Hepatic Impairment

LINZESS 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 is metabolized within the gastrointestinal tract [see Use in Specific Populations (8.6)].

Renal Impairment

LINZESS 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 [see Use in Specific Populations (8.6)].

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, and 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 bodyweight. Limited systemic exposure to linaclotide 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 eva luating 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.
13.2 Animal Toxicology and/or Pharmacology

Linaclotide caused deaths in two separate toxicology studies in juvenile mice. The mechanism for these deaths is unknown [see Contraindications (4) and Warnings and Precautions (5.1)].
 
Linaclotide caused deaths at 10 mcg/kg/day in neonatal mice after oral administration of 1 or 2 daily doses, starting on post partum day 7. Deaths were also observed in juvenile mice after a single oral administration on post partum day 14 (100 mcg/kg) and post partum day 21 (600 mcg/kg). The deaths were identified in mice with ages approximately equivalent to human infants and children less than 2 years of age. There were no deaths in the control groups. There are currently no data for mice between ages of 21 days and 6 weeks. Linaclotide did not cause death in a study in older juvenile mice age 6 weeks (approximately equivalent to humans age 12 to 17 years) at a dose of 20,000 mcg/kg/day for 28 days. Linaclotide did not cause death in adult mice, rats, rabbits and monkeys at dose levels up to 5,000 mcg/kg/day. The maximum recommended dose in adults is approximately 5 mcg/kg/day, based on a 60-kg body weight. Animal and human doses of linaclotide should not be compared directly for eva luating relative exposure [see Nonclinical Toxicology (13.1)].
14 CLINICAL STUDIES
14.1 Irritable Bowel Syndrome with Constipation (IBS-C)

The efficacy of LINZESS for the management of symptoms of IBS-C was established in two double-blind, placebo-controlled, randomized, multicenter trials in adult patients (Trials 1 and 2). A total of 800 patients in Trial 1 and 804 patients in Trial 2 [overall mean age of 44 years (range 18 - 87 years with 5% at least 65 years of a