2.1 Recommended Dosage

The recommended dosage of TRULANCE 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, 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.

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.

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 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.

6.1 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)] .

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of TRULANCE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to TRULANCE exposure.

• Hypersensitivity Reactions: skin itching, hives, rash
• Vomiting

8.1 Pregnancy

8.2 Lactation

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.

8.5 Geriatric Use

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.

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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.

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-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 constipation, characterized by a stool pattern such that at least 25% of defecations are hard or lumpy stools and no more than 25% of defecations are loose or watery stool.

Patients who met these criteria were excluded if they demonstrated the following during the last 2 weeks of the screening period:

• Worst abdominal pain intensity (WAPI) score of 0 on an 11-point scale for more than 2 days during each week
• An average WAPI of less than 3 for either week
• More than 3 complete spontaneous bowel movements (CSBMs) or more than six spontaneous bowel movements (SBMs) per week in either week
• Bristol Stool Form Scale (BSFS) of 7 for any SBM recorded
• More than 1 day in either week with a BSFS of 6 for any SBM recorded
• No use of rescue laxative (bisacodyl) within 72 hours before randomization

The efficacy of TRULANCE was assessed using a responder analysis based on abdominal pain intensity and a stool frequency responder (CSBM) endpoint. Efficacy was assessed using information provided by patients on a daily basis through an electronic phone diary system.

A responder was defined as a patient who met both the abdominal pain intensity and stool frequency responder criteria in the same week for at least 6 of the 12 treatment weeks. The abdominal pain intensity and stool frequency responder criteria assessed each week were defined as:

• Abdominal pain intensity responder: a patient who experienced a decrease in the weekly average of worst abdominal pain in the past 24 hours score (measured daily) of at least 30% compared with baseline weekly average.
• Stool frequency responder: a patient who experienced an increase of at least 1 CSBM per week from baseline.

The responder rates are shown in Table 4.

In both studies, the proportion of responders who were also weekly responders for at least 2 of the 4 treatment weeks in month 3, the last month of treatment was greater in the TRULANCE groups compared to placebo.

Over the 12-week treatment period, improvements were observed in both stool consistency (as measured by the BSFS) and in the amount of straining with bowel movements (amount of time pushing or physical effort to pass stool) in the 3 mg TRULANCE group as compared to placebo.

Following completion of the study drug treatment period, patients continued to record data in the daily diary for a 2-week Post-Treatment Period. During this time, TRULANCE-treated patients generally returned to baseline for these study endpoints.

In Studies 3 and 4, a third randomized treatment arm of TRULANCE 6 mg once daily did not demonstrate additional treatment benefit over the 3 mg dose. Therefore, TRULANCE 6 mg once daily is not recommended [see Dosage and Administration (2.1)].

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. Keep TRULANCE in the original bottle. Do not remove desiccant from the bottle. Do not subdivide or repackage.

Diarrhea

To stop TRULANCE and contact their healthcare provider if they experience severe diarrhea [see Warnings and Precautions (5.2)] .

Accidental Ingestion

Accidental ingestion of TRULANCE in children, especially in children less than 6 years of age, may result in severe diarrhea and dehydration. Instruct patients to take steps to store TRULANCE securely and out of reach of children and to dispose of unused TRULANCE [see Contraindications (4), Warnings and Precautions (5.2)] .

Administration and Handling 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 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 described in the Medication Guide.
• To keep TRULANCE in a dry place. Protect from moisture. 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)] .