Linaclotide Oral

Irritable Bowel Syndrome with Constipation

Linaclotide is used in adults for the symptomatic treatment of irritable bowel syndrome (IBS) with constipation.^[1]

Efficacy and safety of linaclotide for the symptomatic treatment of IBS with constipation have been evaluated in 2 randomized, double-blind, placebo-controlled studies (trial 31 and trial 302) in adults (mean age 44 years; 90% female; 77% white, 19% black, and 12% Hispanic) who met Rome II criteria for IBS.^[1][2][3][4] Eligible patients also were required to meet the following criteria during the 14-day baseline period: a mean abdominal pain score of at least 3 (on a scale of 0-10), fewer than 3 complete spontaneous bowel movements (CSBMs) per week, and 5 or fewer spontaneous bowel movements (SBMs) per week.^[1][2][3] In both studies, patients were randomized to receive linaclotide 290 mcg once daily or placebo.^[1][2][3][4] In trial 31, the assigned treatment was continued for 12 weeks; patients who completed 12 weeks of linaclotide therapy then were rerandomized to receive linaclotide 290 mcg once daily or placebo for 4 additional weeks, while those who had received placebo for 12 weeks were reassigned to receive linaclotide 290 mg once daily for 4 weeks.^[1][2] In trial 302, the originally assigned treatment was continued for 26 weeks.^[1][3] In both studies, the primary end point was efficacy over the first 12 weeks.^[1][2][3] Data on patients' symptoms were collected via daily patient reports.^[1][2][3][4]

In the first study (trial 31),^[6] 34% of patients receiving linaclotide and 21% of patients receiving placebo achieved the combined efficacy end point (defined as at least 30% improvement in mean abdominal pain score and an increase of one or more CSBMs per week compared with baseline) in the same week for at least 6 out of 12 weeks of treatment.^[1][2] The individual components of this end point were achieved by 50 and 49%, respectively, of patients receiving linaclotide and 37 and 30%, respectively, of those receiving placebo.^[1][2] In patients who switched to placebo after completing 12 weeks of linaclotide therapy, abdominal pain scores and CSBM frequency returned toward baseline values within 1 week following drug discontinuance; those who continued receiving linaclotide maintained their response over 4 additional weeks of treatment.^[1][2]

In the second study (trial 302),^[6] 34% of patients receiving linaclotide and 14% of those receiving placebo achieved the combined efficacy end point (at least 30% improvement in mean abdominal pain score and an increase of one or more CSBMs per week compared with baseline) in the same week for at least 6 out of the first 12 weeks of treatment.^[1][3] The individual components of this end point were achieved by 49 and 48%, respectively, of patients receiving linaclotide and 34 and 23%, respectively, of those receiving placebo.^[1][3] Results for the entire 26-week treatment period were consistent with those for the first 12 weeks, with 32% of linaclotide-treated patients and 13% of placebo recipients achieving the combined end point for at least 13 out of 26 weeks.^[3]

In both studies, assessments of changes in individual symptoms of IBS, measures of bowel function (frequency of SBMs, stool consistency, amount of straining with bowel movements), and patient ratings of the adequacy and degree of relief also favored linaclotide over placebo.^[1][2][3] Improvements in abdominal pain scores were apparent within the first week of linaclotide therapy and were maximal in 6-9 weeks; maximal effects on CSBM frequency were achieved within the first week of therapy.^[1][2][3]

A post-hoc analysis of data from trials 31 and 302 indicated that linaclotide improved abdominal symptoms in subsets of patients with severe symptoms at baseline (defined as any baseline abdominal pain, discomfort, bloating, fullness, or cramping rated 7 or greater on a scale of 0-10).^[6] At 12 weeks, the mean change in abdominal symptom scores from baseline in these subsets of patients was substantially greater in patients receiving linaclotide compared with those receiving placebo.^[6]

Chronic Idiopathic Constipation

Linaclotide is used in adults for the symptomatic treatment of chronic idiopathic constipation.^[1]

Efficacy and safety of linaclotide (145 or 290 mcg daily) for the symptomatic treatment of chronic idiopathic constipation have been evaluated in 2 randomized, double-blind, placebo-controlled studies (trial 01 and trial 303) in adults who reported having had fewer than 3 SBMs per week and having experienced straining, lumpy or hard stools, and/or a sensation of incomplete evacuation during more than 25% of bowel movements for at least 12 weeks out of the previous 12 months.^[1][5] Patients were excluded if they met Rome II criteria for IBS.^[1][5] In the 2 studies combined, the mean age of patients was 48 years, and most patients were female (89%) and white (76%; 22% black, 10% Hispanic).^[1] In each study, patients were randomized to receive linaclotide 290 mcg, linaclotide 145 mcg, or placebo once daily for 12 weeks.^[1][5] In trial 303, patients who completed 12 weeks of linaclotide therapy were rerandomized to receive linaclotide (at the originally assigned dosage) or placebo for 4 additional weeks, while those who had received placebo for 12 weeks were reassigned to receive linaclotide 290 mcg daily for 4 weeks.^[1][5] Data on bowel function and patients' symptoms were collected via daily patient reports.^[1][5] The combined primary efficacy end point was defined as 3 or more CSBMs per week and an increase of at least 1 CSBM per week compared with baseline for at least 9 weeks during the 12-week treatment period.^[1][5]

Results from trial 303 showed that 19, 20, or 3% of patients receiving linaclotide 290 mcg, linaclotide 145 mcg, or placebo, respectively, achieved the combined efficacy end point.^[1][5][14] In patients who switched to placebo after receiving 12 weeks of linaclotide therapy, CSBM and SBM frequency returned toward baseline values within 1 week following drug discontinuance; those who continued receiving linaclotide maintained their response over 4 additional weeks of treatment.^[1][5]

Results from trial 01 showed that 20, 15, or 6% of patients receiving linaclotide 290 mcg, linaclotide 145 mcg, or placebo, respectively, achieved the combined efficacy end point.^[1][5][14]

Although both dosages of linaclotide were effective, the studies provided no consistent evidence indicating that the 290-mcg daily dosage confers additional clinical benefit beyond that produced by the 145-mcg daily dosage.^[1][14]

In both studies, assessments of changes in individual symptoms of constipation, measures of bowel function (frequency of SBMs, stool consistency, amount of straining with bowel movements), and overall severity of constipation also favored linaclotide over placebo.^[1][5] Maximal effects on CSBM frequency were achieved within the first week of therapy and were sustained throughout the treatment period.^[1][5]

Efficacy of linaclotide at a dosage of 72 mcg daily was established in a third randomized, double-blind, placebo-controlled study in adults who met modified Rome III criteria for functional constipation.^[1] The study design through week 12 was the same as that in trial 01 and trial 303.^[1] The mean age of patients was 46 years, and most patients were female (77%) and white (71%).^[1] The combined efficacy end point (3 or more CSBMs in a given week and an increase of at least 1 CSBM from baseline in the same week for a minimum of 9 weeks out of the 12-week treatment period) was achieved by 13% of patients receiving linaclotide 72 mcg daily compared with 5% of those receiving placebo.^[1] In a separate analysis using an alternate definition of response (3 or more CSBMs in a given week and an increase of at least 1 CSBM from baseline in the same week for a minimum of 9 weeks out of the 12-week treatment period and for at least 3 of the last 4 weeks of the treatment period), response rates were 12% for patients receiving linaclotide 72 mcg daily and 5% for those receiving placebo.^[1]

Administration

Linaclotide is administered orally on an empty stomach, at least 30 minutes prior to the first meal of the day.^[1] Administration immediately after a high-fat breakfast resulted in looser stools and increased frequency of stools when compared with administration in the fasted state.^[1] In clinical trials, linaclotide was administered at least 30 minutes before breakfast.^[1]

Linaclotide capsules should be swallowed whole.^[1] Alternatively, for patients who are unable to swallow whole capsules, linaclotide capsules may be opened and the contents (beads) may be sprinkled on applesauce and administered orally or dispersed in water and administered orally or via a nasogastric or gastrostomy tube.^[1] The manufacturer states that sprinkling the capsule contents of linaclotide capsules on soft foods other than applesauce or dispersing the contents in liquids other than water has not been studied.^[1] The capsules or capsule contents should not be crushed or chewed.^[1]

For administration in applesauce, the entire contents of one capsule of linaclotide should be sprinkled on one teaspoonful of room-temperature applesauce in a clean container.^[1] The entire mixture should be consumed (without chewing) immediately and should not be stored for later use.^[1]

For oral administration mixed in water, the entire contents of one capsule of linaclotide should be added to a clean cup containing approximately 30 mL of room-temperature bottled water, the mixture should be gently swirled for at least 20 seconds, and then the entire contents should be consumed immediately.^[1] Any beads remaining in the cup should be dispersed in an additional 30 mL of water, gently swirled again for at least 20 seconds, and then consumed immediately.^[1] The mixture should not be stored for later use.^[1] The manufacturer states that linaclotide is coated on the surface of the beads and will dissolve off the beads into the water.^[1] Thus, consumption of all the beads is not necessary to deliver a complete dose of the drug.^[1]

For administration via nasogastric or gastrostomy feeding tube, the entire contents of one linaclotide capsule should be added to a clean cup containing 30 mL of room-temperature bottled water, the mixture should be gently swirled for at least 20 seconds, and then the entire contents should be drawn up into an appropriately sized catheter-tipped syringe and administered into the nasogastric or gastrostomy tube rapidly (10 mL per 10 seconds) using steady pressure.^[1] Any beads remaining in the cup should be dispersed in an additional 30 mL of water and the process should be repeated.^[1] Following administration of the dose, the nasogastric or gastrostomy tube should be flushed with at least 10 mL of water.^[1] Because linaclotide is coated on the surface of the beads and will dissolve off the beads into the water, the manufacturer states that it is not necessary to administer all the beads to deliver a complete dose of the drug.^[1]

Dosage

Adult Dosage

Irritable Bowel Syndrome with Constipation

The recommended adult dosage of linaclotide for the symptomatic treatment of irritable bowel syndrome (IBS) with constipation is 290 mcg once daily.^[1]

Chronic Idiopathic Constipation

The recommended adult dosage of linaclotide for the symptomatic treatment of chronic idiopathic constipation is 145 mcg once daily.^[1] A dosage of 72 mcg once daily may be used based on individual presentation and tolerability.^[1]

Special Populations

Dosage adjustments are not needed in patients with renal or hepatic impairment.^[1]

The manufacturer makes no specific dosage recommendations for geriatric patients.^[1]

Contraindications

Linaclotide is contraindicated in infants and children younger than 6 years of age.^[1] (See Pediatric Use under Warnings/Precautions: Specific Populations, in Cautions.) The drug also is contraindicated in any patient with known or suspected mechanical GI obstruction.^[1]

Warnings/Precautions

Warnings

Pediatric Risk

In toxicology studies, linaclotide caused deaths due to dehydration in neonatal mice when administered in single, clinically relevant, adult oral doses.^[1] Linaclotide is contraindicated in infants and children younger than 6 years of age and should be avoided in children and adolescents 6 years to younger than 18 years of age.^[1] (See Pediatric Use under Warnings/Precautions: Specific Populations, in Cautions.)

Other Warnings and Precautions

Diarrhea

Diarrhea may occur, generally during the first 2 weeks of linaclotide therapy.^[1] The incidence of diarrhea is similar in patients with either irritable bowel syndrome (IBS) with constipation or chronic idiopathic constipation.^[1] In clinical trials in patients with these conditions, severe diarrhea was reported in 2% of patients receiving a linaclotide dosage of 145 or 290 mcg daily and in less than 1% of those receiving a dosage of 72 mcg daily.^[1] Cases of severe diarrhea that were associated with dizziness, syncope, hypotension, and electrolyte abnormalities (hypokalemia and hyponatremia) and that required hospitalization or administration of IV fluids have been reported during postmarketing experience with the drug.^[1] If severe diarrhea occurs, linaclotide therapy should be interrupted and the patient should be rehydrated.^[1]

Specific Populations

Pregnancy

Since systemic absorption of linaclotide and its active metabolite is negligible following oral administration, the drug is not expected to result in fetal exposure if administered to pregnant women.^[1] However, available data on use of linaclotide in pregnant women are insufficient to inform fetal risk.^[1]

No adverse effects on embryofetal development were observed in rats or rabbits when linaclotide was administered orally during organogenesis at dosages of up to 100,000 or 40,000 mcg/kg daily, respectively.^[1] Severe maternal toxicity and associated effects on fetal morphology were observed in mice at dosages of at least 40,000 mcg/kg daily.^[1] No developmental abnormalities and no effects on growth, learning and memory, or fertility were observed in the offspring of rats that received linaclotide orally at dosages up to 100,000 mcg/kg daily during the period of organogenesis through lactation.^[1] Limited systemic exposure to linaclotide was achieved in rats, rabbits, and mice during the period of organogenesis.^[1] Animal and human doses should not be compared directly for evaluating relative exposure.^[1]

Lactation

It is not known whether linaclotide is distributed into human milk, affects milk production, or affects the breast-fed infant.^[1]

Systemic absorption of linaclotide and its active metabolite is negligible following oral administration.^[1] It is not known whether the negligible systemic absorption observed in adults will result in clinically important exposure in breast-fed infants.^[1] The benefits of breast-feeding and the importance of linaclotide to the woman should be considered along with potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.^[1] Exposure of infants to linaclotide could result in serious adverse effects.^[1] (See Pediatric Use under Warnings/Precautions: Specific Populations, in Cautions.)

Pediatric Use

Linaclotide is contraindicated in infants and children younger than 6 years of age and should be avoided in children and adolescents 6 years to younger than 18 years of age.^[1]

Safety and efficacy of linaclotide in pediatric patients younger than 18 years of age have not been established, and the drug has caused deaths within 24 hours of administration in toxicology studies in neonatal mice (age approximately equivalent to a human age of 0-28 days).^[1] In neonatal mice, administration of linaclotide 10 mcg/kg daily caused deaths on postnatal day 7.^[1] Tolerability to linaclotide increased with age in juvenile mice.^[1] In 2-week-old mice, linaclotide was well tolerated at a dosage of 50 mcg/kg daily, but deaths occurred after a single oral dose of 100 mcg/kg.^[1] In 3-week-old mice, linaclotide was well tolerated at a dosage of 100 mcg/kg daily, but deaths occurred after a single oral dose of 600 mcg/kg.^[1] The deaths in neonatal mice were due to rapid and severe dehydration resulting from increased fluid secretion into the intestine as a consequence of guanylate cyclase-C (GC-C) stimulation.^[1] Because of increased intestinal expression of GC-C, infants and children younger than 6 years of age may be at greater risk of developing diarrhea and its potentially serious consequences compared with individuals 6 years of age and older.^[1] Although no deaths occurred in older juvenile mice, use of the drug in children and adolescents 6 years to younger than 18 years of age should be avoided because of the deaths reported in younger mice and the lack of safety and efficacy data in pediatric patients.^[1]

Geriatric Use

Clinical studies of linaclotide did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger adults.^[1] In clinical trials in patients with IBS with constipation, 5% of patients were 65 years of age or older, while 1% were 75 years of age and older; in clinical trials in patients with chronic idiopathic constipation, 11% were 65 years of age or older, while 2% were 75 years of age and older.^[1] In general, dosage should be selected with caution in geriatric patients because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and/or drug therapy.^[1]

Hepatic Impairment

Linaclotide has not been studied in patients with hepatic impairment.^[1] However, because linaclotide is metabolized within the GI tract and has negligible systemic bioavailability following oral administration, hepatic impairment is not expected to affect metabolism or clearance of the drug or its metabolite.^[1]

Renal Impairment

Linaclotide has not been studied in patients with renal impairment.^[1] However, because linaclotide is metabolized within the GI tract and has negligible systemic bioavailability following oral administration, renal impairment is not expected to affect clearance of the drug or its metabolite.^[1]

Common Adverse Effects

Adverse effects reported in 2% or more of patients receiving linaclotide 290 mcg daily for the treatment of IBS with constipation, and more frequently with the drug than with placebo, include diarrhea,^[1][2][3] abdominal pain,^[1][2][3] flatulence,^[1][2][3] abdominal distension,^[1][2][3] viral gastroenteritis,^[1][3] and headache.^[1][2][3]

Adverse effects reported in 2% or more of patients receiving linaclotide 145 mcg daily for the treatment of chronic idiopathic constipation, and more frequently with the drug than with placebo, include diarrhea,^[1][5] abdominal pain,^[1][5] flatulence,^[1] abdominal distension,^[1][5] upper respiratory tract infection,^[1][5] and sinusitis.^[1][5]

Adverse effects reported in 2% or more of patients receiving linaclotide 72 mcg daily for the treatment of chronic idiopathic constipation, and more frequently with the drug than with placebo, include diarrhea^[1] and abdominal distension.^[1]

No formal drug interaction studies have been conducted with linaclotide to date.^[1] However, systemic exposure to linaclotide and its active metabolite is negligible following oral administration at recommended dosages, and in vitro studies indicate that linaclotide does not interact with cytochrome P-450 (CYP) isoenzymes or with common efflux and uptake transporters, including the P-glycoprotein (P-gp) efflux transporter.^[1] Thus, no interactions mediated by CYP enzymes or common transporters are anticipated.^[1]

Linaclotide, a guanylate cyclase-C (GC-C) agonist, is a 14-amino acid peptide structurally related to endogenous guanylin peptide hormones that regulate fluid and electrolyte balance in the intestine.^{[1][2][3][5][13]} The parent drug and its active metabolite bind to GC-C receptors on the luminal surface of the intestinal epithelium, which increases intracellular and extracellular concentrations of cyclic guanosine monophosphate (cGMP).^{[1][2][3][4][5][7][13]} In turn, increased intracellular concentrations of cGMP trigger a signal-transduction cascade activating the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel.^[1][2][3][5] This results in secretion of chloride and bicarbonate into the intestinal lumen causing increased intestinal fluid and accelerated intestinal transit.^{[1][2][3][4][5]} Linaclotide has been shown to change stool consistency and increase stool frequency.^[1]

In animal models, linaclotide also decreased visceral hyperalgesia and abdominal pain.^[1][8][10] This effect in animals is thought to be mediated by activation of GC-C leading to increased extracellular concentrations of cGMP, which inhibits colonic nociceptors.^{[1][7][9][10]} Further research is needed to determine the precise mechanism(s) by which linaclotide relieves abdominal pain in patients with irritable bowel syndrome (IBS) with constipation.^[11]

After oral administration, linaclotide is minimally absorbed with negligible systemic bioavailability.^[1][7] Linaclotide is metabolized by carboxypeptidase A within the GI tract to an active metabolite; both the parent drug and active metabolite are further degraded within the intestinal lumen to smaller peptides and amino acids.^[1][7] Following multiple-dose oral administration, about 3-5% of the drug is recovered in feces as active peptide, principally as active metabolite.^[1][7]

Importance of reading the manufacturer's patient information (medication guide) prior to initiation of therapy and each time the prescription is refilled.^[1]

Importance of advising patients that accidental ingestion of linaclotide by a child, especially a child younger than 6 years of age, may result in severe diarrhea and dehydration; importance of keeping linaclotide out of reach of children and of properly disposing of any unused drug.^[1] (See Pediatric Use under Warnings/Precautions: Specific Populations, in Cautions.)

Importance of advising patients that abdominal pain or diarrhea may occur and that they should discontinue linaclotide and contact their clinician if severe diarrhea or unusual or severe abdominal pain occurs, especially if associated with hematochezia or melena.^[1]

Importance of taking linaclotide once daily on an empty stomach; the capsule should be swallowed whole, and the capsule or capsule contents should not be crushed or chewed.^[1] Importance of advising patient of alternative forms of administration if patient is unable to swallow whole capsule.^[1]

Importance of storing linaclotide in the original container, with the lid tightly closed and the contents protected from moisture; importance of not removing the desiccant from the container and of not repackaging the capsules.^[1]

If a dose is missed, the missed dose should be omitted and the next dose taken at the regularly scheduled time.^[1] Two doses should not be taken at the same time to make up for a missed dose.^[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.)

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.

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