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Plecanatide

Class: GI Drugs, Miscellaneous
Chemical Name: (7→15)-Bis(disulfide),cyclic (4→12),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-l-leucine
Molecular Formula: C65H104N18O26S4
CAS Number: 467426-54-6
Brands: Trulance

Warning

  • Contraindicated in infants and children <6 years of age; avoid use in children and adolescents 6 to <18 years of age.1 Single oral doses caused deaths due to dehydration in young juvenile mice.1 (See Pediatric Use under Cautions.)

  • Safety and efficacy not established in patients <18 years of age.1

Introduction

Guanylate cyclase-C (GC-C) agonist; stimulates secretion of chloride and bicarbonate into intestinal lumen, which increases intestinal fluid and accelerates intestinal transit.1 2 5 6 7 8 9 10 11

Uses for Plecanatide

Chronic Idiopathic Constipation

Symptomatic treatment of chronic idiopathic constipation in adults.1 2 3

Plecanatide Dosage and Administration

Administration

Oral Administration

Administer orally without regard to food.1 Administration with meals may result in looser stools.1

Swallow tablets whole.1

If patient cannot swallow whole tablet, crush tablet and mix in applesauce and administer orally or disperse tablet in water and administer orally or via a nasogastric or gastric feeding tube.1 Use these mixtures immediately; do not store for later use.1 Administration in other soft foods or liquids not studied.1

If a dose is missed, do not double the dose.1 Administer the next dose at the regularly scheduled time.1

Oral Administration in Applesauce

Crush 3-mg tablet to a powder and mix with 1 teaspoonful of room-temperature applesauce.1 Administer entire mixture immediately.1

Oral Administration as Aqueous Dispersion

Place 3-mg tablet in a cup, add approximately 30 mL of room-temperature water, gently swirl for ≥10 seconds to disperse the disintegrating tablet, then administer immediately.1

Disperse any residue remaining in the cup in an additional 30 mL of water, gently swirl for ≥10 seconds, then administer immediately.1

Administration via Nasogastric or Gastric Tube

Place 3-mg tablet in a cup, add approximately 30 mL of room-temperature water, gently swirl for ≥15 seconds to disperse the disintegrating tablet.1 Flush the nasogastric or gastric feeding tube with 30 mL of water, then draw up entire contents of the plecanatide dispersion into a syringe and administer immediately.1

Disperse any residue remaining in the cup in an additional 30 mL of water, gently swirl for ≥15 seconds, and administer using the same syringe.1 Then use the same syringe or a new syringe to flush the nasogastric or gastric feeding tube with ≥10 mL of water.1

Dosage

Adults

Chronic Idiopathic Constipation
Oral

3 mg once daily.1

Higher dosage (6 mg daily) not recommended; provides no additional clinical benefit but may increase adverse effects.1 13

Special Populations

Hepatic Impairment

Manufacturer makes no specific dosage recommendations.1

Renal Impairment

Manufacturer makes no specific dosage recommendations.1

Geriatric Patients

Manufacturer makes no specific dosage recommendations.1

Cautions for Plecanatide

Contraindications

  • Infants and children <6 years of age.1 (See Pediatric Use under Cautions.)

  • Known or suspected mechanical GI obstruction.1

Warnings/Precautions

Warnings

Pediatric Risk

Lethality reported in young juvenile mice.1 Contraindicated in infants and children <6 years of age; avoid use in children and adolescents 6 to <18 years of age.1 (See Pediatric Use under Cautions.)

Other Warnings and Precautions

Diarrhea

Diarrhea resulting in drug discontinuance occurred in 2% of patients receiving 3-mg daily dosage (generally within 4 weeks of drug initiation); severe diarrhea reported in 0.6% of patients (generally within first 3 days of treatment).1

Interrupt plecanatide and rehydrate patient if severe diarrhea develops.1

Specific Populations

Pregnancy

Not expected to result in fetal exposure if administered to pregnant women; however, available data on use in pregnant women are insufficient to inform fetal risk.1

No evidence of adverse embryofetal developmental effects in studies in mice and rabbits; no developmental abnormalities and no effects on growth, learning and memory, or fertility observed in the offspring of exposed mice.1

Lactation

Not known whether plecanatide distributes into human milk, affects human milk production, or affects breast-fed infant.1

Not known whether the negligible systemic absorption observed in adults will result in clinically important exposure in breast-fed infants.1 Potential for serious adverse effects if exposure occurs.1 Consider benefits of breast-feeding and importance of the drug to the woman; also consider any potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.1 (See Pediatric Use under Cautions.)

Pediatric Use

Contraindicated in infants and children <6 years of age; avoid use in children and adolescents 6 to <18 years of age.1 Safety and efficacy in pediatric patients <18 years of age not established, and deaths reported within 24 hours of administration in juvenile mice (age approximately equivalent to human age of 1 month to <2 years).1

Deaths in young juvenile mice occurred after single oral doses of 0.5 and 10 mg/kg administered on postnatal days 7 and 14, respectively.1 Deaths apparently due to dehydration resulting from increased fluid secretion into the intestine as a consequence of GC-C stimulation.1

Do not directly compare animal and human doses for evaluating relative exposure.1

Because of increased intestinal expression of GC-C, infants and children <6 years of age may be at a greater risk of developing diarrhea and its potentially serious consequences compared with individuals ≥6 years of age.1 Although no deaths observed in older juvenile mice, avoid use of plecanatide in children and adolescents 6 to <18 years of age because of deaths reported in younger mice and lack of safety and efficacy data in pediatric patients.1

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether they respond differently than younger adults.1 Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.1

Hepatic Impairment

No formal studies, but not appreciably absorbed after oral administration.1 12

Renal Impairment

No formal studies, but not appreciably absorbed after oral administration.1 12

Common Adverse Effects

Diarrhea.1 2

Interactions for Plecanatide

Plecanatide and its active metabolite do not inhibit CYP2C9 or CYP3A4, do not induce CYP3A4, and are not substrates or inhibitors of P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) in vitro.1

Only enzyme and transporter systems expressed in GI tract evaluated for interaction potential, since plasma concentrations not measurable following oral administration at recommended dosages.1 12

Plecanatide Pharmacokinetics

Absorption

Bioavailability

Minimally absorbed; negligible systemic bioavailability following oral administration.1

Food

Administration with meal resulted in looser stools.1

Plasma Concentrations

At recommended adult dosage, plasma concentrations are below measurable levels.1

Distribution

Extent

Expected to be minimally distributed into tissues.1

Plasma Protein Binding

Minimal or no binding to albumin or α1-acid glycoprotein.1

Elimination

Metabolism

Metabolized in GI tract to an active metabolite via lysis of the terminal leucine moiety; parent drug and active metabolite are proteolytically degraded within intestinal lumen to smaller peptides and naturally occurring amino acids.1

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C).1

Keep in original container, tightly closed and protected from moisture.1 Do not remove desiccant from container.1 Do not subdivide or repackage.1

Actions

  • Binds to GC-C receptor on luminal surface of intestinal epithelium.1 2 6 7 9 Stimulation of GC-C causes increased concentrations of cyclic guanosine monophosphate (cGMP), which activates the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel leading to secretion of chloride and bicarbonate into intestinal lumen; results in increased intestinal fluid and accelerated intestinal transit.1 2 6 7 8 9

  • Reduces abdominal muscle contractions, increases fluid secretion into the GI tract, accelerates intestinal transit, and changes stool consistency in animal models.1

Advice to Patients

  • Importance of reading patient information (medication guide) provided by the manufacturer.1

  • Potential for severe diarrhea and dehydration if accidentally ingested by a child, especially a child <6 years of age.1 Importance of keeping plecanatide out of reach of children and of properly disposing of any unused drug.1 (See Pediatric Use under Cautions.)

  • Diarrhea may occur; importance of discontinuing plecanatide and notifying clinician if diarrhea becomes severe.1

  • Importance of advising patient of alternative forms of administration if patient is unable to swallow whole tablets.1

  • Importance of storing plecanatide in the original container, protected from moisture; remove polyester coil from container after opening, but do not remove desiccant from container and do not repackage.1

  • If a dose is missed, omit the missed dose and take the next dose at the regularly scheduled time.1 Do not take 2 doses at the same time.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Plecanatide

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

3 mg

Trulance

Synergy

AHFS DI Essentials. © Copyright 2017, Selected Revisions July 10, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Synergy Pharmaceuticals, Inc. Trulance (plecanatide) tablets prescribing information. New York, NY; 2017 Jan.

2. Miner PB, Koltun WD, Wiener GJ et al. A Randomized Phase III Clinical Trial of Plecanatide, a Uroguanylin Analog, in Patients With Chronic Idiopathic Constipation. Am J Gastroenterol. 2017; [PubMed 28169285]

3. 12-week study of plecanatide for CIC (The National CIC3 study) (CIC). From ClinicalTrials.gov registry. Accessed 2017 Mar 20.

5. Corsetti M, Whorwell P. Novel pharmacological therapies for irritable bowel syndrome. Expert Rev Gastroenterol Hepatol. 2016; 10:807-15. [PubMed 26907518]

6. Shailubhai K, Comiskey S, Foss JA et al. Plecanatide, an oral guanylate cyclase C agonist acting locally in the gastrointestinal tract, is safe and well-tolerated in single doses. Dig Dis Sci. 2013; 58:2580-6. [PubMed 23625291]

7. Al-Salama ZT, Syed YY. Plecanatide: First Global Approval. Drugs. 2017; 77:593-598. [PubMed 28255961]

8. Nusrat S, Miner PB. New pharmacological treatment options for irritable bowel syndrome with constipation. Expert Opin Emerg Drugs. 2015; 20:625-36. [PubMed 26548544]

9. Jiang C, Xu Q, Wen X et al. Current developments in pharmacological therapeutics for chronic constipation. Acta Pharm Sin B. 2015; 5:300-9. [PubMed 26579459]

10. Corsetti M, Tack J. New pharmacological treatment options for chronic constipation. Expert Opin Pharmacother. 2014; 15:927-41. [PubMed 24661106]

11. Koliani-Pace J, Lacy BE. Update on the Management of Chronic Constipation. Curr Treat Options Gastroenterol. 2017; 15:126-134. [PubMed 28116695]

12. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number: 208745Orig1s000: Clinical pharmacology and biopharmaceutics review(s). From FDA website.

13. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number: 208745Orig1s000: Medical review(s). From FDA website.

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