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Linzess (Linaclotide Capsules)
Forest Laboratories, Inc.
LINZESS- linaclotide capsule, gelatin coated
Forest Laboratories, Inc.
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use LINZESS safely and effectively. See full prescribing information for LINZESS.
LINZESS (linaclotide) capsules, for oral use
Initial U.S. Approval: 2012
WARNING: PEDIATRIC RISK
See full prescribing information for complete boxed warning.
LINZESS is contraindicated in pediatric patients up to 6 years of age. Avoid use of LINZESS in pediatric patients 6 through 17 years of age. Linaclotide caused deaths in young juvenile mice (4, 5.1, 8.4, 13.2).
INDICATIONS AND USAGE
LINZESS is a guanylate cyclase-C agonist indicated in adults for treatment of:
■Irritable bowel syndrome with constipation (IBS-C) (1.1)
■Chronic idiopathic constipation (CIC) (1.2)
DOSAGE AND ADMINISTRATION
■IBS-C: Take 290 mcg orally once daily (2.1)
■CIC: Take 145 mcg orally once daily (2.2)
■Take on empty stomach at least 30 minutes prior to first meal of the day (2.1, 2.2)
DOSAGE FORMS AND STRENGTHS
Capsules: 145 mcg and 290 mcg (3)
CONTRAINDICATIONS
■Pediatric patients up to 6 years of age (4)
■Patients with known or suspected mechanical gastrointestinal obstruction (4)
WARNINGS AND PRECAUTIONS
■Diarrhea: Patients may experience severe diarrhea. Hold or stop LINZESS (5.2)
ADVERSE REACTIONS
Most common adverse reactions (incidence of at least 2%) reported in IBS-C or CIC patients are diarrhea, abdominal pain, flatulence and abdominal distension. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Forest Pharmaceuticals, Inc., at 1- 800- 678-1605 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
Revised: 08/2012
FULL PRESCRIBING INFORMATION: CONTENTS *
WARNING: PEDIATRIC RISK
1 INDICATIONS AND USAGE
1.1 Irritable Bowel Syndrome with Constipation (IBS-C)
1.2 Chronic Idiopathic Constipation (CIC)
2 DOSAGE AND ADMINISTRATION
2.1 Irritable Bowel Syndrome with Constipation (IBS-C)
2.2 Chronic Idiopathic Constipation (CIC)
2.3 Important Administration Instructions
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Pediatric Risk
5.2 Diarrhea
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
7 DRUG INTERACTIONS
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Hepatic or Renal Impairment
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
13.2 Animal Toxicology and/or Pharmacology
14 CLINICAL STUDIES
14.1 Irritable Bowel Syndrome with Constipation (IBS-C)
14.2 Chronic Idiopathic Constipation (CIC)
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
*
Sections or subsections omitted from the full prescribing information are not listed.
FULL PRESCRIBING INFORMATION
1WARNING: PEDIATRIC RISK
LINZESS is contraindicated in pediatric patients up to 6 years of age. Avoid use in pediatric patients 6 through 17 years of age. In nonclinical studies, administration of a single, clinically relevant adult oral dose of linaclotide caused deaths in young juvenile mice [see Contraindications (4), Warnings and Precautions (5.1), Use in Specific Populations (8.4) and Nonclinical Toxicology (13.2)].
11 INDICATIONS AND USAGE
1.11.1 Irritable Bowel Syndrome with Constipation (IBS-C)
LINZESS (linaclotide) is indicated in adults for the treatment of irritable bowel syndrome with constipation (IBS-C).
1.21.2 Chronic Idiopathic Constipation (CIC)
LINZESS is indicated in adults for the treatment of chronic idiopathic constipation (CIC).
22 DOSAGE AND ADMINISTRATION
2.12.1 Irritable Bowel Syndrome with Constipation (IBS-C)
The recommended dose of LINZESS is 290 mcg taken orally once daily on an empty stomach, at least 30 minutes prior to the first meal of the day.
2.22.2 Chronic Idiopathic Constipation (CIC)
The recommended dose of LINZESS is 145 mcg taken orally once daily on an empty stomach, at least 30 minutes prior to the first meal of the day.
2.32.3 Important Administration Instructions
Swallow capsules whole; do not break apart or chew.
33 DOSAGE FORMS AND STRENGTHS
-
145 mcg capsules are white to off-white opaque with gray imprint “FL 145”
-
290 mcg capsules are white to off-white opaque with gray imprint “FL 290”
44 CONTRAINDICATIONS
LINZESS is contraindicated in:
-
Pediatric patients up to 6 years of age [see Warnings and Precautions (5.1), Use in Specific Populations (8.4) and Nonclinical Toxicology (13.2)]
-
Patients with known or suspected mechanical gastrointestinal obstruction
55 WARNINGS AND PRECAUTIONS
5.15.1 Pediatric Risk
LINZESS is contraindicated in pediatric patients up to 6 years of age. In nonclinical studies, deaths occurred within 24 hours in young juvenile mice (1 to 3 week-old mice; approximately equivalent to human pediatric patients less than 2 years of age) following administration of one or two daily oral doses of linaclotide [see Contraindications (4), Use in Specific Populations (8.4) and Nonclinical Toxicology (13.2)].
Avoid the use of LINZESS in pediatric patients 6 through 17 years of age. Linaclotide did not cause deaths in older juvenile mice (approximately equivalent to humans ages 12 to 17 years). Although there were no deaths in older juvenile mice, given the deaths in young juvenile mice and the lack of clinical safety and efficacy data in pediatric patients, avoid the use of LINZESS in pediatric patients 6 through 17 years of age [see Use in Specific Populations (8.4) and Nonclinical Toxicology (13.2)].
5.25.2 Diarrhea
Diarrhea was the most common adverse reaction of LINZESS-treated patients in the pooled IBS-C and CIC double-blind placebo-controlled trials. Severe diarrhea was reported in 2% of the LINZESS-treated patients. The incidence of diarrhea was similar between the IBS-C and CIC populations [see Adverse Reactions (6.1)].
Instruct patients to stop LINZESS if severe diarrhea occurs and to contact their healthcare provider, who should consider dose suspension [see Patient Counseling Information (17)].
66 ADVERSE REACTIONS
6.16.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
During clinical development, approximately 2570, 2040, and 1220 patients with either IBS-C or CIC were treated with LINZESS for 6 months or longer, 1 year or longer, and 18 months or longer, respectively (not mutually exclusive).
Irritable Bowel Syndrome with Constipation (IBS-C)
Most Common Adverse Reactions
The data described below reflect exposure to LINZESS in the two placebo-controlled clinical trials involving 1605 adult patients with IBS-C (Trials 1 and 2). Patients were randomized to receive placebo or 290 mcg LINZESS once daily on an empty stomach for up to 26 weeks. Demographic characteristics were comparable between treatment groups [see Clinical Studies (14.1)]. Table 1 provides the incidence of adverse reactions reported in at least 2% of IBS-C patients in the LINZESS treatment group and at an incidence that was greater than in the placebo group.
Table 1: Adverse Reactions Reported in at least 2% of LINZESS-treated Patients and at an Incidence Greater than in Placebo Group Patients in the Two Phase 3 Placebo-controlled Trials (1 and 2) in IBS-C
|
|
|
Adverse Reactions |
LINZESS
290 mcg
[N=807]
% |
Placebo
[N=798]
% |
Gastrointestinal
Diarrhea
Abdominal paina
Flatulence
Abdominal distension |
20
7
4
2 |
3
5
2
1 |
Infections and Infestations
Viral Gastroenteritis |
3 |
1 |
Nervous System Disorders
Headache |
4 |
3 |
Diarrhea
Diarrhea was the most commonly reported adverse reaction of the LINZESS-treated patients in the pooled IBS-C pivotal placebo-controlled trials. In these trials, 20% of LINZESS-treated patients reported diarrhea compared to 3% of placebo-treated patients. Severe diarrhea was reported in 2% of the LINZESS-treated patients versus less than 1% of the placebo-treated patients, and 5% of LINZESS-treated patients discontinued due to diarrhea vs less than 1% of placebo-treated patients. The majority of reported cases of diarrhea started within the first 2 weeks of LINZESS treatment. Fecal incontinence and dehydration were each reported in less than or equal to 1% of patients in the LINZESS treatment group [see Warnings and Precautions (5.2)].
Adverse Reactions Leading to Discontinuation
In placebo-controlled trials in patients with IBS-C, 9% of patients treated with LINZESS and 3% of patients treated with placebo discontinued prematurely due to adverse reactions. In the LINZESS treatment group, the most common reasons for discontinuation due to adverse reactions were diarrhea (5%) and abdominal pain (1%). In comparison, less than 1% of patients in the placebo group withdrew due to diarrhea or abdominal pain.
Adverse Reactions Leading to Dose Reductions
In the open-label, long-term trials, 2147 patients with IBS-C received 290 mcg of LINZESS daily for up to 18 months. In these trials, 29% of patients had their dose reduced or suspended secondary to adverse reactions, the majority of which were diarrhea or other GI adverse reactions.
Other Adverse Reactions
Adverse reactions that were reported in at least 1% and less than 2% of IBS-C patients in the LINZESS treatment group and at an incidence greater than in the placebo treatment group are listed below by body system:
Gastrointestinal Disorders: gastroesophageal reflux disease, vomiting
General Disorders and Administration Site Conditions: fatigue
Other Adverse Events
In placebo-controlled trials in patients with IBS-C, less than 1% LINZESS-treated patients and no placebo-treated patients reported hematochezia; no patient in either treatment group reported melena. Less than 1% of LINZESS-treated and placebo treated patients reported allergic reactions, urticaria, or hives as adverse events.
Chronic Idiopathic Constipation (CIC)
Most Common Adverse Reactions
The data described below reflect exposure to LINZESS in the two double-blind placebo-controlled clinical trials of 1275 adult patients with CIC (Trials 3 and 4). Patients were randomized to receive placebo or 145 mcg LINZESS or 290 mcg LINZESS once daily on an empty stomach, for at least 12 weeks. Demographic characteristics were comparable between both LINZESS treatment groups and placebo [see Clinical Studies (14.2)]. Only data for the recommended LINZESS 145 mcg dose and placebo are presented. Table 2 provides the incidence of adverse reactions reported in at least 2% of CIC patients in the 145 mcg LINZESS treatment group and at an incidence that was greater than in the placebo treatment group.
Table 2: Adverse Reactions Reported in at least 2% of 145 mcg LINZESS-treated Patients and at an Incidence Greater than in Placebo Group Patients in the Two Phase 3 Placebo-controlled Trials (3 and 4) in CIC
|
|
|
Adverse Reactions |
LINZESS
145 mcg
[N=430]
% |
Placebo
[N=423]
% |
Gastrointestinal
Diarrhea
Abdominal paina
Flatulence
Abdominal distension |
16
7
6
3 |
5
6
5
2 |
Infections and Infestations
Upper respiratory tract infection
Sinusitis |
5
3 |
4
2 |
Diarrhea
Diarrhea was the most commonly reported adverse reaction of the LINZESS-treated patients in the two pooled placebo-controlled CIC trials. In these trials, 16% of LINZESS-treated patients reported diarrhea compared to 5% of placebo-treated patients. Severe diarrhea was reported in 2% of the 145 mcg LINZESS-treated patients versus less than 1% of the placebo-treated patients, and 5% of LINZESS-treated patients discontinued due to diarrhea vs less than 1% of placebo-treated patients. The majority of reported cases of diarrhea started within the first 2 weeks of LINZESS treatment. Fecal incontinence was reported in 1% of patients in the LINZESS treatment group, compared with less than 1% in the placebo group. Dehydration was reported in less than 1% of patients in the LINZESS treatment group [see Warnings and Precautions (5.2)].
Adverse Reactions Leading to Discontinuation
In placebo-controlled trials in patients with CIC, 8% of patients treated with LINZESS and 4% of patients treated with placebo discontinued prematurely due to adverse reactions. In the 145 mcg LINZESS treatment group, the most common reasons for discontinuation due to adverse reactions were diarrhea (5%) and abdominal pain (1%). In comparison, less than 1% of patients in the placebo group withdrew due to diarrhea or abdominal pain.
Adverse Reactions Leading to Dose Reductions
In the open-label, long-term trials, 1129 patients with CIC received 290 mcg of LINZESS daily for up to 18 months. In these trials, 27% of patients had their dose reduced or suspended secondary to adverse reactions, the majority of which were diarrhea or other GI adverse reactions.
Other Adverse Reactions
Adverse reactions that were reported in at least 1% and less than 2% of CIC patients in the 145 mcg LINZESS treatment group and at an incidence greater than in the placebo treatment group are listed below by body system:
Gastrointestinal Disorders: dyspepsia, fecal incontinence
Infections and Infestations: viral gastroenteritis
Other Adverse Events
In placebo-controlled trials in patients with CIC, less than 1% of both LINZESS-treated and placebo-treated patients reported rectal hemorrhage, hematochezia or melena. Less than 1% of LINZESS-treated and placebo-treated patients reported allergic reactions, urticaria, or hives as adverse events.
77 DRUG INTERACTIONS
No drug-drug interaction studies have been conducted with LINZESS. 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 anticipated [see Clinical Pharmacology (12.3)].
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).
88 USE IN SPECIFIC POPULATIONS
8.18.1 Pregnancy
Pregnancy Category C
Risk Summary
There are no adequate and well-controlled studies with LINZESS 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. LINZESS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Animal Data
The potential for linaclotide to cause teratogenic effects was studied in rats, rabbits and mice. Oral administration of up to 100,000 mcg/kg/day in rats and 40,000 mcg/kg/day in rabbits produced no maternal toxicity and no effects on embryo-fetal development. In mice, oral dose levels of at least 40,000 mcg/kg/day produced severe maternal toxicity including death, reduction of gravid uterine and fetal weights, and effects on fetal morphology. Oral doses of 5000 mcg/kg/day did not produce maternal toxicity or any adverse effects on embryo-fetal development in mice.
The maximum recommended human dose is approximately 5 mcg/kg/day, based on a 60-kg body weight. Limited systemic exposure to linaclotide was achieved at the tested dose levels in animals (AUC = 40, 640, and 25 ng•hr/mL in rats, rabbits, and mice, respectively, at the highest dose levels), whereas no detectable exposure occurred in humans. Therefore, animal and human doses should not be compared directly for eva luating relative exposure.
8.28.3 Nursing Mothers
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 Clinical Pharmacology (12.3)].
Caution should be exercised when LINZESS is administered to nursing women [see Contraindications (4), Warnings and Precautions (5.1) and Use in Specific Populations (8.4)].
8.38.4 Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
LINZESS is contraindicated in pediatric patients up to 6 years of age. In nonclinical studies, deaths occurred within 24 hours in young juvenile mice (1 to 3 week-old-mice; approximately equivalent to human pediatric patients less than 2 years of age) following administration of one or two daily oral doses of linaclotide [see Contraindications (4), Warnings and Precautions (5.1) and Nonclinical Toxicology (13.2)].
Avoid the use of LINZESS in pediatric patients 6 through 17 years of age. Linaclotide did not cause deaths in older juvenile mice (approximately equivalent to humans age 12 to 17 years). Although there were no deaths in older juvenile mice, given the deaths in young juvenile mice and the lack of clinical safety and efficacy data in pediatric patients, avoid the use of LINZESS in pediatric patients 6 through 17 years of age [see Warnings and Precautions (5.1) and Nonclinical Toxicology (13.2)].
8.48.5 Geriatric Use
Irritable Bowel Syndrome with Constipation (IBS-C)
Of 1605 IBS-C patients in the placebo-controlled clinical studies of LINZESS, 85 (5%) were at least 65 years of age, while 20 (1%) were at least 75 years old. Clinical studies of LINZESS did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
Chronic Idiopathic Constipation (CIC)
Of 1275 CIC patients in the placebo-controlled clinical studies of LINZESS, 155 (12%) were at least 65 years of age, while 30 (2%) were at least 75 years old. Clinical trials of LINZESS did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
8.58.6 Hepatic or Renal Impairment
No dose adjustment is necessary based on hepatic or renal function [see Clinical Pharmacology (12.3)].
910 OVERDOSAGE
There is limited experience with overdose of LINZESS. During the clinical development program of LINZESS, single doses of 2897 mcg were administered to 22 healthy volunteers; the safety profile in these subjects was consistent with that in the overall LINZESS-treated population, with diarrhea being the most commonly reported adverse reaction.
1011 DESCRIPTION
LINZESS (linaclotide) is a guanylate cyclase-C agonist. Linaclotide is a 14-amino acid peptide with the following chemical name: L-cysteinyl-L-cysteinyl-L-glutamyl-L-tyrosyl-L-cysteinyl-L-cysteinyl-L-asparaginyl-L-prolyl-L-alanyl-L-cysteinyl-L-threonyl-glycyl-L-cysteinyl-L-tyrosine, cyclic (1-6), (2-10), (5-13)-tris (disulfide).
The molecular formula of linaclotide is C59H79N15O21S6 and its molecular weight is 1526.8. The amino acid sequence for linaclotide is shown below:
Linaclotide is an amorphous, white to off-white powder. It is slightly soluble in water and aqueous sodium chloride (0.9%). LINZESS contains linaclotide-coated beads in hard gelatin capsules. LINZESS is available as 145 mcg and 290 mcg capsules for oral administration.
The inactive ingredients of LINZESS capsules include: calcium chloride dihydrate, L-leucine, hypromellose, microcrystalline cellulose, gelatin, and titanium dioxide.
1112 CLINICAL PHARMACOLOGY
11.112.1 Mechanism of Action
Linaclotide is a guanylate cyclase-C (GC-C) agonist. 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, mainly through activation of the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel, resulting in increased intestinal fluid and accelerated transit. In animal models, linaclotide has been shown to both accelerate GI transit and reduce intestinal pain. The linaclotide-induced reduction in visceral pain in animals is thought to be mediated by increased extracellular cGMP, which was shown to decrease the activity of pain-sensing nerves.
11.212.2 Pharmacodynamics
Although the pharmacologic effects of LINZESS in humans have not been fully eva luated, in clinical studies, LINZESS has been shown to change stool consistency as measured by the Bristol Stool Form Scale (BSFS) and increase stool frequency.
11.312.3 Pharmacokinetics
Absorption
LINZESS is minimally absorbed with low systemic availability following oral administration. Concentrations of linaclotide and its active metabolite in plasma are 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 (t½) 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.
Elimination
Active peptide recovery in the stool samples of fed and fasted subjects following the daily administration of 290 mcg of LINZESS for seven days averaged about 5% (fasted) and about 3% (fed) and virtually all as the active metabolite.
Food Effect
In a cross-over study, 18 healthy subjects were given L |
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