Constella · 4.8 Undesirable effects · 1

HOS-155519 · has-adverse-reaction-information · PDF-Seite 4

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). 4 Table 1 Adverse reactions reported in clinical studies and from post-marketing experience at the recommended dose of 290 micrograms per day MedDRA Very system organ Common Uncommon Rare Not known common class Infections and Gastroenteritis infestations viral Immune system Anaphylactic disorders reaction Metabolism and Hypokalaemia nutrition Dehydration disorders Decreased appetite Nervous system Dizziness disorders Vascular Orthostatic disorders hypotension Faecal incontinence Defecation urgency Abdominal

Auszug; vollständigen Abschnitt im Original lesen.

HOS-155515 · has-contraindication-information · PDF-Seite 3

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Patients with known or suspected mechanical gastrointestinal obstruction.

HOS-155514 · has-indication-information · PDF-Seite 2

Constella is indicated for the symptomatic treatment of moderate to severe irritable bowel syndrome with constipation (IBS-C) in adults.

HOS-155517 · has-interaction-information · PDF-Seite 3

No interaction studies have been performed. Linaclotide is rarely detectable in plasma following administration of the recommended clinical doses and in vitro studies have shown that linaclotide is neither a substrate nor an inhibitor/inducer of the cytochrome P450 enzyme system and does not interact with a series of common efflux and uptake transporters (see section 5.2). A food interaction clinical study in healthy subjects showed that linaclotide was not detectable in plasma either in fed or in fasted conditions at the therapeutic doses. Taking Constella in the fed condition produced more frequent and looser stools, as well as more gastrointestinal adverse events, than when taking it under fasting conditions (see section 5.1). The capsule should be taken 30 minutes before a meal (see section 4.2). Concomitant treatment with proton pump inhibitors, laxatives or NSAIDs may increase the risk of diarrhoea. Caution should be used when co-administering Constella with such medications. In cases of severe or prolonged diarrhoea, absorption of other oral medicinal products may be affected. The efficacy of oral contraceptives may be reduced and the use of an additional contraceptive method is recommended to prevent possible failure of oral contraception (see the prescribing information of the oral contraceptive). Caution should be exercised when prescribing medicinal products absorbed in the intestinal tract with a narrow therapeutic index such as levothyroxine as their efficacy may be reduced. 3

HOS-155518 · has-pregnancy-information · PDF-Seite 4

Pregnancy There is limited amount of data from the use of linaclotide in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of Constella during pregnancy. Breast-feeding Constella is minimally absorbed following oral administration. In a milk-only lactation study in seven lactating women, who were already taking linaclotide therapeutically, neither linaclotide nor its active metabolite were detected in the milk. Therefore, breastfeeding is not expected to result in exposure of the infant to linaclotide and Constella can be used during breast-feeding. The effect of linaclotide or its metabolite on milk production in lactating women have not been studied. Fertility Animal studies indicate that there is no effect on male or female fertility.

HOS-155516 · has-warning-information · PDF-Seite 3

Constella should be used after organic diseases have been ruled out and a diagnosis of moderate to severe IBS-C (see section 5.1) is established. Patients should be aware of the possible occurrence of diarrhoea and lower gastrointestinal bleeding during treatment. They should be instructed to inform their physician if severe or prolonged diarrhoea or lower gastrointestinal bleeding occurs (see section 4.8). Should prolonged (e.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. Additional caution should be exercised in patients who are prone to a disturbance of water or electrolyte balance (e.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. Elderly patients There are limited data in elderly patients (see section 5.1). Because of the higher risk of diarrhoea seen in the clinical trials (see section 4.8), special attention should be given to these patients and the treatment benefit- risk ratio should be carefully and periodically assessed.