TRULANCE

Guanylate Cyclase-C Agonists for Constipation

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.

elevated hepatic enzymes / Delayed / 0-2.0

diarrhea / Early / 5.0-5.0
flatulence / Early / 0-2.0
nausea / Early / 0-2.0
pharyngitis / Delayed / 0-2.0
sinusitis / Delayed / 0-2.0
dizziness / Early / 0-2.0
infection / Delayed / 0-2.0
vomiting / Early / Incidence not known
pruritus / Rapid / Incidence not known
urticaria / Rapid / Incidence not known
rash / Early / Incidence not known

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.

Trulance

Rx

Oral guanylate cyclase-C agonist
For adults with chronic idiopathic constipation (CIC) or irritable bowel syndrome with constipation (IBS-C); may cause severe diarrhea in some patients
Contraindicated in patients less than 6 years of age due to serious dehydration

3 mg PO once daily taken with or without food.

3 mg PO once daily.

Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

There are no drug interactions associated with Plecanatide products.

Plecanatide/Trulance Oral Tab: 3mg

3 mg PO daily.

3 mg PO daily.

Avoid use.

6 to 12 years: Avoid use.
1 to 5 years: Contraindicated.

Contraindicated.

Contraindicated.

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.

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.

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.