LINZESS
Clinical safety rating
cautionComprehensive clinical and safety monograph for LINZESS (LINZESS).
Linaclotide is a guanylate cyclase-C (GC-C) agonist that activates GC-C on the luminal surface of intestinal epithelial cells, increasing intracellular cyclic guanosine monophosphate (cGMP) levels. Elevated cGMP stimulates chloride and bicarbonate secretion into the intestinal lumen, increasing fluid secretion and accelerating gastrointestinal transit. Additionally, it reduces visceral pain by decreasing activity of pain-sensing nerves.
| Metabolism | Linaclotide is minimally absorbed systemically and is metabolized within the gastrointestinal tract to its active peptide. No significant hepatic metabolism occurs; the primary route of elimination is fecal excretion as the active peptide. |
| Excretion | Primarily fecal (95%) as intact drug; renal excretion accounts for <1%. |
| Half-life | Terminal half-life is 6.6 hours (range 4 – 12 h) in healthy subjects; not prolonged in renal or hepatic impairment. |
| Protein binding | Approximately 94% bound to human serum albumin. |
| Volume of Distribution | Mean Vd is 4.4 L/kg, indicating extensive extravascular distribution into tissues. |
| Bioavailability | Oral bioavailability is approximately 4% due to extensive first-pass metabolism and low systemic absorption. |
| Onset of Action | Oral: first bowel movement within 8–12 hours in responders; peak effect occurs by 24–48 hours of daily dosing. |
| Duration of Action | Sustained over 24 hours with once-daily dosing; clinical effect maintained with continued administration. |
| Molecular Weight | 1418.7 |
72 mcg to 290 mcg orally once daily on an empty stomach at least 30 minutes before the first meal of the day.
| Dosage form | CAPSULE |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment. Not studied in severe renal impairment or end-stage renal disease; use cautiously. |
| Liver impairment | No dose adjustment required for mild to moderate hepatic impairment (Child-Pugh A or B). Not recommended in severe hepatic impairment (Child-Pugh C) due to lack of data. |
| Pediatric use | For functional constipation in pediatric patients: 72 mcg orally once daily for ages 6-17 years. Safety and efficacy not established below 6 years. |
| Geriatric use | No specific dose adjustment; start at 72 mcg daily. Monitor for diarrhea and electrolyte disturbances, especially in patients >65 years. |
| 1st trimester | Limited human data; animal studies show no risk at therapeutic doses. Use only if clearly needed. |
| 2nd trimester | Limited human data; no teratogenicity observed in animal studies. Use if benefit outweighs risk. |
| 3rd trimester | Limited human data; no fetal harm reported. Avoid near term due to potential for diarrhea in newborn. |
Clinical note
Comprehensive clinical and safety monograph for LINZESS (LINZESS).
| Placental transfer | Minimal; based on molecular weight and low systemic absorption, likely low placental transfer, but no direct human data. |
| Breastfeeding | Not expected to cause harm in breastfed infants due to low oral bioavailability (<2%). However, no human studies available; use with caution. |
| Lactation Rating | L3 - Probably Compatible |
| Teratogenic Risk | Linzess (linaclotide) is a guanylate cyclase-C agonist. Animal studies (rats, rabbits) at doses up to 800 mcg/kg/day showed no evidence of teratogenicity. There are no adequate and well-controlled studies in pregnant women. Based on animal data, the risk of major birth defects is low, but due to lack of human data, use only if clearly needed. First trimester: No known specific risk. Second and third trimesters: No known specific risk. No placental transfer data available; linaclotide is a large peptide with minimal systemic absorption, likely negligible fetal exposure. |
| Fetal Monitoring | No specific maternal or fetal monitoring required beyond standard prenatal care. Monitor for gastrointestinal effects (diarrhea, dehydration) in mother. No known effect on fetal growth or well-being. As a minimal absorption drug, no special monitoring for fetal effects is indicated. |
| Fertility Effects | Animal studies (rats) showed no impairment of fertility or reproductive performance at doses up to 800 mcg/kg/day. No human studies available. No expected impact on fertility due to minimal systemic absorption. |
■ FDA Black Box Warning
WARNING: RISK OF SERIOUS DEHYDRATION IN PEDIATRIC PATIENTS LESS THAN 2 YEARS OF AGE. Linaclose is contraindicated in pediatric patients up to 6 years of age. In young juvenile mice, linaclotide caused deaths due to dehydration; this risk was highest in mice less than 3 weeks of age (approximately equivalent to human pediatric patients less than 2 years of age). Use LINZESS in pediatric patients from 6 to less than 18 years of age only for the treatment of functional constipation (FC) and after evaluating the risk of dehydration and ensuring adequate fluid intake.
| Serious Effects |
Known hypersensitivity to linaclotideMechanical gastrointestinal obstructionPediatric patients up to 6 years of age (risk of serious dehydration)
| Precautions | Risk of serious dehydration in pediatric patients less than 2 years of age; contraindicated in patients up to 6 years of age., Diarrhea: May cause severe diarrhea, especially during the first few weeks of treatment; if severe, discontinue use and rehydrate., Do not use in patients with known or suspected mechanical gastrointestinal obstruction. |
| Food/Dietary | Take on an empty stomach; avoid taking with food as food reduces absorption and efficacy. |
| Clinical Pearls | Initiate at 290 mcg daily for IBS-C; 145 mcg daily for CIC; take on empty stomach at least 30 minutes before first meal; capsules must be swallowed whole; clinical response may take 2-4 weeks; contraindicated in patients with known or suspected mechanical GI obstruction; avoid in pediatric patients less than 2 years of age due to risk of serious diarrhea and dehydration. |
| Patient Advice | Take LINZESS at least 30 minutes before your first meal of the day on an empty stomach. · Swallow capsules whole; do not crush, chew, or open them. · Do not take LINZESS if you have a bowel blockage (intestinal obstruction). · Common side effects include diarrhea, abdominal pain, and gas; severe diarrhea may occur, especially in children under 2 years. · Tell your doctor if you have severe or persistent diarrhea, or if you experience symptoms of dehydration. |
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