Linaclotide

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral:

Linzess: 72 mcg, 145 mcg, 290 mcg

Pharmacology

Mechanism of Action

Linaclotide and its active metabolite bind and agonize guanylate cyclase-C on the luminal surface of intestinal epithelium. Intracellular and extracellular cyclic guanosine monophosphate (cGMP) concentrations are subsequently increased resulting in chloride and bicarbonate secretion into the intestinal lumen. Intestinal fluid increases and GI transit is accelerated. Increased extracellular cGMP may decrease visceral pain by reducing pain-sensing nerve activity.

Pharmacokinetics/Pharmacodynamics

Absorption

Minimal systemic availability; plasma concentrations are not measurable when used at recommended doses.

Distribution

Minimal tissue distribution is expected given immeasurable plasma concentrations when used at recommended doses.

Metabolism

Metabolized within GI tract to active metabolite; parent drug and metabolite undergo proteolytic degradation within the intestinal lumen to smaller peptides and amino acids

Excretion

Primarily feces (3% to 5%; as the active metabolite)

Use: Labeled Indications

Chronic idiopathic constipation: Treatment of chronic idiopathic constipation (CIC) in adults

Irritable bowel syndrome with constipation: Treatment of irritable bowel syndrome with constipation (IBS-C) in adults

Contraindications

Pediatric patients <6 years; mechanical gastrointestinal obstruction (known or suspected)

Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to linaclotide or any component of the formulation

Dosage and Administration

Dosing: Adult

Chronic idiopathic constipation (CIC): Oral: 145 mcg once daily; 72 mcg once daily may be used based on patient presentation or tolerability.

Irritable bowel syndrome with constipation (IBS-C): Oral: 290 mcg once daily.

Dosing: Geriatric

Refer to adult dosing; use with caution.

Administration

Administer at least 30 minutes before the first meal of the day on an empty stomach; loose stools and greater stool frequency may occur after administration with a high-fat breakfast. Swallow capsule whole; do not break, crush, or chew capsules or capsule contents.

For patients with swallowing difficulties, capsules may be opened and administered orally either in applesauce or with water or administered with water via a nasogastric or gastric feeding tube. Mixing beads from capsules in other soft foods or in other liquids has not been tested.

Administration in applesauce: Open capsule and sprinkle entire contents (beads) onto 1 teaspoonful (5 mL) of room temperature applesauce. Swallow entire contents immediately; do not chew the beads. Do not store mixture for future use.

Administration in water: Open capsule and sprinkle entire contents (beads) into a cup with ~30 mL of room temperature bottled water. Gently swirl for at least 20 seconds and swallow immediately; add another 30 mL of water to any remaining beads in cup, swirl for at least 20 seconds, and swallow immediately. Do not store the water-bead mixture for future use. Note: The drug is coated on surface of beads and will dissolve off the beads in water; beads will remain visible and will not dissolve; therefore, it is not necessary to consume all the beads to deliver complete dose.

Administration via nasogastric or gastric feeding tube: Open capsule and empty entire contents (beads) into a clean container with 30 mL of room temperature bottled water. Gently swirl for at least 20 seconds; draw up bead and water mixture with catheter syringe and apply rapid and steady pressure (10 mL per 10 seconds) to dispense the bead-water mixture into the tube; add another 30 mL of water to any remaining beads and repeat process. Flush nasogastric/gastric tube with at least 10 mL of water after administration. Note: Not necessary to flush all the beads through tube to deliver complete dose.

Dietary Considerations

Administer at least 30 minutes before the first meal of the day on an empty stomach. Loose stools and greater stool frequency may occur after administration with a high-fat breakfast.

Storage

Store at 25°C (77°F) in tightly closed, original container with included desiccant packet; excursions permitted between 15°C and 30°C (59°F and 86°F). Do not subdivide or repackage; protect from moisture.

Drug Interactions

There are no known significant interactions.

Adverse Reactions

Adverse reactions reported with use in IBS-C and CIC.

>10%: Gastrointestinal: Diarrhea (16% to 22%)

1% to 10%:

Central nervous system: Headache (4%), fatigue (<2%)

Endocrine & metabolic: Dehydration (≤1%)

Gastrointestinal: Abdominal pain (7%), flatulence (4% to 6%), abdominal distension (2% to 3%), viral gastroenteritis (≤3%), severe diarrhea (2%), dyspepsia (<2%), fecal incontinence (<2%), gastroesophageal reflux disease (<2%), vomiting (<2%)

Respiratory: Upper respiratory tract infection (5%), sinusitis (3%)

<1%, postmarketing, and/or case reports: Hematochezia, hypersensitivity reaction, melena, nausea, rectal hemorrhage, urticaria

Warnings/Precautions

Concerns related to adverse effects:

• Diarrhea: May cause diarrhea; severe diarrhea associated with dizziness, syncope, hypotension, and electrolyte abnormalities (hypokalemia and hyponatremia) requiring hospitalization or IV fluids has also been reported; consider discontinuation of therapy and rehydration if severe diarrhea occurs. Administration with a high-fat meal may worsen diarrhea.

Special populations:

• Pediatric patients: Serious dehydration: [US Boxed Warning]: Use is contraindicated in pediatric patients <6 years of age. Avoid use in pediatric patients 6 to 17 years. In studies in neonatal mice, administration of a single oral dose of linaclotide caused deaths due to dehydration. The safety and effectiveness of linaclotide has not been established in patients <18 years.

Monitoring Parameters

IBS-C: Abdominal pain, spontaneous bowel movement quality and frequency

CIC: Frequency of straining during bowel movements; spontaneous bowel movement quality and frequency

Pregnancy

Pregnancy Considerations

Linaclotide and its metabolite are not measurable in plasma when used at recommended doses. Maternal use is not expected to result in fetal exposure.

Patient Education

What is this drug used for?

• It is used to treat irritable bowel syndrome.
• It is used to treat constipation.

Frequently reported side effects of this drug

• Abdominal pain
• Common cold symptoms
• Passing gas

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Black, tarry, or bloody stools
• Severe diarrhea
• Persistent diarrhea
• Abdominal edema
• Bloating
• Dehydration like dry skin, dry mouth, dry eyes, increased thirst, fast heartbeat, dizziness, fast breathing, or confusion.
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.