4.1. Therapeutic indications

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

4.2. Posology and method of administration

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.

Special populations

Patients with renal or hepatic impairment

No dose adjustments are required for patients with hepatic or renal impairment (see section 5.2).

Elderly patients

For elderly patients, although no dose adjustment is required, the treatment should be carefully monitored and periodically re-assessed (see section 4.4).

Paediatric population

The safety and efficacy of Constella in children less than 18 years have not yet been established. No data are available.

Constella should not be used in children and adolescents (see section5.1).

Method of administration

Oral use. The capsule should be taken at least 30 minutes before a meal (see section 4.5).

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Patients with known or suspected mechanical gastrointestinal obstruction.

4.4. Special warnings and precautions for use

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.

4.5. Interaction with other medicinal products and other forms of interaction

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

4.6. Fertility, pregnancy and lactation

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.

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

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).

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

Not known

Infections and infestations

Gastroenteritis viral

Immune system disorders

Anaphylactic reaction

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. 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 of suspected adverse reactions

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 Yellow Card Scheme;

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

An overdose may result in symptoms resulting from an exaggeration of the known pharmacodynamic effects of the medicinal product, mainly diarrhoea. In a study in healthy volunteers receiving a single dose of 2 897 micrograms (up to 10-fold the recommended therapeutic dose) the safety profile in these subjects was consistent with that in the overall population, with diarrhoea being the most commonly reported adverse event.

Should an overdose occur, the patient should be treated symptomatically, and supportive measures instituted as required