Plecanatide is an oral guanylate cyclase-C agonist approved for adults for treatment of chronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation (IBS-C). Guidelines strongly recommend plecanatide to treat global IBS-C symptoms. In two randomized, 12-week studies of more than 2,600 patients with CIC, plecanatide-treated patients achieved the primary endpoint of significantly greater efficacy responder rates compared to placebo (Study 1: 21% vs. 10%; Study 2: 21% vs. 13%, p less than 0.005 for both studies). Efficacy responders were defined as patients who had at least 3 complete spontaneous bowel movements (CSBMs) in a given week and an increase of at least 1 CSBM over baseline in the same week for at least 9 weeks out of the 12-week period, including at least 3 of the last 4 weeks. Plecanatide-treated patients also had improvements as compared to placebo in stool frequency (as measured by the number of spontaneous bowel movements per week), stool consistency (as measured by the Bristol Stool Form Scale), and straining with bowel movements. In 2 randomized controlled trials involving more than 2,100 patients with IBS-C, significantly more patients achieved the primary endpoint (30% or more reduction in worst abdominal pain and an increase of 1 or more CSBM vs. baseline, in the same week, for at least half of the 12 treatment weeks) with plecanatide vs. placebo (30% vs. 18%; p less than 0.001, and 21% vs. 14%; p = 0.009).
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
Oral Solid Formulations
-Plecanatide can be taken with or without food.
-Swallow the tablet whole.
-For adults with swallowing difficulties, consider crushing the tablets and administering the dose with applesauce or in water as follows:-Administration with applesauce: In a clean container, crush the tablet to a powder and mix with 1 teaspoonful of room temperature applesauce. Consume the tablet-applesauce mixture immediately. Do not store the mixture for later use.
-Administration in water for oral ingestion: Place the tablet in a clean cup. Pour approximately 30 mL of room temperature water into the cup. Mix by gently swirling the tablet and water mixture for at least 10 seconds. The tablet will fall apart into the water. Swallow the entire mixture immediately. If any portion of the tablet remains in the cup, add another 30 mL of water, swirl for 10 seconds, and swallow immediately. Do not store the mixture for later use.
-Administration in water via nasogastric or gastric feeding tube: Place the tablet in a clean cup with 30 mL of room temperature water. Mix by gently swirling the tablet and water mixture for at least 15 seconds. The tablet will fall apart into the water. Flush the nasogastric or gastric feeding tube with 30 mL of water using an appropriate syringe. Draw up the mixture using the syringe and immediately administer via the nasogastric or gastric feeding tube. Do not reserve for future use. 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. Using the same or a fresh syringe, flush tube after dosing with a minimum of 10 mL of water.
-Mixing plecanatide tablets in other soft foods or in other liquids has not been tested.
Diarrhea was the most common adverse reaction with plecanatide and mostly occurred within 4 weeks of treatment initiation. In the chronic idiopathic constipation (CIC) trials, diarrhea was reported in 5% of patients compared to 1% of patients receiving placebo. In the irritable bowel syndrome with constipation (IBS-C) trials, diarrhea was reported in 4.3% of patients compared to 1% of patients receiving placebo. In the CIC trials, severe diarrhea was reported in 0.6% of patients receiving plecanatide compared to 0.3% of patients receiving placebo. In the IBS-C trials, severe diarrhea was reported in 1% of patients compared to 0.1% of patients receiving placebo. Severe diarrhea was reported to occur within the first 3 days of treatment. Diarrhea was the most common adverse reaction leading to discontinuation of therapy in both the CIC and IBS-C trials. In the CIC trials, 2% of plecanatide treated patients and 0.5% of placebo-treated patients withdrew from trials due to diarrhea. In the IBS-C trials, 1.2% of plecanatide treated patients and 0% of placebo-treated patients withdrew from trials due to diarrhea. Adverse reactions reported during the CIC trials in less than 2% of plecanatide-treated patients and at an incidence greater than placebo were: abdominal distention, flatulence, abdominal tenderness, and elevated hepatic enzymes (2 patients with alanine aminotransferase (ALT) greater than 5 to 15 times the upper limit of normal (ULN) and 3 patients with aspartate aminotransferase (AST) greater than 5 times the ULN). Adverse reactions reported during the IBS-C trials in 1% or more but less than 2% of plecanatide-treated patients and at an incidence greater than placebo were: nausea and elevated hepatic enzymes (2 patients with alanine aminotransferase (ALT) greater than 5 to 15 times the upper limit of normal (ULN). Vomiting has been reported during postmarketing experience with plecanatide.
During the chronic idiopathic constipation (CIC) trials, sinusitis and upper respiratory tract infection were reported in less than 2% of plecanatide-treated patients and at an incidence greater than placebo. Adverse reactions reported during the irritable bowel syndrome with constipation (IBS-C) trials in 1% or more but less than 2% of plecanatide-treated patients and at an incidence greater than placebo were: naso-pharyngitis, upper respiratory tract infection, urinary tract infection, and dizziness.
Postmarketing cases of hypersensitivity reactions, including pruritus, hives (urticaria), and rash have been reported with plecanatide.
Plecanatide is contraindicated in patients with known or suspected mechanical GI obstruction. Patients with current symptoms (e.g., abdominal pain) that may be suggestive of mechanical GI obstruction should be medically evaluated before using plecanatide. It is prudent to use plecanatide cautiously in patients with GI disease who are at risk of mechanical GI obstruction. Common causes of mechanical obstruction include abdominal adhesions, hernias, tumors (gastric cancer, disseminated intraperitoneal cancer), foreign bodies (including cholelithiasis), diverticulitis, inflammatory bowel disease (Crohn's disease), Hirschsprung's disease, fecal impaction, and volvulus.
Plecanatide should not be administered to patients with severe diarrhea. Diarrhea is the most common adverse effect of plecanatide. Inform patients to notify their health care provider if they develop diarrhea. For severe cases of diarrhea, the healthcare provider should suspend plecanatide treatment and rehydrate the patient.
Plecanatide is contraindicated in neonates, infants, and children up to 6 years of age. In nonclinical studies, deaths due to dehydration occurred within 24 hours in young juvenile mice (1 to 3 week-old mice; approximately equivalent to human pediatric patients less than 2 years of age) after administration of single oral doses of plecanatide; deaths did not occur in older juvenile mice (approximately equivalent to humans ages 12 to 17 years). Nevertheless, due to the deaths in young juvenile mice and the lack of clinical safety and efficacy data in pediatric patients, use should be avoided in pediatric patients 6 to 17 years of age.
There are no adequate and well-controlled studies of plecanatide use during human pregnancy; a drug-associated risk for major birth defects or miscarriage cannot be determined. Animal data suggest no effects on embryo-fetal development with oral administration of plecanatide in mice and rabbits during organogenesis at doses much higher than the recommended human dosage. Plecanatide is minimally absorbed with low systemic availability following oral administration, suggesting that clinically significant amounts will not cross to the embryo or fetus. Nevertheless, both plecanatide and its active metabolite are proteolytically degraded within the intestinal lumen to smaller peptides and naturally occurring amino acids and these may be absorbed and cross the placenta.
Maternal use of plecanatide is not expected to result in clinically relevant exposure to plecanatide or its active metabolite in breast-feeding infants. After administration of multiple doses of plecanatide 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 plecanatide 3 mg once daily for up to 12 weeks. Both plecanatide and its active metabolite are proteolytically degraded within the intestinal lumen to smaller peptides and naturally occurring amino acids and these may be absorbed and excreted into milk. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition.
For the treatment of chronic idiopathic constipation (CIC):
Oral dosage:
Adults: 3 mg PO once daily taken with or without food.
Children and Adolescents 6 to 17 years: Safety and efficacy have not been established. Based on the results of preclinical data, use should be avoided.
Infants and Children 5 years and younger: Use is contraindicated.
For the treatment of irritable bowel syndrome with constipation (IBS-C):
Oral dosage:
Adults: 3 mg PO once daily.
Maximum Dosage Limits:
-Adults
3 mg PO daily.
-Geriatric
3 mg PO daily.
-Adolescents
Avoid use.
-Children
6 to 12 years: Avoid use.
1 to 5 years: Contraindicated.
-Infants
Contraindicated.
-Neonates
Contraindicated.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
There are no drug interactions associated with Plecanatide products.
Plecanatide is structurally related to 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 in 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. This action results in increased intestinal fluid and accelerated gastrointestinal (GI) transit. In animal models, plecanatide has been shown to increase fluid secretion into the GI tract, accelerate GI transit, and cause changes in stool consistency. In addition, in an animal model of visceral pain, plecanatide reduced abdominal muscle contractions, a measure of intestinal pain; the mechanism has not been studied.
Plecanatide is administered orally. Plecanatide is expected to be minimally distributed to tissues, due to unmeasurable plasma concentrations following therapeutic oral doses. Metabolism takes place within the gastrointestinal tract to the principal, active metabolite by loss of the terminal tyrosine moiety. Both plecanatide and the metabolite are proteolytically degraded within the intestinal lumen to smaller peptides and naturally occurring amino acids. No excretion studies have been conducted in humans.
Affected cytochrome P450 isoenzymes or transporters: None
Neither plecanatide nor its active metabolite inhibited CYP2C9 and CYP3A4, and they did not induce CYP3A4 in vitro. Plecanatide and its active metabolite are neither substrates nor inhibitors of the transporters P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) in vitro.
-Route-Specific Pharmacokinetics
Oral Route
Following oral administration, plecanatide is minimally absorbed with negligible systemic availability. Concentrations of plecanatide and its active metabolite in plasma are below the limit of quantitation after an oral plecanatide dose of 3 mg. Therefore, standard pharmacokinetic parameters such as AUC, Cmax, and half-life cannot be calculated.
Effects of Food: Plecanatide was studied in healthy subjects under 3 different conditions: fasted; following a low-fat, low-calorie meal; and following a high-fat, high-calorie meal. 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.
-Special Populations
Hepatic Impairment
Plecanatide has not been evaluated in patients with hepatic impairment.
Renal Impairment
Plecanatide has not been evaluated in patients with renal impairment.
Geriatric
Clinical studies to determine the impact of age on the pharmacokinetics of plecanatide have not been conducted. Further, clinical evaluation of plecanatide did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
Gender Differences
Clinical studies to determine the impact of gender on the pharmacokinetics of plecanatide have not been conducted.
Ethnic Differences
Clinical studies to determine the impact of race on the pharmacokinetics of plecanatide have not been conducted.
Obesity
Clinical studies to determine the impact of weight on the pharmacokinetics of plecanatide have not been conducted.