Constella

Posology The recommended dose is one capsule (290 micrograms) once daily. Physicians should periodically assess the need for continued treatment. The efficacy of linaclotide has been established in double-blind placebo-controlled studies for up to 6 months.

If patients have not experienced improvement in their symptoms after 4 weeks of treatment, the patient should be re-examined and the benefit and risks of continuing treatment reconsidered. 2). 4). Paediatric population The safety and efficacy of Constella in children less than 18 years have not yet been established.

No data are available. 1). Method of administration Oral use. 5). 3

Summary of the safety profile Linaclotide has been given orally to 1 166 patients with IBS-C in controlled clinical studies. Of these patients, 892 patients received linaclotide at the recommended dose of 290 micrograms per day. Total exposure in the clinical development plan exceeded 1 500 patient-years.

The most frequently reported adverse reaction associated with Constella therapy was diarrhoea, mainly mild to moderate in intensity, occurring in less than 20% of patients. In rare and more severe cases, this may – as a consequence – lead to the occurrence of dehydration, hypokalaemia, blood bicarbonate decrease, dizziness, and orthostatic hypotension.

Other common adverse reactions (>1%) were abdominal pain, abdominal distension and flatulence. Tabulated list of adverse reactions The following adverse reactions were reported in clinical studies and in post-marketing experience (Table 1) at the recommended dose of 290 micrograms per day with frequencies corresponding to: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (1/1 000 to < 1/100), rare (1/10 000 to < 1/1 000) and very rare (< 1/10 000) and not known (cannot be estimated from the available data).

5 Table 1 Adverse reactions reported in clinical studies and from post-marketing experience at the recommended dose of 290 micrograms per day MedDRA system organ class Very common Common Uncommon Rare Unknown Infections and infestations Gastroenteritis viral Metabolism and nutrition disorders Hypokalaemia Dehydration Decreased appetite Nervous system disorders Dizziness Vascular disorders Orthostatic hypotension Gastrointestinal disorders Diarrhoea Abdominal pain Flatulence Abdominal distension Faecal incontinence Defecation urgency Lower gastrointestinal haemorrhage including haemorrhoidal haemorrhage and rectal haemorrhage Nausea Vomiting Gastrointestinal Perforation Skin and subcutaneous tissue disorders Urticaria Rash Investigations Blood bicarbonate decreased Description of selected adverse reactions Diarrhoea is the most common adverse reaction and is consistent with the pharmacological action of the active substance.

1) is established. Patients should be aware of the possible occurrence of diarrhoea and lower gastrointestinal bleeding during treatment. 8). g. more than 1 week) or severe diarrhoea occur, medical advice should be sought and temporary discontinuation of linaclotide until diarrhoea episode is resolved may be considered.

g. elderly, patients with cardiovascular (CV) diseases, diabetes, hypertension), and electrolyte control should be considered. Cases of intestinal perforation have been reported after use of linaclotide in patients with conditions that may be associated with localised or diffuse weakness of the intestinal wall.

Patients should be advised to seek immediate medical care in case of severe, persistent, or worsening abdominal pain; linaclotide should be discontinued if these symptoms occur. Linaclotide has not been studied in patients with chronic inflammatory conditions of the intestinal tract, such as Crohn’s disease and ulcerative colitis; therefore it is not recommended to use Constella in these patients.

1). 8), special attention should be given to these patients and the treatment benefit- risk ratio should be carefully and periodically assessed.

1. Patients with known or suspected mechanical gastrointestinal obstruction.