Linaclotide is a selective guanylate cyclase C agonist. In adults, linaclotide is indicated for the treatment of irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC). It is also indicated for the treatment of functional constipation (FC) in pediatric patients 6 to 17 years of age. Guidelines strongly recommend linaclotide to treat global IBS-C symptoms in adults. Safety and effectiveness for the management of IBS-C were established in two double-blind clinical trials; in clinical studies, linaclotide was associated with a reduction in the amount of abdominal pain as well as an increase in the number of complete spontaneous bowel movements compared to placebo. Safety and effectiveness for the management of CIC in adults were established with two additional double-blind clinical studies. In these studies, adults with CIC randomized to receive linaclotide experienced more complete spontaneous bowel movements as compared to placebo. Other drug-associated benefits observed during CIC studies included improvements in the frequency and consistency of spontaneous bowel movements, as well as improvements in the amount of straining with each bowel movement. The safety and efficacy of linaclotide for the treatment of FC in pediatric patients 6 to 17 years of age were established in a 12-week double-blind, placebo-controlled, randomized, multicenter, clinical trial (n = 328). The 12-week change from baseline in spontaneous bowel movement (SBM) frequency rate was 2.6 in the linaclotide group compared with 1.3 in the placebo group (treatment difference, 1.3; 95% CI: 1.3 to 1.8), and SBM frequency improved during week 1 and was maintained throughout the 12-week trial. Diarrhea is the most common side effect in adult and pediatric patients. Linaclotide has a boxed warning regarding the risk of serious dehydration in pediatric patients younger than 2 years of age.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
Oral Solid Formulations
-Administer on an empty stomach, at least 30 minutes prior to a meal, at approximately the same time each day.
-Do not crush, cut, or chew capsule or capsule contents; swallow whole.
-Missed dose: If a dose is missed, skip the missed dose and take the next dose at the regular time. Do not take 2 doses at the same time.
-For patients who are unable to swallow the capsules whole, the capsules may be opened and administered with applesauce or in water as follows:
--Administration with applesauce: Place 1 teaspoon of applesauce in a clean container. Open capsule and sprinkle entire contents (beads) over the applesauce. Consume all the beads immediately. DO NOT chew. Do not store the bead-applesauce mixture for later use.
-Administration in water for oral ingestion: Pour 30 mL of room temperature bottled water into clean cup. Open capsule and swirl entire contents (beads) into the water for at least 20 seconds. Swallow the entire mixture immediately. If any beads remain in the cup, add another 30 mL of water, swirl for 20 seconds, and swallow immediately. Do not store the bead-water mixture for later use. NOTE: The drug is coated on the surface of the beads and will dissolve off the beads into the water; the beads will remain intact and not dissolve. Therefore, it is not necessary to consume all the beads to deliver the complete dose.
-Administration in water via nasogastric or gastric feeding tube: Pour 30 mL of room temperature bottled water into clean container. Open capsule and swirl entire contents (beads) into the water for at least 20 seconds. Draw up the bead/water mixture into a catheter-tipped syringe. Immediately administer the contents of the syringe into the tube using rapid and consistent pressure (rate: 10 mL/10 seconds). Add another 30 mL of water to any beads remaining in the container and repeat the process. Flush tube after dosing with a minimum of 10 mL of water. NOTE: The drug is coated on the surface of the beads and will dissolve off the beads into the water; the beads will remain intact and not dissolve. Therefore, it is not necessary to flush all the beads through to deliver the complete dose.
Diarrhea was the most common adverse reaction reported in linaclotide-treated patients in adult and pediatric clinical trials. In adult clinical trials, diarrhea was reported in 16% to 22% of linaclotide-treated patients; severe diarrhea was reported in 2% or less of patients. Overall, diarrhea and abdominal pain were the most common reasons for drug discontinuation and/or dose reductions in adult clinical trials. In the pediatric clinical trial (n = 328), diarrhea was reported in 4% of linaclotide-treated patients; one pediatric patient in the linaclotide-treated group reported severe diarrhea and discontinued treatment. In both adult and pediatric trials, the majority of reported cases of diarrhea started within the first 2 weeks of treatment. Cases of severe diarrhea associated with dizziness, syncope, hypotension, and electrolyte abnormalities (i.e., hypokalemia, hyponatremia) have been reported during postmarketing use of the drug. In some cases, drug recipients required hospitalization and treatment with intravenous fluids. If severe diarrhea occurs, consider dose suspension and rehydration. Other gastrointestinal adverse reactions reported in linaclotide-treated patients in adult clinical trials include abdominal pain (7%), flatulence (4% to 6%), abdominal distension (1% to 3%), and viral gastroenteritis (3% or less). Gastroesophageal reflux disease, dyspepsia, defecation urgency, fecal incontinence, and vomiting were reported in less than 2% of linaclotide-treated patients. Nausea (n = 2), abdominal discomfort (n = 1), and dehydration (n = 1) were reported rarely in pediatric patients. Hematochezia or melena, rectal hemorrhage (GI bleeding), and nausea have been reported during postmarketing use of linaclotide.
Headache was reported in 4% of adult patients treated with linaclotide in clinical trials.
Hypersensitivity reactions, including anaphylaxis or anaphylactoid reactions, angioedema, and rash (i.e., hives or urticaria), have been reported during postmarketing experience with linaclotide.
Upper respiratory tract infection (5%) and sinusitis (3%) have been reported in adult patients treated with linaclotide in clinical trials.
Linaclotide 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 linaclotide. It is prudent to use linaclotide 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.
Linaclotide should not be administered to patients with severe diarrhea. Diarrhea is a common adverse effect of linaclotide. Cases of severe diarrhea associated with dizziness, syncope, hypotension, and electrolyte abnormalities (i.e., hypokalemia, hyponatremia) have been reported during postmarketing use of the drug. In some cases, drug recipients required hospitalization and treatment with intravenous fluids. Inform patients to notify their health care provider if they develop diarrhea. For severe cases of diarrhea, practitioner should consider suspending linaclotide treatment and initiating rehydration as needed.
Linaclotide is contraindicated in neonates, infants, and children younger than 2 years of age. A GC-C ontogeny study measured GC-C mRNA expression levels in duodenal and colonic mucosal tissue samples from children aged 6 months to 17 years (n = 99) to evaluate the risk of diarrhea and severe dehydration due to GC-C agonism in children. The results showed no age-dependent trend in GC-C intestinal expression in children 2 to 17 years of age. However, there are insufficient data available on GC-C intestinal expression in children younger than 2 years of age to assess the risk of developing diarrhea and its potentially serious consequences. In preclinical studies, deaths due to dehydration occurred within 24 hours in neonatal mice (human age equivalent of approximately 0 to 28 days) following oral administration of linaclotide which increased fluid secretion as a consequence of age-dependent elevated GC-C agonism resulting in rapid and severe dehydration.
The available data on linaclotide use during human pregnancy are insufficient to inform any drug-associated risk for major birth defects and miscarriage. However, linaclotide and its active metabolite are negligibly absorbed systemically following oral administration, and maternal use is not expected to result in fetal exposure to the drug. In animal developmental studies, adverse fetal effects were observed only with maternal toxicity and at doses of linaclotide much higher than the maximum recommended human dose.
Use of linaclotide during breast-feeding is not expected to result in exposure to linaclotide or its active metabolite in the breastfed child. Following oral administration of a maternal therapeutic dosage of 72 mcg, 145 mcg, or 290 mcg of linaclotide once daily for 3 days, the concentrations of linaclotide and its metabolite were below the limits of quantitation (less than 0.25 ng/mL and less than 1 ng/mL, respectively) in all breast milk samples collected over 24 hours. There is no information on the effects of linaclotide or its active metabolite on milk production. Consider the developmental and health benefits of breast-feeding along with the maternal clinical need for linaclotide treatment and potential adverse effects on the breastfed child.
For the treatment of constipation:
-for the treatment of chronic idiopathic constipation (CIC):
Oral dosage:
Adults: 145 mcg PO once daily. A dosage of 72 mcg once daily may be used based on patient presentation and tolerability.
-for the treatment of functional constipation (FC):
Oral dosage:
Children and Adolescents 6 to 17 years: 72 mcg PO once daily.
For the treatment of irritable bowel syndrome with constipation (IBS-C):
Oral dosage:
Adults: 290 mcg PO once daily.
Maximum Dosage Limits:
-Adults
290 mcg/day PO.
-Geriatric
290 mcg/day PO.
-Adolescents
72 mcg/day PO.
-Children
6 to 12 years: 72 mcg/day PO.
2 to 5 years: Safety and efficacy have not been established.
1 year: 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
Anticholinergics: (Moderate) Anticholinergics can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation or constipation-associated irritable bowel syndrome, such as linaclotide.
Atropine: (Moderate) Anticholinergics can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation or constipation-associated irritable bowel syndrome, such as linaclotide.
Atropine; Difenoxin: (Moderate) Anticholinergics can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation or constipation-associated irritable bowel syndrome, such as linaclotide.
Belladonna; Opium: (Moderate) Anticholinergics can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation or constipation-associated irritable bowel syndrome, such as linaclotide.
Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) Anticholinergics can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation or constipation-associated irritable bowel syndrome, such as linaclotide.
Benztropine: (Moderate) Anticholinergics can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation or constipation-associated irritable bowel syndrome, such as linaclotide.
Budesonide; Glycopyrrolate; Formoterol: (Moderate) Anticholinergics can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation or constipation-associated irritable bowel syndrome, such as linaclotide.
Chlordiazepoxide; Clidinium: (Moderate) Anticholinergics can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation or constipation-associated irritable bowel syndrome, such as linaclotide.
Dicyclomine: (Moderate) Anticholinergics can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation or constipation-associated irritable bowel syndrome, such as linaclotide.
Diphenoxylate; Atropine: (Moderate) Anticholinergics can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation or constipation-associated irritable bowel syndrome, such as linaclotide.
Flavoxate: (Moderate) Anticholinergics can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation or constipation-associated irritable bowel syndrome, such as linaclotide.
Glycopyrrolate: (Moderate) Anticholinergics can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation or constipation-associated irritable bowel syndrome, such as linaclotide.
Glycopyrrolate; Formoterol: (Moderate) Anticholinergics can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation or constipation-associated irritable bowel syndrome, such as linaclotide.
Homatropine; Hydrocodone: (Moderate) Anticholinergics can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation or constipation-associated irritable bowel syndrome, such as linaclotide.
Hyoscyamine: (Moderate) Anticholinergics can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation or constipation-associated irritable bowel syndrome, such as linaclotide.
Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Moderate) Anticholinergics can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation or constipation-associated irritable bowel syndrome, such as linaclotide.
Indacaterol; Glycopyrrolate: (Moderate) Anticholinergics can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation or constipation-associated irritable bowel syndrome, such as linaclotide.
Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Moderate) Anticholinergics can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation or constipation-associated irritable bowel syndrome, such as linaclotide.
Methscopolamine: (Moderate) Anticholinergics can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation or constipation-associated irritable bowel syndrome, such as linaclotide.
Neostigmine; Glycopyrrolate: (Moderate) Anticholinergics can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation or constipation-associated irritable bowel syndrome, such as linaclotide.
Oxybutynin: (Moderate) Anticholinergics can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation or constipation-associated irritable bowel syndrome, such as linaclotide.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Moderate) Anticholinergics can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation or constipation-associated irritable bowel syndrome, such as linaclotide.
Propantheline: (Moderate) Anticholinergics can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation or constipation-associated irritable bowel syndrome, such as linaclotide.
Scopolamine: (Moderate) Anticholinergics can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation or constipation-associated irritable bowel syndrome, such as linaclotide.
Trihexyphenidyl: (Moderate) Anticholinergics can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation or constipation-associated irritable bowel syndrome, such as linaclotide.
Linaclotide is a guanylate cyclase-C (GC-C) agonist. Both linaclotide 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, linaclotide has been shown to both accelerate GI transit and reduce intestinal pain. The linaclotide induced reduction in visceral pain in animals is thought to be mediated by increased extracellular cGMP, which was shown to decrease the activity of pain-sensing nerves.
Linaclotide is administered orally. Linaclotide 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 linaclotide and the metabolite are proteolytically degraded within the intestinal lumen to smaller peptides and naturally occurring amino acids. Active peptide recovery in the stool samples of fed and fasted subjects following the daily administration of 290 mcg for 7 days averaged about 5% (fasted) and about 3% (fed) and virtually all as the active metabolite.
Affected cytochrome P450 isoenzymes and drug transporters: None
-Route-Specific Pharmacokinetics
Oral Route
Following oral administration, linaclotide is minimally absorbed with low systemic availability. Concentrations of linaclotide and its active metabolite in plasma are below the limit of quantitation after oral doses of 145 mcg or 290 mcg. Therefore, standard pharmacokinetic parameters such as AUC, Cmax, and half-life cannot be calculated.
Effects of food
Linaclotide is administered on an empty stomach, at least 30 minutes before breakfast. In clinical trials, linaclotide was tested under both non-fed and fed conditions. Taking linaclotide immediately after the high fat breakfast resulted in looser stools and a higher stool frequency compared with taking it in the fasted state.
-Special Populations
Hepatic Impairment
Hepatic impairment is not expected to affect the clearance of linaclotide or its metabolite due to the low systemic availability following oral administration and its metabolism within the GI tract.
Renal Impairment
Renal impairment is not expected to affect the clearance of linaclotide or its metabolite due to the low systemic availability following oral administration and its metabolism within the GI tract.
Geriatric
Clinical studies of linaclotide did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.