Linaclotide
Regulatory sources consulted
Approved indications
- United States: treatment of irritable bowel syndrome with constipation in adults, 290 micrograms once daily.
- United States: treatment of chronic idiopathic constipation in adults, 145 or 72 micrograms once daily.
- United States: treatment of irritable bowel syndrome with constipation in patients aged 7 years and older, 145 micrograms once daily.
- United States: treatment of functional constipation in patients aged 2 years and older, 72 micrograms once daily.
- Spain: symptomatic treatment of moderate to severe irritable bowel syndrome with constipation in adults.
Contraindications
Absolute
- Known or suspected mechanical gastrointestinal obstruction; in the United States, patients younger than 2 years because of severe dehydration risk.
Clinical warnings
- Major warning · It may cause severe diarrhoea; temporarily stop until it resolves and assess hydration and electrolytes, especially in vulnerable patients. — AEMPS CIMA, Constella, ficha técnica 112801002, sección 4.4; DailyMed, Linzess, sección 5
- Boxed warning · In the United States paediatric population, severe dehydration risk requires strict adherence to DailyMed label age and indication limits. — DailyMed, Linzess, setid 09beda19-56d6-4a56-afdc-9a77b70b2ef3, boxed warning
Drug interactions
- ModerateProton-pump inhibitors, laxatives or non-steroidal anti-inflammatory medicines
Mechanism: Concomitant treatment may increase diarrhoea risk; severe or prolonged diarrhoea may alter absorption of oral medicines.
Recommendation: Use caution with these treatments and assess oral medicines with a narrow therapeutic index if severe or prolonged diarrhoea occurs.
https://cima.aemps.es/cima/dochtml/ft/112801002/FT_112801002.html
Adverse events
Common (≥1%)
Diarrhoea · Abdominal pain · Abdominal distension · Flatulence
Rare but serious
Dehydration · Hypokalaemia · Orthostatic hypotension · Intestinal perforation
Pregnancy and lactation
According to the Spanish product information, use during pregnancy should preferably be avoided. The Spanish product information allows use during breastfeeding because linaclotide and its active metabolite were not detected in milk in the cited study.
Recent literature (PubMed)
Irritable bowel syndrome is one of the most common functional bowel disorders, and has a substantial impact on patients' daily lives, as well as a big economic impact on society. It is characterised by abdominal pain, bloating and abdominal distention and altered bowel movements, with a predominance of diarrhoea, constipation, or alternation of these signs, which cannot be explained by a structural or biochemical abnormality. Its aetiopathogenesis and pathophysiological mechanism are unknown. The disease affects 5%-10% of healthy individuals at any given time and, in most people, has a relapsing-remitting course. This article reviews some of the main and most current evidence on its epidemiology, risk factors, pathophysiology, clinical manifestations, diagnostic approach, and therapeutic options, both dietary, pharmacological and psychotherapeutic. Linaclotide is minimally absorbed from the gastrointestinal tract and the drug and its active metabolite are not measurable in milk following administration of doses up to 290 mcg daily. Linaclotide appears to be acceptable in nursing mothers and no special precautions are required.
Chronic idiopathic constipation (CIC) is a common disorder associated with significant impairment in quality of life. This clinical practice guideline, jointly developed by the American Gastroenterological Association and the American College of Gastroenterology, aims to inform clinicians and patients by providing evidence-based practice recommendations for the pharmacological treatment of CIC in adults. The American Gastroenterological Association and the American College of Gastroenterology formed a multidisciplinary guideline panel that conducted systematic reviews of the following agents: fiber, osmotic laxatives (polyethylene glycol, magnesium oxide, lactulose), stimulant laxatives (bisacodyl, sodium picosulfate, senna), secretagogues (lubiprostone, linaclotide, plecanatide), and serotonin type 4 agonist (prucalopride). The panel prioritized clinical questions and outcomes and used the Grading of Recommendations Assessment, Development, and Evaluation framework to assess the certainty of evidence for each intervention. The Evidence to Decision framework was used to develop clinical recommendations based on the balance between the desirable and undesirable effects, patient values, costs, and health equity considerations. The panel agreed on 10 recommendations for the pharmacological management of CIC in adults. Based on available evidence, the panel made strong recommendations for the use of polyethylene glycol, sodium picosulfate, linaclotide, plecanatide, and prucalopride for CIC in adults. Conditional recommendations were made for the use of fiber, lactulose, senna, magnesium oxide, and lubiprostone. This document provides a comprehensive outline of the various over-the-counter and prescription pharmacological agents available for the treatment of CIC. The guidelines are meant to provide a framework for approaching the management of CIC; clinical providers should engage in shared decision making based on patient preferences as well as medication cost and avai
Traditionally, the treatment of chronic constipation has focused on lifestyle modification, dietary guidance and therapy, and osmotic and stimulant laxatives. Recently, several drugs with new mechanisms of action have been introduced as treatments for chronic constipation. In Japan, polyethylene glycol and lactulose can now be administered under insurance coverage. The number of treatment options for constipation has increased dramatically. First, lifestyle modifications and dietary therapies must be implemented. If constipation does not improve sufficiently, specialized functional tests are performed to diagnose physiological subgroups. If functional tests are not available, patients are classified as having the "decreased frequency of defecation" type or the "difficult defecation" type based on the patient's symptoms, with treatment applied according to each type. Medical therapy includes osmotic laxatives, secretagogues, bile acid transporter inhibitors, probiotics, prokinetics, and Kampo medicines. The temporary use of stimulant laxatives, suppositories, enemas, and digital evacuation is also recommended. The usefulness of biofeedback is yet to be determined.
Irritable bowel syndrome (IBS) is a chronic functional gastrointestinal disorder which presents with abdominal pain and altered bowel habits. It affects about 20% of the general population, mainly women, and has a considerable impact on the quality of life and health care costs. Four different entities of IBS have been identified: IBS with constipation (IBS‑ C), IBS with diarrhea (IBS D), IBS with a mixed pattern of constipation and diarrhea, and unclassified IBS. Although the precise pathogenesis of IBS remains unclear, its multifactorial nature is evident and includes environmental and host factors. Management of patients with this disease is challenging and a personalized approach is required. A strong, reassuring physician‑ patient relationship is crucial, followed by patient education, dietary advice, and stress reduction. For nonresponding patients, the therapeutic approach may include nonpharmacological therapies and / or pharmacotherapy. The choice of pharmacological treatment is based on the predominant symptom and a prespecified time point should be planned for effectiveness evaluation and dose adjustment. In patients with IBS‑ D, the therapeutic options include mainly antibiotics, such as rifaximin, peripheral opioid agonists, mixed opioid agonists / antagonists, bile acid sequestrants, and antagonists of serotonin 5‑ hydroxytryptamine type 3 receptors. Bulking agents and osmotic laxatives represent the first line therapy for IBS‑ C, while lubiprostone and linaclotide should be reserved for difficult to treat patients. The involvement of gastrointestinal microbiota constitutes a fascinating field of exploration as it offers the potential to be modulated by the use of probiotics, prebiotics, synbiotics as well as fecal microbiota transplantation. This review offers an updated overview on the recent advances in the treatment of IBS.