Linaclotide

Concomitant treatment with proton pump inhibitors, laxatives or NSAIDs may increase the risk of diarrhoea. Caution should be used when co-administering linaclotide 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.

In cases of severe or prolonged diarrhoea, absorption of other oral medicinal products may be affected. 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.

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 linaclotide in these patients.

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. 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.

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. As a precautionary measure, it is preferable to avoid the use of linaclotide during pregnancy.

It is unknown whether linaclotide is excreted in human milk. A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from linaclotide therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

Fertility

Animal studies indicate that there is no effect on male or female fertility.

Linaclotide has no or negligible influence on the ability to drive and use machines.

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 linaclotide 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.

List of adverse reactions

The following adverse reactions were reported in controlled clinical studies 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).

Infections and infestations

Common: Gastroenteritis viral

Metabolism and nutrition disorders

Uncommon: Hypokalaemia, Dehydration, Decreased appetite

Nervous system disorders

Common: Dizziness

Vascular disorders

Uncommon: Orthostatic hypotension

Gastrointestinal disorders

Very common: Diarrhoea

Common: Abdominal pain, Flatulence, Abdominal distension

Uncommon: Faecal incontinence, Defecation urgency, Lower gastrointestinal haemorrhage including haemorrhoidal haemorrhage and rectal haemorrhage, Nausea, Vomiting

Skin and subcutaneous tissue disorders

Uncommon: Urticaria

Unknown: Rash

Investigations

Rare: 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. 2% of treated patients experienced severe diarrhoea and 5% of patients discontinued treatment due to diarrhoea in clinical studies.

The majority of reported cases of diarrhoea were mild (43%) to moderate (47%); 2% of treated patients experienced severe diarrhoea. Approximately half of the diarrhoea episodes started within the first week of treatment.

The diarrhoea resolved within seven days in about one third of patients, however 80 patients (50%) experienced diarrhoea with a duration of more than 28 days (representing 9.9% of all patients treated with linaclotide).

Five percent of patients discontinued treatment due to diarrhoea in clinical studies. In those patients in whom diarrhoea led to discontinuation, it resolved after a few days of discontinuing treatment.

Elderly (>65 years), hypertensive and diabetic patients reported diarrhoea more frequently as compared to the overall IBS-C population included in the clinical trials.