Linzess (linaclotide)

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

Linaclotide capsules should be swallowed whole. 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. 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. The capsules or capsule contents should not be crushed or chewed.

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. The entire mixture should be consumed (without chewing) immediately and should not be stored for later use.

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. 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. The mixture should not be stored for later use. The manufacturer states that linaclotide is coated on the surface of the beads and will dissolve off the beads into the water. Thus, consumption of all the beads is not necessary to deliver a complete dose of the drug.

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. Any beads remaining in the cup should be dispersed in an additional 30 mL of water and the process should be repeated. Following administration of the dose, the nasogastric or gastrostomy tube should be flushed with at least 10 mL of water. 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.

No dosing information is available for this tab.

No formal drug interaction studies have been conducted with linaclotide to date. 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. Thus, no interactions mediated by CYP enzymes or common transporters are anticipated.

There are no contraindication interactions for this drug.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Laxatives/Trofinetide

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Trofinetide commonly causes diarrhea of mild to moderate severity. Laxatives may increase the incidence or severity of diarrhea.(1)

CLINICAL EFFECTS: Concurrent use of laxatives with trofinetide may increase the risk of severe diarrhea.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients should stop laxatives before starting trofinetide. If diarrhea occurs, consider anti-diarrheal treatment and monitor hydration status. If severe diarrhea or dehydration occurs, interrupt, reduce dose, or discontinue trofinetide.(1)

DISCUSSION: In clinical trials, 85% of patients on trofinetide developed diarrhea. Concurrent use of laxatives may increase this risk.(1)

Laxatives; Stool Softeners/Tenapanor

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Tenapanor commonly causes diarrhea of mild to moderate severity. Laxatives and stool softeners may increase the incidence or severity of diarrhea.(1)

CLINICAL EFFECTS: Concurrent use of laxatives or stool softeners with tenapanor may increase the risk of severe diarrhea.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of tenapanor states that patients should be instructed to avoid stool softeners and laxatives with tenapanor. If severe diarrhea occurs, tenapanor should be discontinued.(1)

DISCUSSION: In clinical trials, 43-53% of CKD patients on dialysis treated with tenapanor developed diarrhea. Diarrhea usually occurred soon after treatment initiation and was severe in 5% of patients.(1)

There are no moderate interactions for this drug.

Linaclotide is contraindicated in infants and children younger than 6 years of age. (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.

• Gastrointestinal obstruction

• Diarrhea

There are no moderate contraindications for this drug.

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, abdominal pain, flatulence, abdominal distension, viral gastroenteritis, and headache.

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, abdominal pain, flatulence, abdominal distension, upper respiratory tract infection, and sinusitis.

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 and abdominal distension.

Less Frequent

• Severe diarrhea
• Viral gastroenteritis

Rare or Very Rare

• Anaphylaxis
• Angioedema
• Bloody stools
• Rectal bleeding

More Frequent

• Abdominal distension
• Acute abdominal pain
• Diarrhea
• Flatulence

Less Frequent

• Dyspepsia
• Fatigue
• Fecal incontinence
• Gastroesophageal reflux disease
• Headache disorder
• Sinusitis
• Upper respiratory infection
• Vomiting

Rare or Very Rare

• Black tarry stools
• Nausea
• Urticaria

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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.

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). In neonatal mice, administration of linaclotide 10 mcg/kg daily caused deaths on postnatal day 7. Tolerability to linaclotide increased with age in juvenile mice. 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. 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. 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. 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. 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.

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. However, available data on use of linaclotide in pregnant women are insufficient to inform fetal risk.

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. Severe maternal toxicity and associated effects on fetal morphology were observed in mice at dosages of at least 40,000 mcg/kg daily. 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. Limited systemic exposure to linaclotide was achieved in rats, rabbits, and mice during the period of organogenesis. Animal and human doses should not be compared directly for evaluating relative exposure.

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

Systemic absorption of linaclotide and its active metabolite is negligible following oral administration. It is not known whether the negligible systemic absorption observed in adults will result in clinically important exposure in breast-fed infants. 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. Exposure of infants to linaclotide could result in serious adverse effects. (See Pediatric Use under Warnings/Precautions: Specific Populations, in Cautions.)

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. 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. 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.