Constella

1 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX I 

 

SUMMARY OF PRODUCT CHARACTERISTICS 

 



 

2 

1. NAME OF THE MEDICINAL PRODUCT 

 

Constella 290 micrograms hard capsules 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

 

Each capsule contains 290 micrograms of linaclotide. 

 

For the full list of excipients, see section 6.1. 

 

 

3. PHARMACEUTICAL FORM 

 

Hard capsule. 

 

White to off-white-orange opaque capsule (18 mm x 6.35 mm) marked “290” with grey ink. 

 

 

4. CLINICAL PARTICULARS 

 

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 aged 0 to18 years have not yet been established. No data are 

available.  

 

This medicinal product should not be used in children and adolescents (see sections 4.4 and 5.1). 

 

Method of administration 

 

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

 

 

 



 

3 

4.3 Contraindications 

 

Hypersensitivity to linaclotide 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.  

 

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. 

 

Paediatric population 

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. 

 

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. 

 

 

 

 



 

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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. 

 

Lactation 

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. 

 

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 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).  

 



 

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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 

 

 

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 national reporting system listed in Appendix V. 

 

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. 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


 

6 

5. PHARMACOLOGICAL PROPERTIES 

 

5.1  Pharmacodynamic properties 

 

Pharmacotherapeutic group: Drugs for constipation, other drugs for constipation, ATC Code: A06AX04 

 

Mechanism of action 

Linaclotide is a Guanylate Cyclase-C receptor agonist (GCCA) with visceral analgesic and secretory 

activities. 

 

Linaclotide is a 14-amino acid synthetic peptide structurally related to the endogenous guanylin peptide 

family. Both linaclotide and its active metabolite bind to the GC-C receptor, on the luminal surface of the 

intestinal epithelium. Through its action at GC-C, linaclotide has been shown to reduce visceral pain and 

increase GI transit in animal models and increase colonic transit in humans. Activation of GC-C results in an 

increase in concentrations of cyclic guanosine monophosphate (cGMP), both extracellularly and 

intracellularly. Extracellular cGMP decreases pain-fiber activity, resulting in reduced visceral pain in animal 

models. Intracellular cGMP causes secretion of chloride and bicarbonate into the intestinal lumen, through 

activation of the cystic fibrosis transmembrane conductance regulator (CFTR), which results in increased 

intestinal fluid and accelerated transit. 

 

Pharmacodynamic effects 

In a cross-over food interaction study, 18 healthy subjects were administered Constella 290 micrograms for 7 

days both in the fasting and fed state. Taking Constella immediately after a high fat breakfast resulted in 

more frequent and looser stools, as well as more gastrointestinal adverse events, compared with taking it in 

the fasted state. 

 

Clinical efficacy and safety  

The efficacy of linaclotide was established in two randomised, double-blind, placebo-controlled Phase 3 

clinical studies in patients with IBS-C. In one clinical study (study 1), 804 patients were treated with 

Constella 290 micrograms or placebo once daily for 26 weeks. In the second clinical study (study 2), 800 

patients were treated for 12 weeks, and then re-randomised for an additional 4 weeks treatment period. 

During the 2-weeks pre-treatment baseline period, patients had a mean abdominal pain score of 5.6 (0-10 

scale) with 2.2% of abdominal pain-free days, a mean bloating score of 6.6 (0-10 scale), and an average of 

1.8 spontaneous bowel movements (SBM)/week. 

 

The characteristics of the patient population included in Phase 3 clinical trials were as follows: mean age of 

43.9 years [range 18 - 87 years with 5.3% ≥ 65 years of age], 90.1% female. All patients met Rome II criteria 

for IBS-C and were required to report a mean abdominal pain score of ≥ 3 on a 0-to-10-point numeric rating 

scale (criteria that correspond to a moderate to severe IBS population), < 3 complete spontaneous bowel 

movements and ≤ 5 SBMs per week during a 2-week baseline period. 

 

The co-primary endpoints in both clinical studies were 12-week IBS degree of relief responder rate and 

12 week abdominal pain/discomfort responder rate. An IBS degree of relief responder was a patient that was 

considerably or completely relieved for at least 50% of the treatment period; an abdominal pain/discomfort 

responder was a patient that had an improvement of 30% or more for at least 50% of the treatment period. 

 

For the 12 weeks data, study 1 shows that 39% of the patients treated with linaclotide compared with 17% of 

the patients treated with placebo showed response to IBS degree of relief (p<0.0001) and 54% of the patients 

treated with linaclotide compared with 39% of the patients treated with placebo showed response to 

abdominal pain/discomfort (p<0.0001). Study 2 shows that 37% of the patients treated with linaclotide 

compared with 19% of the patients treated with placebo showed response to IBS degree of relief (p<0.0001) 

and 55% of the patients treated with linaclotide compared with 42% of the patients treated with placebo 

showed response to abdominal pain/discomfort (p=0.0002).   

 

For the 26 weeks data, study 1 shows that 37% and 54% of the patients treated with linaclotide compared 

with 17% and 36% of the patients treated with placebo showed response to IBS degree of relief (p<0.0001) 

and abdominal pain/discomfort (p<0.0001) respectively.  



 

7 

 

In both studies, these improvements were seen by week 1 and sustained over the entire treatment periods 

(Figures 1 and 2). Linaclotide has been shown not to cause rebound effect when the treatment was stopped 

after 3 months continuous treatment. 

 

 
Other signs and symptoms of IBS-C including bloating, complete spontaneous bowel movement (CSBM) 

frequency, straining, stool consistency, were improved in linaclotide treated patients vs. placebo (p<0.0001) 

as shown in the following table. These effects were reached at 1 week and sustained over the entire treatment 

periods. 

 

Effect of linaclotide on IBS-C symptoms during the first 12 weeks of treatment in the pooled phase 3 

efficacy clinical studies (studies 1 and 2). 

 

Main secondary efficacy 

parameters 

  

Placebo 

(N =797) 

Linaclotide 

(N =805)  

  

  

Baseline  

Mean 

12-

weeks 

Mean 

Change 

from 

baseline  

Mean 

Baseline 

Mean 

12-

weeks 

Mean 

Change 

from 

baseline  

Mean 

LS mean 

difference 

Bloating  

(11-point NRS) 
6.5 5.4 –1.0  6.7 4.6 –1.9 –0.9* 

CSBM/week 0.2 1.0  0.7  0.2 2.5  2.2  1.6* 

Stool consistency  

(BSFS Score) 
2.3 3.0  0.6 2.3 4.4  2.0  1.4* 

Straining  

(5-point ordinal scale) 
3.5 2.8 – 0.6 3.6 2.2 –1.3 –0.6* 

*p<0.0001, linaclotide vs placebo. LS: Least Square  

CSBM: Complete Spontaneous Bowel Movement 

  

Treatment with linaclotide also resulted in significant improvements in validated and disease-specific 

Quality of Life measure (IBS-QoL; p<0.0001), and EuroQoL (p = 0.001). Clinically meaningful response in 

overall IBS-QoL (> 14 points difference) was achieved in 54% of linaclotide treated patients vs. 39% in 

placebo treated patients. 

 

 

 

 

Fig 1.     IBS Degree of reli ef  responder   Fig 2 .  Abdominal pain/discomfort responder    

0 

10 

20 

30 

40 

50 

60 

70 

1 2 3 4 5 6 7 8 9 10 11 12 

290 µg 

Placeb

o 

Trial Week 

Responders 

(%) 

* * * 
* * 

* * * * * 

* 

* 

Pooled Phase III Efficacy clinical studies (Study 1 and 2) 
OC Approach (ITT Population) 

* p value < 0.0001 

  

0 

10 

20 

30 

40 

50 

60 

70 

1 2 3 4 5 6 7 8 9 10 11 12 

290 µg 

Placebo 

Trial Week 

Responders 

(%) 

* 

* * * 
* * 

* 

* * * * * 
* p value < 0.0001 

Pooled Phase III Efficacy clinical studies (Study 1 and 2) 
OC Approach (ITT Population) 

  

  



 

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Paediatric population 

The European Medicines Agency has deferred the obligation to submit the results of clinical studies with 

Constella in one or more subsets of the paediatric population in functional constipation (see section 4.2 for 

information on paediatric use). 

 

5.2 Pharmacokinetic properties 

 

Absorption 

In general, linaclotide is minimally detectable in plasma following therapeutic oral doses and therefore 

standard pharmacokinetic parameters cannot be calculated. 

 

Following single doses of up to 966 micrograms and multiple doses up to 290 micrograms of linaclotide, 

there were no detectable plasma levels of parent compound or the active metabolite (des-tyrosine). When 

2,897 micrograms was administered on day 8, following a 7-day course of 290 micrograms/day, linaclotide 

was detectable in only 2 of 18 subjects at concentrations just above the lower limit of quantification of 

0.2 ng/ml (concentrations ranged from 0.212 to 0.735 ng/ml). In the two pivotal phase 3 studies in which 

patients were dosed with 290 micrograms of linaclotide once daily, linaclotide was only detected in 2 out of 

162 patients approximately 2 h following the initial linaclotide dose (concentrations were 0.241 ng/ml to 

0.239 ng/ml) and in none of the 162 patients after 4 weeks of treatment. The active metabolite was not 

detected in any of the 162 patients at any time point. 

 

Distribution 

As linaclotide is rarely detectable in plasma following therapeutic doses, standard distribution studies have 

not been conducted. It is expected that linaclotide is negligibly or not systemically distributed.  

 

Biotransformation 

Linaclotide is metabolised locally within the gastrointestinal tract to its active primary metabolite, des-

tyrosine. Both linaclotide and des-tyrosine active metabolite are reduced and enzymatically proteolyzed 

within the gastrointestinal tract to smaller peptides and naturally occurring amino acids. 

The potential inhibitory activity of linaclotide and its active primary metabolite MM-419447 on the human 

efflux transporters BCRP, MRP2, MRP3, and MRP4 and the human uptake transporters OATP1B1, 

OATP1B3, OATP2B1, PEPT1 and OCTN1 was investigated in vitro. Results of this study showed that 

neither peptide is an inhibitor of the common efflux and uptake transporters studied at clinically relevant 

concentrations. 

 

The effect of linaclotide and its metabolites to inhibit the common intestinal enzymes (CYP2C9 and 

CYP3A4) and liver enzymes (CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4) or to induce liver 

enzymes (CYP1A2, 2B6, and 3A4/5) was investigated in vitro. Results of these studies showed that 

linaclotide and des-tyrosine metabolite are not inhibitors or inducers of the cytochrome P450 enzyme system. 

 

Elimination 

Following a single oral dose of 2,897 micrograms linaclotide on day 8, after a 7-day course of 

290 micrograms/day in 18 healthy volunteers, approximately 3 to 5% of the dose was recovered in the 

faeces, virtually all of it as the des-tyrosine active metabolite. 

 

Age and gender 

Clinical studies to determine the impact of age and gender on the clinical pharmacokinetics of linaclotide 

have not been conducted because it is rarely detectable in plasma. Gender is not expected to have any impact 

on dosing. For age related information, please see sections 4.2., 4.4., and 4.8. 

 

Renal impairment 

Constella has not been studied in patients who have renal impairment. Linaclotide is rarely detectable in 

plasma, therefore, renal impairment would not be expected to affect clearance of the parent compound or its 

metabolite. 

 

 

 



 

9 

Hepatic impairment 

Constella has not been studied in patients who have hepatic impairment. Linaclotide is rarely detectable in 

plasma and is not metabolised by liver cytochrome P450 enzymes, therefore, hepatic impairment would not 

be expected to affect the metabolism or clearance of the parent drug or its metabolite.  

 

5.3 Preclinical safety data 

 

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, 

repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction and development. 

 

 

6. PHARMACEUTICAL PARTICULARS 

 

6.1 List of excipients 

 

Capsule contents 

Microcrystalline cellulose  

Hypromellose 4-6 mPa’s – substitution type 2910 

Calcium chloride dihydrate 

Leucine 

 

Capsule shell 

Titanium dioxide (E 171) 

Gelatin  

Red iron oxide (E172) 

Yellow iron oxide (E172) 

 

Capsule ink 

Shellac 

Propylene glycol 

Concentrated ammonia solution 

Potassium hydroxide 

Titanium dioxide (E 171) 

Black iron oxide (E172)  

 

6.2 Incompatibilities 

 

Not applicable. 

 

6.3 Shelf life 

 

Unopened bottle for 28, 90 and multipack containing 112 (4 packs of 28) capsules: 3 years. 

Unopened bottle for 10 capsules: 2 years.  

After first opening: 18 weeks. 

 

6.4 Special precautions for storage 

 

Do not store above 30ºC. Keep the bottle tightly closed in order to protect from moisture. 

 

The bottle contains one or more sealed canisters containing silica gel to keep the capsules dry. Keep the 

canisters in the bottle. 

 

6.5 Nature and contents of container 

 

White high density polyethylene (HDPE) bottle with a tamper evident seal and a child-resistant closure, 

together with one or more desiccant canisters containing silica gel.  



 

10 

 

Pack sizes: 10, 28 or 90 capsules and multipacks containing 112 (4 packs of 28) capsules. Not all pack sizes 

may be marketed. 

 

6.6 Special precautions for disposal 

 

Any unused medicinal product or waste material should be disposed of in accordance with local 

requirements.  

 

7. MARKETING AUTHORISATION HOLDER 

 

Allergan Pharmaceuticals International Limited 

Clonshaugh Business & Technology Park Dublin 17, D17 E400 

Ireland 

 

8. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/12/801/001 

EU/1/12/801/002 

EU/1/12/801/004 

EU/1/12/801/005 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 

 

Date of first authorisation: 26 November 2012 

Date of latest renewal: 28 August 2017 

 

 

10. DATE OF REVISION OF THE TEXT 

 

Detailed information on this medicinal product is available on the website of the European Medicines 

Agency http://www.ema.europa.eu. 



 

11 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX II 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE 

OF THE MEDICINAL PRODUCT 

 

 

 

 

 

 



 

12 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

 

Name and address of the manufacturer responsible for batch release 

Allergan Pharmaceuticals International Limited 

Clonshaugh Business & Technology Park 

Dublin 17, D17 E400 

Ireland 

 

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 

Medicinal product subject to medical prescription. 

 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION  

 

• Periodic Safety Update Reports 
The requirements for submission of periodic safety update reports for this medicinal product are set out in 

the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC 

and any subsequent updates published on the European medicines web-portal.  

 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE 

OF THE MEDICINAL PRODUCT  

 

• Risk Management Plan (RMP) 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 

agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent 

updates of the RMP. 

 

An updated RMP should be submitted: 

• At the request of the European Medicines Agency; 

• Whenever the risk management system is modified, especially as the result of new information being 
received that may lead to a significant change to the benefit/risk profile or as the result of an important 

(pharmacovigilance or risk minimisation) milestone being reached. 

 

 



 

13 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX III 

LABELLING AND PACKAGE LEAFLET 



 

14 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

A. LABELLING 

 



 

15 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  

 

CARTON CONTAINING SINGLE BOTTLE 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Constella 290 micrograms hard capsules 

linaclotide 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each capsule contains 290 micrograms of linaclotide 

 

 

3. LIST OF EXCIPIENTS 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Hard capsule. 

10 capsules 

28 capsules 

90 capsules 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use 

Oral use  

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF 

THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

Once opened, use within 18 weeks. 

 

9. SPECIAL STORAGE CONDITIONS 

 

Do not store above 30C 

Keep the bottle tightly closed in order to protect from moisture 

 

 



 

16 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR 

WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Allergan Pharmaceuticals International Limited 

Clonshaugh Business & Technology Park Dublin 17, D17 E400 

Ireland 

 

 

12. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/12/801/001 10 capsules 

EU/1/12/801/002 28 capsules 

EU/1/12/801/004 90 capsules 

 

 

13. BATCH NUMBER 

 

Lot  

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

constella 290 mcg  

 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC:  

SN:  

NN:  

 

 

 

 



 

17 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  

 

OUTER CARTON CONTAINING 4 x 28 CAPSULE BOTTLES (MULTIPACK) WITH BLUE BOX 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Constella 290 micrograms hard capsules 

linaclotide 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each capsule contains 290 micrograms of linaclotide 

 

 

3. LIST OF EXCIPIENTS 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Hard capsule. 

Multipack : 112 (4 packs of 28) capsules  

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use 

Oral use  

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF 

THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

Once opened, use within 18 weeks. 

9. SPECIAL STORAGE CONDITIONS 

 

Do not store above 30C 

Keep the bottle tightly closed in order to protect from moisture 

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR 

WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 



 

18 

 

Allergan Pharmaceuticals International Limited 

Clonshaugh Business & Technology Park 

Dublin 17, D17 E400 

Ireland 

 

 

12. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/12/801/005 Multipack: 112 (4 packs  of 28) capsules  

 

 

13. BATCH NUMBER 

 

Lot  

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

constella 290 mcg  

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC:  

SN:  

NN:  

 

 

 



 

19 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  

 

INNER CARTON CONTAINING SINGLE 28 CAPSULE BOTTLES (MULTIPACK) 

 

WITHOUT BLUE BOX 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Constella 290 micrograms hard capsules 

linaclotide 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each capsule contains 290 micrograms of linaclotide 

 

 

3. LIST OF EXCIPIENTS 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Hard capsule. 

28 capsules. Component of a multipack, can’t be sold separately. 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use 

Oral use  

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF 

THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

Once opened, use within 18 weeks. 

9. SPECIAL STORAGE CONDITIONS 

 

Do not store above 30C 

Keep the bottle tightly closed in order to protect from moisture 

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR 

WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 

 



 

20 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Allergan Pharmaceuticals International Limited 

Clonshaugh Business & Technology Park 

Dublin 17, D17 E400 

Ireland 

 

 

12. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/12/801/005 Multipack: 112 (4 packs of 28) capsules   

 

 

13. BATCH NUMBER 

 

Lot  

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

constella 290 mcg  

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

 



 

21 

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 

 

BOTTLE 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Constella 290 micrograms hard capsules 

linaclotide 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each capsule contains 290 micrograms of linaclotide 

 

 

3. LIST OF EXCIPIENTS 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Hard capsule. 

10 capsules 

28 capsules 

90 capsules 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use 

Oral use  

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF 

THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

Once opened, use within 18 weeks. 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

Do not store above 30C 

Keep the bottle tightly closed in order to protect from moisture 

 

 



 

22 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR 

WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Allergan Pharmaceuticals International Limited 

Clonshaugh Business & Technology Park Dublin 17, D17 E400 

Ireland 

 

12. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/12/801/001 10 capsules 

EU/1/12/801/002 28 capsules 

EU/1/12/801/004 90 capsules 

EU/1/12/801/005 Multipack: 112 (4 packs of28) capsules 

 

 

13. BATCH NUMBER 

 

Lot  

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

 



 

23 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B. PACKAGE LEAFLET 



 

24 

 

Package leaflet: Information for the patient 

 

Constella 290 micrograms hard capsules 

linaclotide 

 

. 

 

Read all of this leaflet carefully before you start taking this medicine because it contains important 

information for you. 

- Keep this leaflet. You may need to read it again.  
- If you have any further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if  

their signs of illness are the same as yours. 

- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 

not listed in this leaflet. See section 4. 

 

What is in this leaflet 

 

1. What Constella is and what it is used for  

2. What you need to know before you take Constella  

3. How to take Constella  

4. Possible side effects  

5. How to store Constella 

6. Contents of the pack and other information 

 

 

1. What Constella is and what it is used for 

 

What Constella is used for 

Constella contains the active substance linaclotide. It is used to treat the symptoms of moderate to severe 

irritable bowel syndrome (often just called “IBS”) with constipation in adult patients. 

 

IBS is a common gut disorder.  The main symptoms of IBS with constipation include: 

• stomach or abdominal pain,  

• feeling bloated,  

• infrequent, hard, small or pellet-like stools (faeces). 
 

These symptoms may vary from person to person.  

 

How Constella works 

Constella acts locally in your gut, helping you to feel less pain and less bloated, and to restore the normal 

functioning of your bowels. It is not absorbed into the body, but attaches to receptor called guanylate cyclase 

C on the surface of your gut. By attaching to this receptor, it blocks the sensation of pain and allows liquid to 

enter from the body into the gut, thereby loosening the stools and increasing your bowel movements.  

 

2. What you need to know before you take Constella  

Do not take Constella 

- if you are allergic to linaclotide or any of the other ingredients of this medicine (listed in section 6). 
- if you or your doctor know that you have a blockage in your stomach or bowels.  
 

Warnings and precautions  

Your doctor has given this medicine to you after excluding other diseases, especially of your bowels and 

concluding that you suffer from IBS with constipation. Because these other diseases may have the same 

symptoms as IBS, it is important that you report any change or irregularity in symptoms to your doctor 

promptly. 

 



 

25 

If you experience severe or prolonged diarrhoea (passing of frequent watery stools for 7 days or more), stop 

taking Constella and contact your doctor (see section 4). Make sure you drink plenty of fluids to replace the 

water and electrolytes like potassium lost from the diarrhoea.  

 

Talk to your doctor if you experience bleeding from the bowel or rectum. 

 

Take special care if you are older than 65 years, as there is a higher risk you experience diarrhoea. 

 

Take also special care if you have severe or prolonged diarrhoea and an additional disease, such as high 

blood pressure, previous disease of the heart and blood vessels (e.g. such as previous heart attacks) or 

diabetes. 

 

Talk to your doctor if you suffer from inflammatory diseases of the guts such as Crohn’s disease or  

ulcerative colitis as Constella is not recommended in these patients. 

 

Children and adolescents 

Do not give this medicine to children and adolescents under the age of 18 years because the safety and 

efficacy of Constella in this age group has not been established. 

 

Other medicines and Constella 

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines: 

▪ Some medicines may not work as effectively if you have severe or prolonged diarrhoea, such as: 
- Oral contraceptives. If you have very bad diarrhoea, the contraceptive pill may not work properly and 

the use of an extra method of contraception is recommended. See the instructions in the patient leaflet 

of the contraceptive pill you are taking. 

- Medicines that need careful and exact dosing, such as levothyroxine (a hormone to treat reduced 
function of the thyroid gland). 

▪ Some medicines may increase the risk of diarrhoea when taken with Constella, such as: 
-  Medicines to treat stomach ulcers or excessive production of stomach acid called Proton Pump 

Inhibitors. 

-  Medicines to treat pain and inflammation called NSAIDs. 

-  Laxatives.  

 

Constella with food  

Constella produces more frequent bowel movements and diarrhoea (looser stools) when it is taken with food 

than when it is taken on an empty stomach (see section 3). 

 

Pregnancy and breast-feeding  

Limited information is available on the effects of Constella in pregnant and breast-feeding women.  

 

Do not take this medicine if you are pregnant, think you may be pregnant or are planning to have a baby, 

unless your doctor advises you to do so. 

 

If you are breast-feeding, do not take Constella unless your doctor advises to do so. 

 

Driving and using machines 

Constella will not affect your ability to drive or use machines 

 

 

3. How to take Constella 

 

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you 

are not sure.  

 

The recommended dose is one capsule (i.e. 290 micrograms of linaclotide) taken orally once a day. The 

capsule should be taken at least 30 minutes before a meal. 

 



 

26 

If you have not experienced improvement in your symptoms after 4 weeks of treatment, you should contact 

your doctor. 

 

If you take more Constella than you should 

The most likely effect of taking too much Constella is diarrhoea. Contact your doctor or pharmacist if you 

have taken too much of this medicine. 

 

If you forget to take Constella 

Do not take a double dose to make up for a forgotten dose. Just take the next dose at the scheduled time and 

continue as normal. 

 

If you stop taking Constella 

It is preferable to discuss stopping treatment with your doctor before actually doing so.  However, treatment 

with Constella can be safely stopped at any time.  

 

If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 

 

 

4. Possible side effects 

 

Like all medicines, this medicine can cause side effects, although not everybody gets them. 

 

Very common side effects (may affect more than 1 in 10 people): 

 

• diarrhoea   

 

Diarrhoea is normally short lived; however, if you experience severe or prolonged diarrhoea (passing 

frequent or watery stools for 7 days or more) and feel lightheaded, dizzy or faint, stop taking Constella and 

contact your doctor.  

 

Common side effects (may affect up to 1 in 10 people): 

 

• stomach or abdominal pain 

• feeling bloated  

• wind 

• stomach flu (viral gastroenteritis) 

• feeling dizzy 

 

Uncommon side effects (may affect up to 1 in 100 people): 

 

• lack of control over passing stools (faecal incontinence) 

• urgency to pass stools 

• feeling lightheaded after standing up quickly  

• dehydration 

• low level of potassium in your blood 

• decreased appetite 

• rectal bleeding 

• bleeding from the bowel or rectum including bleeding from piles/haemorrhoids 

• nausea 

• vomiting 

• hives (urticaria) 

 

Rare side effects (may affect up to 1 in 1,000 people): 

 

• bicarbonate decrease in your blood 
 

Side effects with frequency not known (frequency cannot be estimated from the available data): 



 

27 

 

• Rash 
 

Reporting of side effects 

If you get any side effects, talk to your  doctor or pharmacist. This includes any possible side effects not 

listed in this leaflet. You can also report side effects directly via the national reporting system listed in 

Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 

 

 

5. How to store Constella 

 

Keep this medicine out of the sight and reach of children. 

 

Do not use this medicine after the expiry date which is stated on the carton and the bottle after ¨EXP¨. The 

expiry date refers to the last day of that month. 

Once the bottle is opened, the capsules should be used within 18-weeks. 

 

Do not store above 30ºC. Keep the bottle tightly closed in order to protect from moisture.  

 

Warning: The bottle contains one or more sealed canisters containing silica gel to keep the capsules dry. 

Keep the canisters in the bottle. Do not swallow them. 

 

Do not use this medicine if you notice any signs of damage to the bottle or any change in the appearance of 

the capsules. 

 

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw 

away medicines you no longer use. These measures will help protect the environment. 

 

 

6. Contents of the pack and other information 

 

What Constella contains  

 

- The active substance is linaclotide. Each capsule contains 290 micrograms of linaclotide. 
 

- The other ingredients are : 
 

Capsule content: microcrystalline cellulose, hypromellose, calcium chloride dihydrate and leucine. 

 

Capsule shell: red iron oxide (E172), titanium dioxide (E171), yellow iron oxide (E172) and gelatin. 

 

Printing ink: shellac, propylene glycol, concentrated ammonia solution, potassium hydroxide, titanium 

dioxide (E171) and black iron oxide (E172). 

 

What Constella looks like and contents of the pack 

 

The capsules are white to off-white-orange opaque hard capsules marked “290” with grey ink. 

 

They are packaged in a white, high density polyethylene (HDPE) bottle with a tamper evident seal and a 

child-resistant screw cap, together with one or more desiccant canisters containing silica gel. 

 

Constella is available in packs containing 10, 28 or 90 capsules and in multipacks of 112 capsules 

comprising 4 cartons, each containing 28 capsules. Not all pack-sizes may be marketed. 

 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


 

28 

 

 

 

Marketing Authorisation Holder  

Allergan Pharmaceuticals International Limited 

Clonshaugh Business & Technology Park 

Dublin 17, D17 E400 

Ireland 

 

Manufacturer  

Allergan Pharmaceuticals International Limited 

Clonshaugh Business & Technology Park 

Dublin 17, D17 E400 

Ireland 

 

For any information about this medicine, please contact the local representative of the Marketing 

Authorisation Holder: 

 

België/Belgique/Belgien/ 

Luxembourg/Luxemburg/Nederland 

Allergan n.v 

Tél/Tel: + 32 (0)2 351 2424 

 

Latvija/Lietuva/Eesti 

Allergan Baltics UAB 

Tel: +  371 676 60 831 (LT); +  37 052 072 

777 (LV); +  37 2634 6109 (ET) 

 

България 

Алерган България ЕООД 

Тел.: + 359 (0) 800 20 280 

 

Magyarország 

Allergan Hungary Kft. 

Tel.: + 36 80 100 101 

 

Česká republika 

Allergan CZ s.r.o. 

Tel: + 420 800 188 818 

 

Ireland/Malta 

Allergan  Pharmaceuticals International 

Limited 

Tel: + 1800 931 787 (IE); + 356 27780331 

(MT) 

 

Danmark/Norge/Suomi/Finland/Sverige 

Allergan Norden AB 

Tlf/Puh/Tel: +  4580884560 (DK); + 47 80 01 04 

97 (NO); + 358 800 115 003 (FI); + 46 8 594 100 

00 (SE) 

 

Österreich 

Pharm-Allergan GmbH 

Tel: + 43 1 99460 6355 

 

Deutschland 

Pharm-Allergan GmbH 

Tel: + 49 69 92038-1050 

 

Polska 

Allergan Sp. z o.o. 

Tel: + 48 22 256 37 00 

 

Ελλάδα/Κύπρος 

Allergan Hellas Pharmaceuticals S.A. 

Τηλ: + 30 210 74 73 300 

 

Portugal 

Profarin Lda. 

Tel: + 351 21 425 3242 

 

España 

Allergan S.A. 

Tel: + 34 91 807 6130 

 

România 

Allergan S.R.L. 

Tel: + 40 21 301 53 02 

 

France 

Allergan France SAS 

Tél: + 33 (0)1 49 07 83 00 

 

 

 

Slovenija 

Ewopharma d.o.o. 

Tel: + 386 (0) 590 848 40 

 



 

29 

Hrvatska 

Ewopharma d.o.o. 

Tel: + 385 1 6646 563 

 

Slovenská republika 

Allergan SK s.r.o. 

Tel: + 421  2 593 961 00 

 

Ísland 

Actavis Pharmaceuticals Iceland ehf. 

Sími: + 354 550 3300 

United Kingdom 

Allergan Ltd 

Tel: + 44 (0) 1628 494026 

 

Italia 

Allergan S.p.A 

Tel: + 39 06 509  562 90 

 

 

 

This leaflet was last revised in  

 

Other sources of information 

 

Detailed information on this medicine is available on the European Medicines Agency web site: 

http://www.ema.europa.eu.  



 

30 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX IV 

SCIENTIFIC CONCLUSIONS AND GROUNDS FOR THE VARIATION TO THE TERMS OF THE 

MARKETING AUTHORISATION(S) 
 
 

 

 
 

 



 

31 

Scientific conclusions 

Taking into account the PRAC Assessment Report on the PSUR(s) for linaclotide, the scientific 

conclusions of CHMP are as follows:  

In view of available data on the signal of “urticaria” from clinical trials and spontaneous reports including 

in 17 cases with a close temporal relationship and a positive de-challenge as well as two cases with a 

positive re-challenge the PRAC considers a causal relationship between linaclotide and urticaria is 

established. The PRAC concluded that the product information of products containing linaclotide should be 

amended accordingly. 

The CHMP agrees with the scientific conclusions made by the PRAC. 

Grounds for the variation to the terms of the marketing authorisation(s) 

On the basis of the scientific conclusions for linaclotide the CHMP is of the opinion that the benefit-risk 

balance of the medicinal product(s) containing linaclotide is unchanged subject to the proposed changes to 

the product information 

The CHMP recommends that the terms of the marketing authorisation(s) should be varied. 

 

 
 

 

 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET
	SCIENTIFIC CONCLUSIONS AND GROUNDS FOR THE VARIATION TO THE TERMS OF THE MARKETING AUTHORISATION(S)