Linaclotide

Linaclotideis a Guanylate Cyclase-C (GC-C) Agonistbelonging toGastrointestinal agent/ Drug for Constipation.

Linaclotide is a guanylate cyclase-C agonist used to treat constipation associated with irritable bowel syndrome or that is idiopathic in nature.

When taken orally, linaclotide is not absorbed into the systemic. No detectable levels of linaclotide or its active metabolite were noted after doses of 125 mg or 290 mg were administered.linaclotide plasma concentrations following therapeutic oral doses are not measurable, linaclotide is expected to be minimally distributed to tissues. Linaclotide metabolized within GI tract to active metabolite, parent drug and metabolite undergo proteolytic degradation within the intestinal lumen to smaller peptides and amino acids. linaclotide primarily excreted via feces (3% to 5%; as the active metabolite).

Linaclotideshows side effects like Diarrhea, stomach pain, swelling or feeling of fullness or pressure in the stomach area, gas, headache.

Linaclotide is available in the form of Oral Capsule.

Linaclotideis available in India, US, France, Italy, Russia, Spain, Canada, China, UK, Malaysia, and Australia.

Linaclotidebelongs to the Gastrointestinal agent/ Drug for Constipation acts as a Guanylate Cyclase-C (GC-C) Agonist.

Linaclotide is an agonist of guanylate cyclase-C (GC-C). Once linaclotide and its active metabolite binds to GC-C, it has local effect on the luminal surface of the intestinal epithelium. Activation of GC-C by linaclotide results in the intra- and extracellular increase of cyclic guanosine monophosphate concentrations (cGMP). This elevation of cGMP levels stimulates the secretion of chloride and bicarbonate into the intestinal lumen via activation of cystic fibrosis transmembrane conductance regulator (CFTR) ion channel. Ultimately, linaclotide helps patients with IBS (especially with constipation) as GI transit is accelerated and the release of intestinal fluid is increased. In animal models, a decrease in visceral pain after administration of linaclotide may be observed. A decrease in the activity of pain-sensing nerves occurs because of an increase in extracellular cGMP.

The Data of Onset and duration of action of Linaclotide is not clinically established.

Linaclotide is available in the form of Oral Capsule.

Linaclotide Capsule is taken orally, usually once daily.

Linaclotide is a guanylate cyclase-C agonist used to treat constipation associated with irritable bowel syndrome or that is idiopathic in nature.

Linaclotideis a Guanylate Cyclase-C (GC-C) Agonist belonging to Gastrointestinal agent/ Drug for Constipation.

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.

Linaclotide is approved for use in the following clinical indications

• Chronic idiopathic constipation
• Irritable bowel syndrome with constipation
• Opioid-induced constipation

• Chronic idiopathic constipation

Oral: 145 mg once daily; 72 mg once daily may be used based on patient presentation or tolerability.

• Irritable bowel syndrome with constipation

Oral: 290 mg once daily; dose may be reduced to 145 mg once daily if patient develops diarrhea (typically occurs within 2 weeks). Symptoms of abdominal pain and bowel function generally improve by day 7; some experts will allow up to an 8- to 12-week trial before considering alternative therapy.

• Opioid-induced constipation

Oral: 145 to 290 mg once daily.

Linaclotide is available in various strengths as 145 mg; 290 mg; 72 mg.

Linaclotide is available in the form of Oral Capsule.

Linaclotide is contraindicated in patients with

• Patients less than 6 years of age due to the risk of serious dehydration.
• Patients with known or suspected mechanical gastrointestinal obstruction.

• Risk of Serious Dehydration in Pediatric Patients

Linaclotide is contraindicated in patients less than 6 years of age. The safety and effectiveness of Linaclotide in patients less than 18 years of age have not been established. In neonatal mice (human age equivalent of approximately 0 to 28 days), linaclotide increased fluid secretion because of GC-C agonism resulting in mortality within the first 24 hours due to dehydration. Due to increased intestinal expression of GC-C, patients less than 6 years of age may be more likely than patients 6 years of age and older to develop severe diarrhea and its potentially serious consequences. Avoid use of Linaclotide in pediatric patients 6 years to less than 18 years of age. Although there were no deaths in older juvenile mice, given the deaths in young juvenile mice and the lack of clinical safety and efficacy data in pediatric patients, avoid the use of Linaclotide in pediatric patients 6 years to less than 18 years of age.

• Diarrhea

Diarrhea was the most common adverse reaction of Linaclotide-treated patients in the pooled IBS-C and CIC double-blind placebo-controlled trials. The incidence of diarrhea was similar between the IBS-C and CIC populations. Severe diarrhea was reported in 2% of 145 mcg and 290 mcg Linaclotide-treated patients, and in<1% of 72 mcg LINZESS-treated CIC patients. In post-marketing experience, severe diarrhea associated with dizziness, syncope, hypotension, and electrolyte abnormalities (hypokalemia and hyponatremia) requiring hospitalization or intravenous fluid administration have been reported in patients treated with LINZESS.

Linaclotide and its active metabolite were not detected in the milk of lactating women. In adults, concentrations of linaclotide and its active metabolite were below the limit of quantitation in plasma following multiple doses of Linaclotide. Maternal use of Linaclotide is not expected to result in exposure to linaclotide or its active metabolite in breastfed infants. There is no information on the effects of linaclotide or its active metabolite on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Linaclotide and any potential adverse effects on the breastfed infant from Linaclotide or from the underlying maternal condition.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the United States general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Common

• Diarrhea, Abdominal distension, Abdominal pain, Bowel urgency, Dyspepsia, Fecal incontinence, Flatulence, Gastro esophageal reflux disease, Viral gastroenteritis, Vomiting, Headache, Sinusitis, Upper respiratory tract infection, Dehydration.

Rare

• Hematochezia, Nausea, Rectal hemorrhage, Anaphylaxis, Angioedema.

The common side effects of Linaclotide include the following

Common side effects

• Diarrhea, Stomach pain, Swelling or feeling of fullness or pressure in the stomach area, Gas, Headache.

Rare side effects

• Unusual or severe stomach pain, Bright red or black, Tarry stools, Hives.

• Pregnancy

Pregnancy Category

Linaclotide and its active metabolite are negligibly absorbed systemically following oral administration, and maternal use is not expected to result in fetal exposure to the drug.The available data on linaclotide use in pregnant women are not sufficient to inform any drug-associated risk for major birth defects and miscarriage. In animal developmental studies, no effects on embryo-fetal development were observed with oral administration of linaclotide in rats and rabbits during organogenesis at doses much higher than the maximum recommended human dosage. Severe maternal toxicity associated with effects on fetal morphology were observed in mice. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the United States general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

• Nursing Mothers

There is no information regarding the presence of linaclotide in human milk, or on its effects on milk production or the breastfed infant. No lactation studies in animals have been conducted. Linaclotide and its active metabolite are negligibly absorbed systemically following oral administration. It is unknown whether the negligible systemic absorption of linaclotide by adults will result in a clinically relevant exposure to breastfed infants. Exposure to linaclotide in breastfed infants has the potential for serious adverse effects. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Linaclotide and any potential adverse effects on the breastfeed infant from Linaclotide or from the underlying maternal condition.

• Pediatric Use

Linaclotide is contraindicated in patients less than 6 years of age. Avoid use of Linaclotide in patients 6 years to less than 18 years of age. The safety and effectiveness of Linaclotide in patients less than 18 years of age have not been established.

• Geriatric Use

Irritable Bowel Syndrome with Constipation (IBS-C)

Of 1605 IBS-C patients in the placebo-controlled clinical studies of Linaclotide, 85 (5%) were 65 years of age and over, while 20 (1%) were 75 years and over. Clinical studies of Linaclotide did not include enough patients aged 65 and over to determine whether they respond differently from younger patients.

Chronic Idiopathic Constipation (CIC)

Of 2498 CIC patients in the placebo-controlled clinical studies of Linaclotide (Trials 3, 4, and 5), 273 (11%) were 65 years of age and over, while 56 (2%) were 75 years and over. Clinical studies of linaclotide did not include enough patients aged 65 and over to determine whether they respond differently from younger patients. In general, dose selection for an elderly patient should be cautious reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant disease or other drug therapy.

Single Linaclotide doses of 2897 mcg were administered to 22 healthy subjects; the safety profile in these subjects was consistent with that in the overall Linaclotide-treated population, with diarrhea being the most reported adverse reaction.

Pharmacodynamic

Information not available.

Pharmacokinetics

• Absorption

When taken orally, linaclotide is not absorbed into the systemic. No detectable levels of linaclotide or its active metabolite were noted after doses of 125 mg or 290 mg were administered.

• Distribution

Linaclotide plasma concentrations following therapeutic oral doses are not measurable, linaclotide is expected to be minimally distributed to tissues.

• Metabolism and Excretion

Linaclotide metabolized within GI tract to active metabolite, parent drug and metabolite undergo proteolytic degradation within the intestinal lumen to smaller peptides and amino acids. linaclotide primarily excreted via feces (3% to 5%; as the active metabolite).

• https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/202811s013lbl.pdf
• https://medlineplus.gov/druginfo/meds/a613007.html
• https://reference.medscape.com/drug/Linaclotide-linaclotide-999768
• https://www.rxlist.com/Linaclotide-drug.htm#clinpharm
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• https://www.uptodate.com/contents/linaclotide-drug-information?search=linaclotide&source=panel_search_result&selectedTitle=1~14&usage_type=panel&kp_tab=drug_general&display_rank=1
• https://www.drugs.com/dosage/linaclotide.html
• https://go.drugbank.com/drugs/DB08890