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

    BOXED WARNING

    Children, infants, neonates

    Linaclotide labeling contains a boxed warning alerting clinicians of the pediatric risk associated with its use. Linaclotide is contraindicated in neonates, infants, and children up to 6 years of age. In nonclinical studies, deaths due to dehydration occurred within 24 hours in young juvenile mice (1 to 3 week-old mice; approximately equivalent to human pediatric patients less than 2 years of age) following administration of 1 or 2 daily oral doses of linaclotide; deaths did not occur in older juvenile mice (approximately equivalent to humans ages 12 to 17 years). Nevertheless, due to the deaths in young juvenile mice and the lack of clinical safety and efficacy data in pediatric patients, use should be avoided in pediatric patients 6 to 17 years of age.

    DEA CLASS

    Rx

    DESCRIPTION

    Selective guanylate cyclase C agonist
    Used for irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC) in adults
    Boxed warning against use in pediatric patients 17 years of age and younger

    COMMON BRAND NAMES

    Linzess

    HOW SUPPLIED

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

    DOSAGE & INDICATIONS

    For the treatment of chronic idiopathic constipation (CIC).
    Oral dosage
    Adults

    145 mcg PO once daily on an empty stomach, at least 30 minutes before the first meal of the day. A dosage of 72 mcg once daily may be used based on patient presentation and tolerability.

    For the treatment of irritable bowel syndrome with constipation (IBS-C).
    Oral dosage
    Adults

    290 mcg PO once daily on an empty stomach, at least 30 minutes before the first meal of the day.

    MAXIMUM DOSAGE

    Adults

    290 mcg/day PO.

    Geriatric

    290 mcg/day PO.

    Adolescents

    Safety and efficacy have not been established.

    Children

    6 to 12 years: Based on the results of preclinical data, use should be avoided.
    1 to 5 years: Contraindicated.

    Infants

    Contraindicated.

    Neonates

    Contraindicated.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    Administer on an empty stomach, at least 30 minutes prior to the first meal of the day.
    Do not crush, cut, or chew capsule or capsule contents; swallow whole.
    For adults with swallowing difficulties, consider administering dose 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: It is not necessary to flush all the beads through to deliver the complete dose.

    STORAGE

    Linzess:
    - Protect from moisture
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    - Store in a dry place
    - Store in original container

    CONTRAINDICATIONS / PRECAUTIONS

    Abdominal pain, cholelithiasis, Crohn's disease, diverticulitis, fecal impaction, gastric cancer, GI disease, GI obstruction, inflammatory bowel disease

    Linaclotide is contraindicated in patients with known or suspected mechanical GI obstruction. Patients with current symptoms (e.g., abdominal pain) that may be suggestive of mechanical GI obstruction should be medically evaluated before using linaclotide. It is prudent to use linaclotide cautiously in patients with GI disease who are at risk of mechanical GI obstruction. Common causes of mechanical obstruction include abdominal adhesions, hernias, tumors (gastric cancer, disseminated intraperitoneal cancer), foreign bodies (including cholelithiasis), diverticulitis, inflammatory bowel disease (Crohn's disease), Hirschsprung's disease, fecal impaction, and volvulus.

    Diarrhea

    Linaclotide should not be administered to patients with severe diarrhea. Diarrhea is a common adverse effect of linaclotide. Cases of severe diarrhea associated with dizziness, syncope, hypotension, and electrolyte abnormalities (i.e., hypokalemia, hyponatremia) have been reported during post-marketing use of the drug. In some cases, drug recipients required hospitalization and treatment with intravenous fluids. Inform patients to notify their health care provider if they develop diarrhea. For severe cases of diarrhea, practitioner should consider suspending linaclotide treatment and initiating rehydration as needed.

    Children, infants, neonates

    Linaclotide labeling contains a boxed warning alerting clinicians of the pediatric risk associated with its use. Linaclotide is contraindicated in neonates, infants, and children up to 6 years of age. In nonclinical studies, deaths due to dehydration occurred within 24 hours in young juvenile mice (1 to 3 week-old mice; approximately equivalent to human pediatric patients less than 2 years of age) following administration of 1 or 2 daily oral doses of linaclotide; deaths did not occur in older juvenile mice (approximately equivalent to humans ages 12 to 17 years). Nevertheless, due to the deaths in young juvenile mice and the lack of clinical safety and efficacy data in pediatric patients, use should be avoided in pediatric patients 6 to 17 years of age.

    Pregnancy

    There are no adequate and well-controlled studies with linaclotide use during human pregnancy; a drug-associated risk for major birth defects or miscarriage cannot be determined. 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. In addition, linaclotide is minimally absorbed with low systemic availability following oral administration, suggesting that clinically significant amounts will not cross to the embryo or fetus. Nevertheless, both linaclotide and its active metabolite are proteolytically degraded within the intestinal lumen to smaller peptides and naturally occurring amino acids and these may be absorbed and cross the placenta.

    Breast-feeding

    There are no data on the presence of linaclotide in animal or human milk, the effects on breast-feeding infants, or the effects on milk production. Linaclotide and its active metabolite are negligibly absorbed systemically following administration of the recommended clinical doses. Both linaclotide and its active metabolite are proteolytically degraded within the intestinal lumen to smaller peptides and naturally occurring amino acids and these may be absorbed and excreted into milk. Nevertheless, the use of linaclotide during breast-feeding appears to be compatible. According to the manufacturer, caution should be exercised when linaclotide is administered to breast-feeding women. Linaclotide labeling alerts clinicians of the potential pediatric risk associated with exposure to drug. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    ADVERSE REACTIONS

    Severe

    diarrhea / Early / 2.0-2.0
    GI bleeding / Delayed / 0-1.0

    Moderate

    fecal incontinence / Early / 0-1.0
    melena / Delayed / 0-1.0
    dehydration / Delayed / 0-1.0
    hyponatremia / Delayed / Incidence not known
    hypotension / Rapid / Incidence not known
    hypokalemia / Delayed / Incidence not known

    Mild

    abdominal pain / Early / 7.0-7.0
    flatulence / Early / 4.0-6.0
    infection / Delayed / 0-5.0
    headache / Early / 0-4.0
    sinusitis / Delayed / 0-3.0
    dyspepsia / Early / 1.0-1.9
    gastroesophageal reflux / Delayed / 1.0-1.9
    vomiting / Early / 1.0-1.9
    fatigue / Early / 1.0-1.9
    urticaria / Rapid / 0-1.0
    syncope / Early / Incidence not known
    dizziness / Early / Incidence not known

    DRUG INTERACTIONS

    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.
    Antidiarrheals: (Moderate) Antidiarrheals can decrease GI motility and may antagonize the effects of drugs used to treat constipation or constipation-associated irritable bowel syndrome, such as linaclotide. Linaclotide may cause diarrhea as a side effect, but temporary drug discontinuation or a reduction in drug dosage alone may resolve the diarrhea.
    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; 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.
    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.
    Atropine; Diphenoxylate: (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; Edrophonium: (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; Hyoscyamine; Phenobarbital; 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.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (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.
    Bismuth Subsalicylate: (Moderate) Antidiarrheals can decrease GI motility and may antagonize the effects of drugs used to treat constipation or constipation-associated irritable bowel syndrome, such as linaclotide. Linaclotide may cause diarrhea as a side effect, but temporary drug discontinuation or a reduction in drug dosage alone may resolve the diarrhea.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Antidiarrheals can decrease GI motility and may antagonize the effects of drugs used to treat constipation or constipation-associated irritable bowel syndrome, such as linaclotide. Linaclotide may cause diarrhea as a side effect, but temporary drug discontinuation or a reduction in drug dosage alone may resolve the diarrhea.
    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.
    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.
    Loperamide: (Moderate) Antidiarrheals can decrease GI motility and may antagonize the effects of drugs used to treat constipation or constipation-associated irritable bowel syndrome, such as linaclotide. Linaclotide may cause diarrhea as a side effect, but temporary drug discontinuation or a reduction in drug dosage alone may resolve the diarrhea.
    Loperamide; Simethicone: (Moderate) Antidiarrheals can decrease GI motility and may antagonize the effects of drugs used to treat constipation or constipation-associated irritable bowel syndrome, such as linaclotide. Linaclotide may cause diarrhea as a side effect, but temporary drug discontinuation or a reduction in drug dosage alone may resolve the diarrhea.
    Mepenzolate: (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.
    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.
    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.

    PREGNANCY AND LACTATION

    Pregnancy

    There are no adequate and well-controlled studies with linaclotide use during human pregnancy; a drug-associated risk for major birth defects or miscarriage cannot be determined. 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. In addition, linaclotide is minimally absorbed with low systemic availability following oral administration, suggesting that clinically significant amounts will not cross to the embryo or fetus. Nevertheless, both linaclotide and its active metabolite are proteolytically degraded within the intestinal lumen to smaller peptides and naturally occurring amino acids and these may be absorbed and cross the placenta.

    There are no data on the presence of linaclotide in animal or human milk, the effects on breast-feeding infants, or the effects on milk production. Linaclotide and its active metabolite are negligibly absorbed systemically following administration of the recommended clinical doses. Both linaclotide and its active metabolite are proteolytically degraded within the intestinal lumen to smaller peptides and naturally occurring amino acids and these may be absorbed and excreted into milk. Nevertheless, the use of linaclotide during breast-feeding appears to be compatible. According to the manufacturer, caution should be exercised when linaclotide is administered to breast-feeding women. Linaclotide labeling alerts clinicians of the potential pediatric risk associated with exposure to drug. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    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.

    PHARMACOKINETICS

    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.

    Oral Route

    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 area under the curve (AUC), maximum concentration (Cmax), and half-life cannot be calculated.
     
    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.