Linzess linaclotide 290 ug Capsule, Gelatin Coated, 30-count — NDC 0456-1202-30 (Billing 00456-1202-30)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Linaclotide is structurally related to human guanylin and uroguanylin and functions as 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. In an animal model of visceral pain, linaclotide reduced abdominal muscle contraction and decreased the activity of pain-sensing nerves by increasing extracellular cGMP.

12.2Pharmacodynamics Food Effect Taking LINZESS immediately after a high fat breakfast resulted in looser stools and a higher stool frequency compared with taking it in the fasted state [see Dosage and Administration ( 2.1 , 2.2 )] . In clinical trials, LINZESS was administered on an empty stomach, at least 30 minutes before a meal, at approximately the same time each day.

12.3Pharmacokinetics Absorption LINZESS is minimally absorbed with negligible systemic availability following oral administration. Concentrations of linaclotide and its active metabolite in plasma are below the limit of quantitation after oral doses of 72 mcg, 145 mcg, or 290 mcg were administered. Therefore, standard pharmacokinetic parameters such as area under the curve (AUC), maximum concentration (C max ), and half-life (t ½ ) cannot be calculated.

Food Effect Neither linaclotide nor its active metabolite were detected in the plasma following administration of LINZESS 290 mcg once daily for 7 days both in the non-fed and fed state in healthy subjects. Distribution Given that linaclotide plasma concentrations following recommended oral doses are not measurable, linaclotide is not expected to be distributed to tissues to any clinically relevant extent. Elimination 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 fed and fasted healthy subjects following administration of LINZESS 290 mcg once daily for seven days averaged about 5% (fasted) and about 3% (fed) and all of it as the active metabolite. Specific Populations Renal and Hepatic Impairment Renal or hepatic impairment is not expected to affect the clearance of linaclotide or the active metabolite because linaclotide metabolism occurs within the gastrointestinal tract and plasma concentrations are not measurable in plasma following administration of the recommended dosage.

Drug Interaction Studies No drug-drug interaction studies have been conducted with LINZESS. Systemic exposures of drug and active metabolite are negligible following oral administration. Linaclotide does not interact with the cytochrome P450 enzyme system based on the results of in vitro studies.

In addition, linaclotide does not interact with common efflux and uptake transporters (including the efflux transporter P-glycoprotein (P-gp)). Based on these in vitro data no drug-drug interactions through modulation of CYP enzymes or common transporters are anticipated.

12.1Mechanism of Action Linaclotide is structurally related to human guanylin and uroguanylin and functions as 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. In an animal model of visceral pain, linaclotide reduced abdominal muscle contraction and decreased the activity of pain-sensing nerves by increasing extracellular cGMP.

12.3Pharmacokinetics Absorption LINZESS is minimally absorbed with negligible systemic availability following oral administration. Concentrations of linaclotide and its active metabolite in plasma are below the limit of quantitation after oral doses of 72 mcg, 145 mcg, or 290 mcg were administered. Therefore, standard pharmacokinetic parameters such as area under the curve (AUC), maximum concentration (C max ), and half-life (t ½ ) cannot be calculated.

Food Effect Neither linaclotide nor its active metabolite were detected in the plasma following administration of LINZESS 290 mcg once daily for 7 days both in the non-fed and fed state in healthy subjects. Distribution Given that linaclotide plasma concentrations following recommended oral doses are not measurable, linaclotide is not expected to be distributed to tissues to any clinically relevant extent. Elimination 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 fed and fasted healthy subjects following administration of LINZESS 290 mcg once daily for seven days averaged about 5% (fasted) and about 3% (fed) and all of it as the active metabolite. Specific Populations Renal and Hepatic Impairment Renal or hepatic impairment is not expected to affect the clearance of linaclotide or the active metabolite because linaclotide metabolism occurs within the gastrointestinal tract and plasma concentrations are not measurable in plasma following administration of the recommended dosage.

Drug Interaction Studies No drug-drug interaction studies have been conducted with LINZESS. Systemic exposures of drug and active metabolite are negligible following oral administration. Linaclotide does not interact with the cytochrome P450 enzyme system based on the results of in vitro studies.

In addition, linaclotide does not interact with common efflux and uptake transporters (including the efflux transporter P-glycoprotein (P-gp)). Based on these in vitro data no drug-drug interactions through modulation of CYP enzymes or common transporters are anticipated.

12.2Pharmacodynamics Food Effect Taking LINZESS immediately after a high fat breakfast resulted in looser stools and a higher stool frequency compared with taking it in the fasted state [see Dosage and Administration ( 2.1 , 2.2 )] . In clinical trials, LINZESS was administered on an empty stomach, at least 30 minutes before a meal, at approximately the same time each day.

14 CLINICAL STUDIES

14.1Irritable Bowel Syndrome with Constipation (IBS-C) in Adults The efficacy of LINZESS for the treatment of IBS-C was established in two double-blind, placebo-controlled, randomized, multicenter trials in adult patients (Trials 1 (NCT00948818) and 2 (NCT00938717)). A total of 800 patients in Trial 1 and 804 patients in Trial 2 [overall mean age of 44 years (range 18 to 87 years), 90% female, 77% white, 19% black, and 12% Hispanic] received treatment with LINZESS 290 mcg or placebo once daily and were evaluated for efficacy.

All patients met Rome II criteria for IBS and were required, during the 2-week baseline period, to meet the following criteria: a mean abdominal pain score of at least 3 on a 0-to-10-point numeric rating scale less than 3 complete spontaneous bowel movements (CSBMs) per week [a CSBM is a spontaneous bowel movement (SBM) that is associated with a sense of complete evacuation; a SBM is a bowel movement occurring in the absence of laxative use], and less than or equal to 5 SBMs per week. The trial designs were identical through the first 12 weeks, and thereafter differed only in that Trial 1 included a 4-week randomized withdrawal (RW) period, and Trial 2 continued for 14 additional weeks (total of 26 weeks) of double-blind treatment.

During the trials, patients were allowed to continue stable doses of bulk laxatives or stool softeners but were not allowed to take laxatives, bismuth, prokinetic agents, or other drugs to treat IBS-C or chronic constipation. Efficacy of LINZESS was assessed using overall responder analyses and change-from-baseline endpoints. Results for endpoints were based on information provided daily by patients in diaries.

The 4 primary efficacy responder endpoints were based on a patient being a weekly responder for either at least 9 out of the first 12 weeks of treatment or at least 6 out of the first 12 weeks of treatment. For the 9 out of 12 weeks combined primary responder endpoint, a patient had to have at least a 30% reduction from baseline in mean abdominal pain, at least 3 CSBMs and an increase of at least 1 CSBM from baseline, all in the same week, for at least 9 out of the first 12 weeks of treatment. Each of the 2 components of the 9 out of 12 weeks combined responder endpoint, abdominal pain and CSBMs, was also a primary endpoint.

For the 6 out of 12 weeks combined primary responder endpoint, a patient had to have at least a 30% reduction from baseline in mean abdominal pain and an increase of at least 1 CSBM from baseline, all in the same week, for at least 6 out of the first 12 weeks of treatment. To be considered a responder for this analysis, patients did not have to have at least 3 CSBMs per week. The efficacy results for the 9 out of 12 weeks and the 6 out of 12 weeks responder endpoints are shown in Tables 3 and 4, respectively.

In both trials, the proportion of patients who were responders to LINZESS 290 mcg was statistically significantly higher than with placebo. Table 3: Efficacy Responder Rates in Two Placebo-Controlled Trials of Adults with IBS-C (Trials 1 and 2): At Least 9 Out of 12 Weeks Trial 1 Trial 2 LINZESS 290 mcg Once Daily (N=405) Placebo (N=395) Treatment Difference [95% CI] LINZESS 290 mcg Once Daily (N=401) Placebo (N=403) Treatment Difference [95% CI] Combined Responder* (Abdominal Pain and CSBM Responder) 12% 5% 7% [3.2%, 10.9%] 13% 3% 10% [6.1%, 13.4%] Abdominal Pain Responder* (≥ 30% Abdominal Pain Reduction) 34% 27% 7% [0.9%, 13.6%] 39% 20% 19% [13.2%, 25.4%] CSBM Responder* (≥ 3 CSBMs and Increase ≥1 CSBM from Baseline) 20% 6% 13% [8.6%, 17.7%] 18% 5% 13% [8.7%, 17.3%] * Primary Endpoints Note: Analyses based on first 12 weeks of treatment for both Trials 1 and 2 CI =Confidence Interval Table 4: Efficacy Responder Rates in Two Placebo-Controlled Trials of Adults with IBS-C (Trials 1 and 2): At Least 6 Out of 12 Weeks Trial 1 Trial 2 LINZESS 290 mcg Once Daily (N=405) Placebo (N=395) Treatment Difference [95% CI] LINZESS 290… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis In 2-year carcinogenicity studies, linaclotide was not tumorigenic in rats at doses up to 3500 mcg/kg/day or in mice at doses up to 6000 mcg/kg/day. The maximum recommended human dose is approximately 5 mcg/kg/day based on a 60-kg body weight. Limited systemic exposure to linaclotide and its active metabolite was achieved at the tested dose levels in animals, whereas no detectable exposure occurred in humans.

Therefore, animal and human doses should not be compared directly for evaluating relative exposure. Mutagenesis Linaclotide was not genotoxic in an in vitro bacterial reverse mutation (Ames) assay or in the in vitro chromosomal aberration assay in cultured human peripheral blood lymphocytes. Impairment of Fertility Linaclotide had no effect on fertility or reproductive function in male and female rats at oral doses of up to 100,000 mcg/kg/day.