Constella: Indications, Dosage, Precautions, Adverse Effects
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Constella - Product Information

Manufacture: Actavis
Country: Canada
Condition: Constipation, Chronic, Constipation, Irritable Bowel Syndrome
Class: Guanylate cyclase-C agonists
Form: Capsules
Ingredients: linaclotide, calcium chloride dihydrate, gelatin, hypromellose, iron oxide black, iron oxide yellow, L-leucine, microcrystalline cellulose, shellac glaze, titanium dioxide

Summary product information

Route of
Administration
Dosage Form /
Strength
Clinically Relevant Nonmedicinal Ingredients
Oral Capsules
145 mcg, 290mcg
Gelatin, microcrystalline cellulose
For a complete listing see DOSAGE FORMS,COMPOSITION AND PACKAGING section.

Indications and clinical use

Irritable Bowel Syndrome with Constipation (IBS-C)

CONSTELLA (linaclotide) is indicated for the treatment of irritable bowel syndrome with constipation (IBS-C) in adults.

Chronic Idiopathic Constipation (CIC)

CONSTELLA is indicated for the treatment of chronic idiopathic constipation (CIC) in adults.

The efficacy of CONSTELLA for the treatment of IBS-C and CIC has been established in double-blind, placebo-controlled studies of up to 26 and 12 weeks duration, respectively [see CLINICAL TRIALS].

Geriatrics (≥ 65 years of age):

Irritable Bowel Syndrome with Constipation

Of 1,605 IBS-C patients in the placebo-controlled clinical studies of CONSTELLA, 85 (5%) were at least 65 years of age, while 20 (1%) were at least 75 years old. Clinical studies of CONSTELLA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

Chronic Idiopathic Constipation

Of 1,275 CIC patients in the placebo-controlled clinical studies of CONSTELLA, 155 (12%) were at least 65 years of age, while 30 (2%) were at least 75 years old. Clinical studies of CONSTELLA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

Pediatrics (< 18 years of age):

CONSTELLA is contraindicated in children under 6 years of age and is not recommended for use in children between 6 and 18 years of age as the safety and efficacy of CONSTELLA in pediatric patients have not been established [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, and TOXICOLOGY, Reproductive and Developmental Toxicity].

Contraindications

CONSTELLA (linaclotide) is contraindicated in:

  • pediatric patients under 6 years of age [see WARNINGS AND PRECAUTIONS].
  • patients who are hypersensitive to linaclotide or to any ingredient in the formulation or component of the container. For a complete listing, see the Dosage Forms, Composition and Packaging section of the Product Monograph.
  • patients with known or suspected mechanical gastrointestinal obstruction.

Warnings and precautions

CONSTELLA (linaclotide) is contraindicated in children up to 6 years of age and is not recommended in children between 6 and 18 years of age [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, Special Populations, TOXICOLOGY, Reproductive and Developmental Toxicity].

Gastrointestinal

Diarrhea

Diarrhea was the most common adverse reaction of CONSTELLA-treated patients in the pooled IBS-C and CIC double-blind placebo-controlled trials. The incidence of diarrhea was higher in linaclotide-treated patients than placebo-treated patients (19.8% versus 3.0% in the IBS-C trials and 15.1% versus 4.7% in the CIC trials). Severe diarrhea was reported in 2% of the CONSTELLA-treated patients. The incidence of diarrhea was similar between the IBS-C and CIC populations.

Instruct patients to stop CONSTELLA if severe diarrhea occurs and to contact their healthcare provider, who should consider dose suspension [see ADVERSE REACTIONS].

Special Populations

Pregnant Women

There are no adequate and well-controlled studies with CONSTELLA in pregnant women. In animal developmental studies, adverse fetal effects were observed only with maternal toxicity and at doses of linaclotide much higher than the maximum recommended human dose. CONSTELLA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus [see TOXICOLOGY, Teratology Studies].

Nursing Women

It is not known whether linaclotide is excreted in human milk; however, linaclotide and its active metabolite are not measurable in plasma following administration of the recommended clinical doses [see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics].

Caution should be exercised when CONSTELLA is administered to nursing women.

Pediatrics (< 18 years of age)

CONSTELLA is contraindicated in children under 6 years of age and is not recommended for use in children between 6 and 18 years of age as the safety and efficacy of CONSTELLA in pediatric patients have not been established. As guanylate cyclase-C (GC-C) is known to be overexpressed at early ages, children may be particularly sensitive to the effects of CONSTELLA and may be more likely to develop diarrhea and its potentially serious consequences [see CONTRAINDICATIONS, ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, and TOXICOLOGY, Reproductive and Developmental Toxicity].

Geriatrics (≥ 65 years of age):

Irritable Bowel Syndrome with Constipation

Of 1,605 IBS-C patients in the placebo-controlled clinical studies of CONSTELLA, 85 (5%) were at least 65 years of age, while 20 (1%) were at least 75 years old. Clinical studies of CONSTELLA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

Chronic Idiopathic Constipation

Of 1,275 CIC patients in the placebo-controlled clinical studies of CONSTELLA, 155 (12%) were at least 65 years of age, while 30 (2%) were at least 75 years old. Clinical studies of CONSTELLA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

Adverse reactions

Adverse Drug Reaction Overview

The safety of CONSTELLA (linaclotide) in irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC) was evaluated in 4,370 patients who were exposed to linaclotide in the Phase 2 and 3 clinical studies. Total exposure of IBS-C patients to linaclotide was 2,253 patient-years and total exposure of CIC patients to linaclotide was 1,394 patient-years.

Oral doses from 72 mcg to 966 mcg once daily were evaluated. Approximately 2,570 patients were treated for 6 months or longer, 2,040 patients for 1 year or longer, and 1,220 patients for 18 months or longer (not mutually exclusive). CONSTELLA was generally well-tolerated, with most adverse events being mild to moderate in intensity.

The most commonly observed adverse reaction in both the CONSTELLA-treated IBS-C and CIC patients in placebo-controlled studies (incidence ≥ 5% and at least twice the rate of placebo) was diarrhea.

In placebo-controlled trials in patients with IBS-C, 9.4% of patients treated with CONSTELLA and 2.9% of patients treated with placebo discontinued prematurely due to adverse reactions. In the CONSTELLA treatment group, the most common reasons for discontinuation due to adverse reactions were diarrhea (5.3%) and abdominal pain (1.2%). In comparison, less than 1% of patients in the placebo group withdrew due to diarrhea or abdominal pain.

In placebo-controlled trials in patients with CIC, 7.6% of patients with CONSTELLA and 4.3% of patients treated with placebo discontinued prematurely due to adverse reactions. In the CONSTELLA treatment group, the most common reasons for discontinuation due to adverse reactions were diarrhea (4.2%) and abdominal pain (1.1%). In comparison, less than 1% of patients in the placebo group withdrew due to diarrhea and abdominal pain.

In placebo-controlled trials in patients with IBS-C, a total of 0.7% of CONSTELLA-treated patients and 1.1% of placebo patients experienced at least 1 serious adverse event. There were no serious adverse events of diarrhea. Of the 7 serious adverse events that were reported in the CONSTELLA patients, 2 (pericarditis and pericardial effusion in 1 patient) were possibly related to treatment. Overall, serious adverse events were low and there was no obvious pattern in the types of serious adverse events experienced in either the placebo or CONSTELLA group.

In placebo-controlled trials in patients with CIC, a total of 2.0% of CONSTELLA-treated patients and 2.4% of placebo patients experienced at least 1 serious adverse event. There were no serious adverse events of diarrhea. Of the 17 serious adverse events that were reported in the CONSTELLA patients, 2 (bronchitis and atrial fibrillation in 1 patient each) were possibly related to treatment. Overall, serious adverse events were low and there was no obvious pattern in the types of serious adverse events experienced in either the placebo or CONSTELLA group.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Irritable Bowel Syndrome with Constipation (IBS-C)

Common Adverse Reactions

The data described below reflect exposure to CONSTELLA in the two double-blind, placebo- controlled clinical trials involving 1,605 adult patients with IBS-C. Patients were randomized to receive placebo or 290 mcg CONSTELLA once daily on an empty stomach, for up to 26 weeks. Demographic characteristics were comparable between the CONSTELLA treatment group and placebo [see CLINICAL TRIALS].

Table 1 provides the incidence of adverse reactions reported in ≥ 1% of CONSTELLA-treated IBS-C patients and at an incidence that was greater than in placebo-treated patients in the Phase 3 placebo-controlled trials.

Table 1: Adverse Reactions Occurring in ≥ 1% of CONSTELLA-Treated Patients and at an Incidence Greater than in Placebo-Treated Patients in Two Phase 3 Placebo-Controlled Trials in IBS-C
System Organ Class
Preferred Term
CONSTELLA
290 mcg /day
n=807
(%)
Placebo
n=798
(%)
Gastrointestinal disorders
Diarrhea 19.8 3.0
Abdominal pain 5.1 3.3
Flatulence 4.3 1.9
Abdominal distension 2.2 1.1
Vomiting 1.7 1.3
Gastroesophageal reflux disease 1.2 0.9
General disorders and administration site condition
Fatigue 1.5 1.4
Infectious disease
Gastroenteritis viral 2.6 1.4
Diarrhea

Diarrhea was the most commonly reported adverse reaction of the CONSTELLA -treated patients in the pooled IBS-C Phase 3 placebo-controlled trials. In these trials, 19.8% of CONSTELLA-treated patients reported diarrhea compared to 3.0% of placebo-treated patients. Severe diarrhea was reported in 2.0% of the CONSTELLA-treated patients versus less than 1% of the placebo-treated patients, and 5.3% of the CONSTELLA-treated patients discontinued due to diarrhea versus less than 1% of placebo-treated patients. The majority of reported cases of diarrhea started within the first 2 weeks of CONSTELLA treatment. Fecal incontinence and dehydration were each reported in less than 1% of patients in the CONSTELLA treatment group [see WARNINGS AND PRECAUTIONS, Gastrointestinal].

Other Adverse Reactions Observed in Clinical Studies

Other adverse reactions that were reported in less than 1% of IBS-C patients are listed below by body system:

Gastrointestinal disorders: Abdominal discomfort, anal fissure, bowel movement irregularity, defecation urgency, eructation, fecal incontinence, feces discoloured, frequent bowel movements, gastrointestinal pain, gastrointestinal sounds abnormal, hemorrhoidal hemorrhage, rectal fissure, rectal tenesmus

Infections and infestations: Gastroenteritis

Investigations: Blood bicarbonate decreased

Chronic Idiopathic Constipation (CIC)

Common Adverse Reactions

The data described below reflect exposure to CONSTELLA in the two double-blind, placebo- controlled clinical trials involving 1,275 adult patients with CIC. Patients were randomized to receive placebo, 145 mcg CONSTELLA or 290 mcg CONSTELLA once daily on an empty stomach, for at least 12 weeks. Of these patients, 430 patients received CONSTELLA at the recommended dose of 145 mcg once daily, while 422 patients were treated with 290 mcg CONSTELLA once daily. Demographic characteristics were comparable between both CONSTELLA treatment groups and placebo [see CLINICAL TRIALS].

Table 2 provides the incidence of adverse reactions reported in ≥ 1% of CONSTELLA-treated CIC patients in the 145 mcg and 290 mcg CONSTELLA treatment groups and at an incidence that was greater than in placebo-treated patients in the Phase 3 placebo-controlled trials.

Table 2: Adverse Reactions Occurring in ≥ 1% of All CONSTELLA-Treated Patients and at an Incidence Greater than in Placebo-Treated Patients in the Two Phase 3 Placebo-Controlled Trials in CIC
System Organ Class
Preferred Term
CONSTELLA
145 mcg /day
n=430
(%)
CONSTELLA
290 mcg /day
n=422
(%)
CONSTELLA
Both Doses
n=852
(%)
Placebo
n=423
(%)
Gastrointestinal
Diarrhea 16.0 14.2 15.1 4.7
Flatulence 5.6 5.0 5.3 5.2
Abdominal pain 4.0 4.7 4.3 3.1
Nausea 3.5 4.3 3.9 3.5
Abdominal distension 3.5 3.6 3.5 2.4
Abdominal pain upper 3.0 1.2 2.1 1.7
Dyspepsia 1.9 0.7 1.3 0.7
Infections and infestations
Gastroenteritis viral 1.9 0.5 1.2 0.5
Nervous system disorders
Dizziness 0.9 1.4 1.2 0.5
Diarrhea

Diarrhea was the most commonly reported adverse reaction of the CONSTELLA-treated patients in the pooled CIC Phase 3 placebo-controlled trials. In these trials 15.1% of all CONSTELLA-treated patients reported diarrhea compared to 4.7% of placebo-treated patients. Severe diarrhea was reported in 1.8% of all CONSTELLA-treated patients versus less than 1% of the placebo-treated patients, and 4.2% of all CONSTELLA-treated patients discontinued due to diarrhea versus less than 1% of placebo-treated patients. The majority of reported cases of diarrhea started within the first 2 weeks of CONSTELLA treatment. Fecal incontinence and dehydration were reported in less than 1% of patients in the CONSTELLA treatment group [see WARNINGS AND PRECAUTIONS, Gastrointestinal].

Other Adverse Reactions Observed in Clinical Studies

Other adverse reactions that were reported in less than 1% of CIC patients are listed below by body system:

Gastrointestinal disorders: Abdominal discomfort, anal fissure, anorectal discomfort, defecation urgency, fecal incontinence, feces discoloured, frequent bowel movements, gastroesophageal reflux disease, gastrointestinal pain, gastrointestinal sounds abnormal, hemorrhoids, mucous stools, proctalgia, rectal spasm

General disorders and administration site conditions: Fatigue

Investigations: Blood magnesium decreased, blood potassium decreased, blood pressure decreased

Metabolism and nutrition disorders: Dehydration, hyponatremia

Nervous system disorders: Presyncope, syncope

Renal and urinary disorders: Azotemia

Vascular disorders: Orthostatic hypotension

Drug interactions

Drug-Drug Interactions

No drug-drug interaction studies have been conducted with CONSTELLA (linaclotide). Linaclotide and its active metabolite are not measurable in plasma following administration of the recommended clinical doses; hence, no systemic drug-drug interactions or drug interactions mediated by plasma protein binding of linaclotide or its metabolite are expected [see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics].

Linaclotide does not interact with the cytochrome P450 enzyme system based on the results of in vitro studies. In addition, linaclotide is neither a substrate nor an inhibitor of the efflux transporter P-glycoprotein (P-gp).

Drug-Food Interactions

Taking CONSTELLA immediately after a high fat breakfast resulted in looser stools and a higher stool frequency compared with taking it in the fasted state, in healthy subjects; the effect in patients with IBS-C and CIC has not been established. In clinical trials, CONSTELLA was administered on an empty stomach, at least 30 minutes before breakfast [see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics].

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Interactions

Interactions with laboratory tests have not been established.

Dosage and administration

Dosing Considerations

Patients should be counselled that improvement of bowel symptoms should occur within the first week of CONSTELLA (linaclotide) treatment, but improvement of abdominal symptoms may take longer [see CLINICAL TRIALS]. Physicians should periodically assess the need for continued treatment with CONSTELLA.

Patients on treatment who experience severe diarrhea should stop CONSTELLA and contact their physician [see WARNINGS AND PRECAUTIONS, Gastrointestinal].

Exceeding the daily dose of 145 mcg for the treatment of CIC is not expected to increase efficacy.

Recommended Dose and Dosage Adjustment

Irritable Bowel Syndrome with Constipation

The recommended dose of CONSTELLA is 290 mcg taken orally once daily on an empty stomach, at least 30 minutes prior to the first meal of the day [see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics].

Chronic Idiopathic Constipation

The recommended dose of CONSTELLA is 145 mcg taken orally once daily on an empty stomach, at least 30 minutes prior to the first meal of the day [see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics].

Special Populations

No dose adjustments are required for patients with hepatic or renal impairment [see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions].

Pediatrics (<18 years of age)

CONSTELLA is contraindicated in children under 6 years of age and is not recommended for use in children between 6 and 18 years of age. [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, and TOXICOLOGY, Reproductive and Developmental Toxicity].

Missed Dose

In the event that a dose is missed, the patient should skip that dose. Do not take two capsules to account for the missed dose. Wait until it is time for the next dose and then take the usual dose on an empty stomach.

Administration

CONSTELLA capsules should be taken orally once daily on an empty stomach, at least 30 minutes prior to the first meal of the day. The capsules should be swallowed whole and should not be broken apart or chewed.

Overdosage

There is limited experience with overdose of CONSTELLA (linaclotide). During the clinical development program of CONSTELLA, single doses of 2897 mcg were administered to 22 healthy volunteers; the safety profile in these subjects was consistent with that in the overall CONSTELLA-treated population, with diarrhea being the most commonly reported adverse reaction.

For management of a suspected drug overdose, contact your regional Poison Control Centre.

Action and clinical pharmacology

Irritable bowel syndrome (IBS) is a functional bowel disorder in which abdominal pain and discomfort are associated with altered defecation. The disorder has a spectrum ranging from mild to severe and is associated with deterioration in quality of life. The etiology and pathophysiology are poorly understood and appear to be multifactorial, resulting from a combination of visceral hypersensitivity, alteration in gastrointestinal (GI) motility, and psychosocial factors. Treatment of IBS is aimed at symptomatic relief of abdominal symptoms (i.e., abdominal pain, abdominal discomfort, and bloating), normalization of defecation, and improvement of quality of life.

Chronic idiopathic constipation (CIC) is a functional GI disorder. Patients with CIC report multiple bowel and abdominal symptoms including straining, gas, hard stools, abdominal discomfort, infrequent bowel movements, bloating, a sense of incomplete evacuation, and abdominal pain. Treatment of CIC is aimed at normalizing the frequency and consistency of bowel movements, as well as relieving the abdominal symptoms commonly associated with this condition.

Mechanism of Action

Linaclotide, a synthetic 14-amino acid peptide, is a potent and selective guanylate cyclase-C (GC-C) agonist with visceral analgesic and secretory activities. This first-in-class orally active peptide is structurally related to the guanylin peptide family, which is involved in the regulation of fluid homeostasis and bowel function of the GI tract. Both linaclotide and its active metabolite bind to GC-C and act locally on the luminal surface of the intestinal epithelium. Activation of GC-C results in an increase in both intracellular and extracellular concentrations of cyclic guanosine monophosphate (cGMP). Elevation in intracellular cGMP stimulates secretion of chloride and bicarbonate into the intestinal lumen, through activation of the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel, resulting in increased intestinal fluid and accelerated transit. Linaclotide has been shown to both accelerate GI transit and reduce intestinal pain. The linaclotide-induced reduction in visceral pain is thought to be mediated by increased extracellular cGMP, which was shown to decrease the activity of pain-sensing nerves.

Pharmacodynamics

Although the pharmacologic effects of CONSTELLA (linaclotide) in humans have not been fully evaluated, CONSTELLA has been shown, in clinical studies, to accelerate colonic transit, soften stools, and increase stool frequency.

Pharmacokinetics

Absorption

CONSTELLA is minimally absorbed with low systemic availability following oral administration. Concentrations of linaclotide and its active metabolite in plasma were below the limit of quantitation after oral doses of 145 mcg or 290 mcg were administered. Therefore, standard pharmacokinetic parameters such as area under the curve (AUC), maximum concentration (Cmax) and half-life (t1/2) cannot be calculated.

Distribution

Given that linaclotide plasma concentrations following therapeutic oral doses are not measurable, linaclotide is expected to be minimally distributed to tissues.

Metabolism

Linaclotide is metabolized within the gastrointestinal tract to its principal, active metabolite by loss of the terminal tyrosine moiety. Both linaclotide and the metabolite are proteolytically degraded within the intestinal lumen to smaller peptides and naturally occurring amino acids.

Excretion

Active peptide recovery in the stool samples of fasted and fed subjects following the daily administration of 290 mcg of linaclotide for seven days averaged ~5 % (fasted) and ~ 3 % (fed) and virtually all as the active metabolite.

Food Effect

In a cross-over study, 18 healthy subjects were administered CONSTELLA 290 mcg for 7 days both in the non-fed and fed state. Neither linaclotide nor its active metabolite was detected in the plasma. Taking CONSTELLA immediately after the high fat breakfast resulted in looser stools and a higher stool frequency compared with taking it in the fasted state. In clinical trials, CONSTELLA was administered on an empty stomach, at least 30 minutes before breakfast.

Special Populations and Conditions

Pediatrics (<18 years of age)

Clinical studies to determine the impact of age on the clinical pharmacokinetics of linaclotide have not been conducted as linaclotide is rarely detectable in plasma. CONSTELLA is contraindicated in children under 6 years of age and is not recommended for use in children between 6 and 18 years of age as the safety and efficacy of CONSTELLA in pediatric patients have not been established [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and TOXICOLOGY, Reproductive and Developmental Toxicity].

Geriatrics

Clinical studies to determine the impact of age on the pharmacokinetics of CONSTELLA have not been conducted. See [WARNINGS AND PRECAUTIONS, Special Populations, Geriatrics] for information regarding patients aged 65 years and older.

Gender

Clinical studies to determine the impact of gender on the pharmacokinetics of CONSTELLA have not been conducted. Gender is not expected to affect the pharmacokinetics of CONSTELLA.

Hepatic Impairment

CONSTELLA has not been specifically studied in patients who have hepatic impairment. Hepatic impairment is not expected to affect the metabolism or clearance of the parent drug or its metabolite because linaclotide has low systemic availability following oral administration and is metabolized within the gastrointestinal tract.

Renal Impairment

CONSTELLA has not been specifically studied in patients who have renal impairment. Renal impairment is not expected to affect clearance of the parent drug or its metabolite because linaclotide has low systemic availability following oral administration and is metabolized within the gastrointestinal tract.

Storage and stability

Store at room temperature (15oC to 25oC).

Keep CONSTELLA (linaclotide) in the original container. Do not subdivide or repackage. Protect from moisture. Do not remove desiccant from the container. Keep bottles tightly closed in a dry place.

Dosage forms, composition and packaging

CONSTELLA (linaclotide) contains linaclotide-coated beads in hard gelatin capsules.
CONSTELLA is available as 145 mcg or 290 mcg capsules for oral administration.

145 mcg Capsules: Each 145 mcg white to off-white, opaque, hard, gelatin capsule is imprinted with a grey imprint “FL 145.” Available in bottles of 30 capsules.

290 mcg Capsules: Each 290 mcg white to off-white, opaque, hard, gelatin capsule is imprinted with a grey imprint “FL 290.” Available in bottles of 30 capsules.

Composition:

The inactive ingredients of CONSTELLA capsules include: calcium chloride dihydrate, gelatin, hypromellose, iron oxide black, iron oxide yellow, L-leucine, microcrystalline cellulose, shellac glaze, and titanium dioxide.