Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Allergan Pharmaceuticals International Limited, Clonshaugh Business & Technology Park Dublin 17, D17 E400, Ireland
Hypersensitivity to linaclotide or to any of the excipients listed in section 6.1.
Patients with known or suspected mechanical gastrointestinal obstruction.
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.
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.
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.
Constella should not be used in children and adolescents as it has not been studied in this population. As GC-C receptor is known to be overexpressed at early ages, children younger than 2 years may be particularly sensitive to linaclotide effects.
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.
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.
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 Constella therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.
Animal studies indicate that there is no effect on male or female fertility.
Constella has no or negligible influence on the ability to drive and use machines.
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.
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).
Common: Gastroenteritis viral
Uncommon: Hypokalaemia, Dehydration, Decreased appetite
Common: Dizziness
Uncommon: Orthostatic hypotension
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
Uncommon: Urticaria
Unknown: Rash
Rare: Blood bicarbonate decreased
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.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
Not applicable.
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