Linzess

Guanylate Cyclase-C Agonists for Constipation
Guanylate Cyclase-C Agonists for IBS-C

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 / Early / 0-2.0
GI bleeding / Delayed / Incidence not known
anaphylactoid reactions / Rapid / Incidence not known
angioedema / Rapid / Incidence not known

fecal incontinence / Early / 0-2.0
hypokalemia / Delayed / Incidence not known
hypotension / Rapid / Incidence not known
dehydration / Delayed / Incidence not known
melena / Delayed / Incidence not known
hyponatremia / Delayed / Incidence not known

abdominal pain / Early / 7.0-7.0
flatulence / Early / 4.0-6.0
infection / Delayed / 5.0-5.0
headache / Early / 4.0-4.0
sinusitis / Delayed / 3.0-3.0
vomiting / Early / 0-2.0
dyspepsia / Early / 0-2.0
gastroesophageal reflux / Delayed / 0-2.0
urticaria / Rapid / 0-1.0
rash / Early / 0-1.0
dizziness / Early / Incidence not known
syncope / Early / Incidence not known
nausea / Early / Incidence not known

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.

Linzess

Rx

Oral selective guanylate cyclase C agonist
Used for irritable bowel syndrome with constipation (IBS-C) or chronic idiopathic constipation (CIC) in adults and functional constipation (FC) in pediatric patients 6 years and older
Boxed warning regarding the risk of serious dehydration in pediatric patients younger than 2 years of age

145 mcg PO once daily. A dosage of 72 mcg once daily may be used based on patient presentation and tolerability.

72 mcg PO once daily.

290 mcg 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.

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.

Linzess Oral Cap: 72mcg, 145mcg, 290mcg

290 mcg/day PO.

290 mcg/day PO.

72 mcg/day PO.

6 to 12 years: 72 mcg/day PO.
2 to 5 years: Safety and efficacy have not been established.
1 year: Contraindicated.

Contraindicated.

Contraindicated.

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

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.

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.