ve metabolite was detected in the plasma. Taking LINZESS immediately after the 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 breakfast.
Specific Populations
Age and Gender
Clinical studies to determine the impact of age and gender on the pharmacokinetics of LINZESS have not been conducted. See Use in Specific Populations (8.5) for information regarding patients aged 65 years and older.
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)].
1213 NONCLINICAL TOXICOLOGY
12.113.1 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.
12.213.2 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 linaclo
