Adverse Reactions (6.1)]. If severe diarrhea occurs, suspend dosing and
`
`
`
`
`
` rehydrate the patient.
`
` 6 ADVERSE REACTIONS
`
`
`
` 6.1 Clinical Trials Experience
`
` Because clinical studies are conducted under widely varying conditions, adverse reaction rates 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.
`
`
`
`
`
` 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. Demographic characteristics were comparable between the TRULANCE and placebo groups
`
`
`
`
`[see Clinical Studies (14)].
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4044252
`
`3
`
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`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 Reactions* in Two Placebo-Controlled Trials of TRULANCE
`
`
`
`
`
`
`
`
`
`
`
`[Study 1 and Study 2] in Patients with CIC
` TRULANCE, 3 mg
`
`
` Placebo
`
`
` (N = 863)
`
`
` (N = 870)
` %
`
` %
`
` Adverse Reaction
`5
`1
`Diarrhea
`
`
`
` * reported in at least 2% of TRULANCE-treated patients and at an incidence greater than placebo
`
` 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).
`
` 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-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
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4044252
`
`4
`
`
`
`

`

`
`
`
`
`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.
` 8.2 Lactation
`
`
` Risk Summary
`
` There is no information regarding the presence of plecanatide in human milk, or its effects on milk production
`
`
`
` or the breastfed infant. No lactation studies in animals have been conducted. Plecanatide 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 a clinically
`
`
`
`
` relevant exposure to breastfed infants. Exposure to plecanatide in breastfed infants has the potential for serious
` adverse effects [see Use in Special Populations (8.4)]. The developmental 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
`
`
`
`
`
`
` 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 juvenile animal toxicity studies. Animal
`
`
`and human doses should not be compared directly for evaluating relative exposure.
` 8.5 Geriatric Use
`
`
` 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. Of 2601 subjects in
` clinical trials of TRULANCE, 273 (10%) were 65 years of age and over, and 47 (2%) were 75 years and over.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4044252
`
`5
`
`
`
`

`

`
`
`
`
`
`In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased
`
`
`
`hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
`
` 11 DESCRIPTION
`
` TRULANCE (plecanatide) is a guanylate cyclase-C (GC-C) agonist. Plecanatide is a 16 amino acid peptide
`
`
`
`with the following chemical name: L-Leucine, L-asparaginyl-L-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:
`S
`S
`H-Asn1-Asp2-Glu3-Cys4-Glu5-Leu6-Cys7-Val8-Asn9-Val10-Ala11-Cys12-Thr13-Gly14-Cys15-Leu16-OH
`S
`S
`
`
`
`
`
`
` 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 a 3 mg tablet for oral administration. The inactive ingredients are magnesium stearate and
`
`
`
`
`microcrystalline cellulose.
`
`12 CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
`
`
`
`
` Plecanatide is structurally related to human uroguanylin, and similar to uroguanylin, plecanatide functions as a
`
`
` guanylate cyclase-C (GC-C) agonist. Both plecanatide 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
`
`
` 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. The mechanism has not been studied.
` 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)].
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4044252
`
`
`
` 6
`
`
`

`

`
` 12.3 Pharmacokinetics
`
` Absorption
`
`Plecanatide is minimally absorbed with negligible systemic availability following oral administration.
`
`
`
`
`Concentrations of plecanatide and its active metabolite in plasma are below the limit of quantitation after an
`
`
`
`
`
`oral TRULANCE dose of 3 mg. Therefore, standard pharmacokinetic parameters such as AUC, maximum
`
`
`
`concentration (Cmax), and half-life (t½) cannot 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 are not measurable, plecanatide is
`
`expected to be minimally distributed in tissues. Oral plecanatide is localized to the GI tract where it exerts its
`
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`effects as a GC-C agonist with negligible systemic exposure. Plecanatide exhibits little to no binding to human
`
`
`serum albumin or human α-1-acid glycoprotein.
`
`Elimination
`
`Metabolism
`
`Plecanatide is metabolized in the GI tract to an active metabolite by loss of the terminal leucine moiety. Both
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`plecanatide and the metabolite are proteolytically degraded within the intestinal lumen to smaller peptides and
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`naturally occurring amino acids.
`
`Excretion
`
`No excretion studies have been conducted in humans. Plecanatide and its active metabolite are not measurable
`
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`in plasma following administration of the recommended clinical doses.
`
`Drug Interaction Studies
`
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`Neither plecanatide nor its active metabolite inhibited the cytochrome P450 (CYP) enzymes 2C9 and 3A4, and
`
`they did not induce CYP3A4 in vitro.
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`Plecanatide and its active metabolite are neither substrates nor inhibitors of the transporters P-glycoprotein
`
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`(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.
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`Plecanatide was not tumorigenic in mice at oral doses up to 90 mg/kg/day or in rats at oral doses up to
`
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`100 mg/kg/day. Limited systemic exposure to plecanatide was achieved at the tested dose levels in animals,
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`whereas no detectable exposure occurred in humans. Therefore, animal and human doses should not be
`
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`compared directly for evaluating relative exposure.
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`Reference ID: 4044252
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`7
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`Mutagenesis
` Plecanatide was not genotoxic in the in vitro bacterial reverse mutation (Ames) assay, in vitro mouse lymphoma
`
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` mutation assay, or the in vivo mouse bone marrow micronucleus assay.
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` Impairment of Fertility
`
`Plecanatide had no effect on fertility or reproductive function in male or female mice at oral doses of up to
`
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`600 mg/kg/day.
`
`
` 14 CLINICAL STUDIES
`
`
`
`
`
` 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
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` 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
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` was administered without respect to food intake. Demographics for these studies included an overall mean age
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` of 45 years (range 18 to 80 years), 80% female, 72% white, and 24% black.
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` To be eligible for the studies, patients were required to meet modified Rome III criteria for at least 3 months
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` prior to the screening visit, with symptom onset for at least 6 months prior to diagnosis. Rome III criteria were
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` modified to require that patients report less than 3 defecations per week, rarely have a loose stool without the
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` use of laxatives, not use manual maneuvers to facilitate defecations, and not meet criteria for IBS-C. In
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` addition, patients were required to report at least two of the following symptoms:
` • Straining during at least 25% of defecations
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` • Lumpy or hard stool in at least 25% of defecations
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` • Sensation of incomplete evacuations for at least 25% of defecations
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` • Sensation of anorectal obstruction/blockage for at least 25% of defecations
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`
`
` 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
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`
` • Bristol Stool Form Scale (BSFS) of 6 or 7 in less than 25% of spontaneous bowel movements (SBMs)
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`
` (an SBM is a bowel movement occurring in the absence of laxative use)
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` • One out of the following three:
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`
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`o BSFS of 1 or 2 in at least 25% of defecations
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`o A straining value recorded on at least 25% of days when a BM was reported
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`o At least 25% of BMs result in a sense of incomplete evacuation
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` 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
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`
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`diary.
` A responder was defined as a patient who had a least 3 CSBMs in a given week and an increase of at least 1
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`
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` 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 2.
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`Reference ID: 4044252
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`8
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` Table 2: Efficacy Responder Rates in the Two Placebo Controlled Studies of CIC: at least 9 of 12 weeks
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`and at least 3 of the last 4 weeks (ITT Population)
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` Study 1
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` Responder^
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` Responder^
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`
` TRULANCE 3 mg
`
` N = 453
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` 21%
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` Study 2
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` TRULANCE 3 mg
`
` N = 430
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` 21%
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` Placebo
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` N = 452
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` 10%
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` Placebo
` N = 440
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` 13%
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`
` Treatment
` Difference#
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`
` [95% CI*]
`
` 11%
` [6.1%, 15.4%]
`
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` Treatment
` Difference#
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`
` [95% CI*]
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` 8%
` [2.6%, 12.4%]
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` * CI = confidence interval
`
`^ 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
`
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`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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`# p-value <0.005
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`
` In both studies, improvements in the frequency of CSBMs/week were seen as early as week 1 with
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` 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
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` 1.1 CSBMs/week.
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` Over the 12 week treatment period, improvements were observed in stool frequency (number of CSBMs/week
`
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` and SBMs/week) and/or stool consistency (as measured by the BSFS), and/or in the amount of straining with
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` bowel movements (amount of time pushing or physical effort to pass stool) in the TRULANCE group as
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` compared to placebo.
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` Following completion of the study drug treatment period, patients continued to record data in the daily diary for
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` a 2 week Post-Treatment Period. During this time, TRULANCE-treated patients generally returned to baseline
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` for these study endpoints.
` In Studies 1 and 2, a third randomized treatment arm of TRULANCE 6 mg once daily did not demonstrate
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` 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)].
`
`
`
` 16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
` TRULANCE tablets are packaged in an aluminum foil unit dose blister pack of 30 in a child-resistant pack or in
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` a white, opaque, high-density polyethylene round bottle with a screw-top polypropylene child-resistant cap and
` heat-activated induction seal. Each bottle container-closure system also contains a desiccant and a polyester
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` coil.
` TRULANCE 3 mg tablets are white to off-white, plain and round, debossed with “SP” on one side and “3” for
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` 3 mg on the other side and supplied as:
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` NDC Number
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`70194-203-30
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`
`70194-003-30
`
`Reference ID: 4044252
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` Size
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`Bottle of 30
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`Aluminum foil unit dose blister pack of 30 in a child-resistant pack
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`9
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`Store at room temperature, 20 to 25°C (68 to 77°F); excursions permitted to 15 to 30°C (59 to 86°F) [see USP
`
`Controlled Room Temperature].
`Keep TRULANCE in a 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.
`
`
` 17 PATIENT COUNSELING INFORMATION
`
`
` Advise the patient to read the FDA-approved patient labeling (Medication Guide).
`
` Advise Patients:
`
` Diarrhea
`To stop TRULANCE and contact their healthcare provider if they experience severe diarrhea [see Warnings
`
`
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`and Precautions (5.2)].
`
`
`Accidental Ingestion
`
`Accidental ingestion of TRULANCE in children, especially in children less than 6 years of age, may result in
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`severe diarrhea and dehydration. Instruct patients to take steps to store TRULANCE securely and out of reach
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`of children and to dispose of unused TRULANCE [see Contraindications (4), Warnings and Precautions (5.2)].
`
`Administration and Handling Instructions
`
`
`• To take TRULANCE once daily with or without food [see Dosage and Administration (2.2)].
`
`
`If a dose is missed, skip the missed dose and take the next dose at the regular time. Do not take two doses at
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`
`•
`the same time.
`
`• To swallow TRULANCE tablets whole.
`
`
`If adult patients have swallowing difficulties, TRULANCE tablets can be crushed and administered orally in
`
`•
`either applesauce or with water, or administered with water via a nasogastric or gastric feeding tube, as
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`described in the Medication Guide.
`
`• To keep TRULANCE in a 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)].
`
`
`
`
`TRULANCE™ is a trademark of Synergy Pharmaceuticals Inc.
`
`Manufactured for:
`
`
`Synergy Pharmaceuticals Inc.
`
`
`
`420 Lexington Avenue, Suite 2012
`
`
`New York, New York 10170
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`Reference ID: 4044252
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`10
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` Medication Guide
`
`
`
` TRULANCE™ (troo’ lans)
` (plecanatide) tablets
`
`What is the most important information I should know about TRULANCE?
`
`• Do not give TRULANCE to children who are less than 6 years of age. It may harm them.
`
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`• You should not give TRULANCE to children 6 years to less than 18 years of age. It may harm
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`them.
`
`See “What are the possible side effects of TRULANCE?” for more information about side effects.
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`What is TRULANCE?
`
`
`
`
`TRULANCE is a prescription medicine used in adults to treat a type of constipation called chronic
`
`idiopathic constipation (CIC). Idiopathic means the cause of the constipation is unknown.
`
`
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`It is not known if TRULANCE is safe and effective in children less than 18 years of age.
`
`Who should not take TRULANCE?
`
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`• Do not give TRULANCE to children who are less than 6 years of age.
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`• Do not take TRULANCE if a doctor has told you that you have a bowel blockage (intestinal obstruction).
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`Before taking TRULANCE, tell your doctor about all of your medica